Download The Epidemiology of Bacillary Angiomatosis and Bacillary Peliosis

Epidemiology of Bacillary
Angiomatosis and Bacillary Peliosis
The
Jordan W. Tappero, MD, MPH; Janet Mohle-Boetani, MD; Jane E. Koehler, MD; B. Swaminathan, PhD;
Timothy G. Berger, MD; Philip E. LeBoit, MD; Laura L. Smith, MD; Jay D. Wenger, MD; Robert W. Pinner, MD;
Carol A. Kemper, MD; Arthur L. Reingold, MD
Objective.\p=m-\Todetermine environmental risk factors for bacillary angiomatosis\x=req-\
bacillary peliosis (BAP), and to confirm infection with Rochalimaea species.
Design.\p=m-\Case-controlstudy.
Setting.\p=m-\Communityand university hospitals and clinics.
Patients.\p=m-\Case patients (N=48) had biopsy-confirmed BAP. Controls (N=94)
were matched to patients by institution and by human immunodeficiency virus (HIV)
serological status.
Main Outcome Measures.\p=m-\Clinicalinformation was obtained from medical
records. Subjects were queried about environmental exposures. Univariate odds
ratios (ORs) with 95% confidence intervals (Cls) were determined. Bivariate analyses were performed on variables associated with disease by univariate analysis.
DNA from 22 available case-patient tissues and from 22 control tissues was amplified with the polymerase chain reaction (PCR) using primers designed to detect
Rochalimaea species.
Results.\p=m-\Weidentified five HIV-negative, immunocompetent case patients;
one HIV-negative, immunodeficient case patient; and 42 HIV-positive case patients.
There were no significant differences between case patients and controls by race,
sex, age, or risk factors for HIV infection. Owning a cat (OR, 2.8; CI, 1.4 to 5.8) and
history of a recent cat lick (OR, 1.95; CI, 1.0 to 3.8), cat scratch (OR, 3.7; CI, 1.7
to 8.0), or cat bite (OR, 3.9; CI, 1.8 to 8.9) were associated with disease in the
univariate analysis. In bivariate analyses, only the variables representing traumatic
contact with a cat (bite or scratch) remained associated with disease. No other environmental exposure was associated with disease. The PCR amplified a DNA
fragment of the size expected for Rochalimaea species in all 22 case-patient tissue
specimens.
Conclusions.\p=m-\Thesedata suggest that BAP is a new zoonosis associated with
both traumatic exposure to cats and infection with Rochalimaea species or a closely
related organism.
(JAMA. 1993;269:770-775)
From the
of
Departments Dermatology (Drs Tappero,
Berger, LeBoit, and Smith), Medicine and Laboratory
Medicine (Dr Koehler), and Pathology (Dr LeBoit), University of California, San Francisco; the Meningitis and
Special Pathogens Branch, Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases
(Drs Tappero, Mohle-Boetani, Swaminathan, Pinner, and
Wenger), and the Mycotic Diseases Branch, DBMD, CID
(Dr Pinner), Centers for Disease Control and Prevention,
Atlanta, Ga; the Divisions of Infectious Diseases, Stanford
(Calif) University Medical Center, and the Santa Clara
Valley Medical Center, San Jose, Calif (Dr Kemper); and
The School of Public Health, Epidemiology Program,
University of California, Berkeley (Dr Reingold).
Reprint requests to Meningitis and Special Pathogens Branch, Centers for Disease Control and Prevention, Mail Stop C09,1600 Clifton Rd, Atlanta, GA 30333
(Dr Tappero).
BACILLARY angiomatosis ( ) was
first described in human immunodefi¬
ciency virus (HlV)-infected patients
who presented with subcutaneous and
cutaneous vascular lesions mimicking
Kaposi's sarcoma.13 Bacillary angioma¬
tosis derives its name from the vascular
proliferation seen on histologie exami¬
nation of affected tissues (including skin,
bone, lymph node, and brain) and from
the presence of numerous bacillary or¬
ganisms demonstrable on Warthin-Starry silver staining or on electron micros¬
copy.48 These bacilli are also visible in
parenchymal vascular lesions of bacil¬
lary peliosis of the liver (bacillary peli¬
osis hepatis) and spleen.910 Because BA
and bacillary peliosis represent differ¬
ent manifestations of the same infec¬
tion, the term bacillary angiomatosisbacillary peliosis (BAP) will be used to
refer to this disease process.
Initially, several observations sug¬
caused by infec¬
tion with the cat-scratch disease (CSD)
bacillus. Warthin-Starry staining and
electron microscopy of tissue sections
from patients with BAP revealed bacil¬
lary organisms resembling those seen in
patients with classic CSD,4·9·11 and sev¬
eral case reports of BAP suggested that
BAP might represent disseminated CSD
in the immunocompromised host.3'7,9,10
In addition, marked similarities were
noted, both clinically and histologically,
between the cutaneous lesions of BA
and verruga peruana (a late manifesta¬
tion of infection with Bartonella bacilliformis).4 However, recent molecular
biologic and microbiologie investigations
confirm that at least two organisms,
Rochalimaea henselae12'lñ and Rochal¬
imaea quintana,12 can cause BA, both of
which are distinct from Afipia felis
(formerly the CSD bacillus) and
gested that BAP was
bacilliformis.1^20
We conducted a case-control study to
identify risk factors for BAP and to test
the hypothesis that our case-patients
with BAP
maea
were
infected with Rochali¬
species or a closely related organ¬
ism. Because of the numerous anecdotal
reports suggesting that cat exposure
preceded symptoms of BAP,3"7·9·10 we
queried subjects in detail regarding a
wide range of animal exposures, includ¬
ing physical and sexual contact, and
questioned pet owners about specific in¬
teractions with their pets. In addition,
because cutaneous lesions of A resem¬
ble those caused by infection with
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bacilliformis,4 and because this organ¬
ism is found only in South America and
is transmitted by an insect vector,21 we
queried subjects in detail regarding for¬
eign travel and exposures to imported
South American goods (including co¬
caine) and to insects. We also explored
plant, soil, water, and traumatic expo¬
sures because CSD has been reported
following skin trauma from wood
splinters, fish hooks, pins, thorns, and
porcupine quills in the absence of cat
contact.22 Finally, we used the polymerase chain reaction (PCR) to test tis¬
sue specimens from case-patients for
the presence of Rochalimaea species
DNA.
METHODS
Case Definition
We defined a case as an illness in a
patient with histologically confirmed le¬
sions of BAP.4·5·7·8 Histologically con¬
firmed BA lesions showed (1) a lobular
proliferation of small, round blood ves¬
sels with plump endothelial cells (with
or without cytologie atypia) protruding
into the vascular lumen; (2) necrosis
present within the centers of vascular
lobules; (3) a mixed inflammatory cell
infiltrate with neutrophils and leukocytoclasis; and (4) granular amphophilic
interstitial material revealing bacilli on
silver staining (eg, Warthin-Starry) or
electron microscopy or both. Histolog¬
ically confirmed parenchymal lesions
showed (1) dilated capillaries or multi¬
ple dilated, blood-filled spaces or (2) a
myxoid stroma containing a mixture of
inflammatory cells and clumps of gran¬
ular amphophilic material (revealing ba¬
cilli on silver staining or electron mi¬
croscopy) or both.
Study Participants
All patients 18 years of age or older
with biopsy-confirmed BAP were eligi¬
ble for enrollment as case patients. Case
patients were identified by reviewing
pathology records at the University of
California, San Francisco, Hospitals and
Clinics. In addition, both University of
California, San Francisco, and San Fran¬
cisco Bay Area community clinicians and
pathologists were asked to notify the
principal investigator (J.W.T.) if they
identified a patient with BAP. Case pa¬
tients identified from outside the San
Francisco Bay Area were recruited from
clinicians and pathologists who were in¬
formed of the study and had identified
a patient with BAP. Histologie tissue
specimens from 48 case patients were
reviewed by a pathologist familiar with
BAP (P.E.L.) to confirm eligibility. Sur¬
rogates (relatives or a significant other)
answered questions about case patients
who had died or had dementia.
Patients 18 years of age or older with¬
out a prior history of BAP were eligible
for enrollment as controls. Health care
providers identified two controls per
BAP case, matched to case patients by
HIV serological status and clinical in¬
stitution. Controls were selected from
the same primary physician outpatient
schedule book (registry, log, or list) as
case patients. Potential controls were
asked to participate by their health care
provider. A copy of the schedule log
used to identify controls was maintained
to verify that each control was selected
as close as possible to the same day in
which the BAP case patient or surro¬
gate was interviewed and to document
the reasons for those declining partici¬
pation. Telephone contact between a
study investigator and eligible controls
required, on average, calling three eli¬
gible controls per case. Before moving
down the schedule log to the next eli¬
gible control, an average of two tele¬
phone calls for each eligible control was
made. Once reached, only seven eligible
controls declined to participate, and 94
controls were enrolled. The study was
approved by the Committee for Human
Research, University of California, San
Francisco.
Questionnaire
Using a standard questionnaire, three
study investigators questioned consent¬
ing case patients and controls (either in
person or by telephone) about demo¬
graphic characteristics, medical histo¬
ry, and recent exposures to water, soil,
plants, and animals. All subjects with an
animal exposure, regardless of species
(dog, cat, bird, rodent, and so forth),
queried using the same set of ques¬
were
tions. For pet owners with one or more
pets of the same type, data were col¬
lected on as many as three household
pets of the same type as well as on pet
contact outside the home. Case patients
were asked about exposures in the 6
months before BAP tissue diagnosis.
Controls were asked about exposures in
the 6 months before enrollment. Clinical
information was extracted from the hos¬
pital and clinic charts of case patients
and controls.
Analyses
A preliminary analysis of the data
from the first 21 case patients enrolled
suggested a possible link between dis¬
and exposure to cats.23 To investi¬
gate this finding further, an addendum
questionnaire with more details about
cat exposure was administered to the
ease
previously enrolled, living case patients
(n=l) and matched controls (n=2) who
could be located, and to all subsequently
enrolled case patients (n=27) and con¬
trols (n=52). Detailed information re¬
garding cat exposure among those own¬
ing a cat was requested for the 6 months
before diagnosis (case patients) or en¬
rollment (controls), and information on
specific insect bites and terrain expo¬
sures was requested for the 1-year pe¬
riod prior to study enrollment.
After the collection of data on the first
35 case patients in this study, it was
suspected that a number of case patients
had been told initially by their physi¬
cians that they had CSD, raising the
possibility that recall bias regarding pri¬
or cat exposure may have been intro¬
duced. Therefore, at the time of enroll¬
ment of the next 13 case patients, all
patients were queried, before adminis¬
tering the questionnaire regarding all
possible diagnoses given to them by their
physician.
Several matched subanalyses were
conducted on the data by excluding sur¬
rogate interviews and excluding case
patients interviewed more than 6 months
following their BAP tissue diagnosis to
investigate the effect of these responses
on the overall results. When necessary,
subanalyses were conducted on un¬
matched data to maintain statistical pow¬
er in the setting of a diminished number
of matched case and control sets for these
analyses. Unmatched analyses included
a comparison of cat exposures among
case patients and controls who owned a
cat or cats and an analysis that com¬
pared cat exposures between case pa¬
tients and controls who had never been
given a diagnosis of CSD.
Statistical Methods
The Mann-Whitney U test was used
to assess differences between two
groups, and matched univariate odds ra¬
tios (ORs) were calculated by the MantelHaenszel method using Epi-Info,24 a sta¬
tistical software package. Unmatched
univariate ORs were calculated using
Epi-Info, on two subanalyses of the data.
For these unmatched analyses,
val¬
ues were calculated using the MantelHaenszel method or the two-tailed Fish¬
er's Exact Test (for analyses with small
numbers of observations). A bivariate
matched analysis was conducted on cat
exposure variables with significant
univariate ORs using the PHREG pro¬
cedure on SAS, a statistical software
package.25
Tissue Studies
Biopsied tissue specimens were re¬
quested from the clinicians and pathol¬
ogists who identified the 48 case pa¬
tients. Following sectioning and Warthin-Starry staining of submitted tissue
samples, 22 tissue specimens containing
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Table 1.—Personal and Behavioral Characteristics of
Study Participants*
Case Patients
(N=48)
Variable
Median age, y
Sex, % male
38.5
Race, % white
Ethnicity, % non-Hispanic
Annual income, % < $10000
Education, % high school or less
Housing,§ % apartment living
90.0
87.5
79.2
Controls
(N=94)
Pt
89.4
.69
79.8
.94
18.3
.57
.85
37.5
47.9
diagnosis,§ % with AIDS
Kaposi's sarcoma,§ %
Pneumocystis carina pneumonia,§ %
Times hospitalized,§ mean
Total days hospitalized,§ mean
25.0
.95
.74
50.0
AIDS
12.0
.07
26.6
0.9
12.2
Homosexual male, %
intravenous drug use, % any use in past 8 y
Cocaine use, % any use in past 8 y
Foreign travel, % in past 5 y
18.8
13.8
.60
50.0
58.3
.94
*AIDS indicates the acquired immunodeficiency syndrome.
tMantel-Haenszel 2.
U test for two groups.
JMann-Whitney
months
to
§Six
prior
diagnosis (case patients)
or
enrollment
well-visualized bacillary organisms were
available for further study. DNA was
extracted from either frozen skin biop¬
sy tissue (seven case patients) or from
formalin-fixed, paraffin-embedded biop¬
sy specimens (15 case patients: 13 skin,
two spleen). In addition, Rochalimaea
species were isolated from cutaneous
BA lesions of three of these patients.12
Extracted DNA was amplified with
PCR, using oligonucleotide primers that
amplify a fragment of the 16S rDNA of
Rochalimaea species,13 but not A feZis.18·20 Twenty-two control specimens
(17 of which were Kaposi's sarcoma)
matched to case patients by history of
HIV infection, tissue type, and method
of fixation and storage were processed
simultaneously and interspersed among
the case-patient tissues. Studies were
conducted at one or both institutions:
the University of California, San Fran¬
cisco, and the Centers for Disease
Control and Prevention.
Frozen tissue was processed using the
protocol described by Reiman et al.13
Formalin-fixed, paraffin-embedded tis¬
sue was prepared as previously de¬
scribed.2'1·27 DNA also was extracted from
a single colony of Afelis (obtained from
Fred Quinn, PhD, Centers for Disease
Control and Prevention) and from the
type strain of R henselae (ATCC 49882).
Precautions were taken to prevent DNA
carryover contamination, and controls
containing DNA extracted simulta¬
neously with case-patient tissues were
included in all reactions, in addition to a
tube without added DNA template.12
Amplified DNA fragments were electrophoretically separated on a 1.5% aga¬
rose gel and stained with ethidium
bromide.
(controls).
RESULTS
Clinical Characteristics
We identified five HIV-negative, immunocompetent BAP case patients28; one
HIV-negative, immunodeficient BAP
case patient10; and 42 HIV-positive BAP
case patients. Surrogate interviews were
necessary for 15 HIV-positive case pa¬
tients enrolled early during the course
of study (14 deceased and one with HIV
dementia). The majority of the 48 case
patients were San Francisco Bay Area
residents at the time of BAP tissue di¬
agnosis, with 15 patients (31%) receiv¬
ing care from one of four University of
California, San Francisco, hospitals and
clinics and 18 (38%) receiving care from
private San Francisco Bay Area hospi¬
tals and clinics. Of the remaining 15 case
patients (31%), six lived in southern Cal¬
ifornia, four in Texas, two in North Caro¬
lina, and one each in Florida, Maryland,
and western Canada. Two controls were
enrolled for each case with the excep¬
tion of only one control being enrolled
for two of the six HIV-negative case
patients.
Among the 42 HIV-positive case pa¬
tients, 14 (34%) had no prior diagnosis of
the acquired immunodeficiency syn¬
drome (AIDS), 19 (45%) had a prior
AIDS diagnosis, and nine (21%) had a
concomitant AIDS diagnosis within 1
month of the time of BAP tissue diag¬
nosis. A prior history of intravenous drug
use was reported by nine (21%) of the 42
HIV-positive case patients. All five HIV-
negative, apparently immunocompetent
case-patients were culture-negative for
HIV-1 and had normal T-cell subsets.28
There were no significant differences
among case patients (N=48) and con-
trois ( =94) by personal characteristics,
risk factors for HIV infection, history of
an AIDS-defming illness (including Kaposi's sarcoma, Pneumocystis carinii
pneumonia, toxoplasmosis, and so forth),
recreational drug use, or foreign travel
(Table 1).
Environmental Exposures
Matched Analyses.—Recent cat ex¬
posures were the only environmental
exposures significantly associated with
BAP disease (Table 2). In the matched
univariate analysis, owning a cat (OR,
2.9; 95% confidence interval [CI], 1.4 to
5.8) and spending a minimum of 1 hour
per day in contact with a cat (OR, 3.2;
CI, 1.5 to 6.7) were associated with dis¬
ease. Because several subjects had more
than one cat, we evaluated differences
in extent of exposure to the one cat with
which the subject spent the most time
(ie, the cat of most frequent exposure).
There was a significant difference be¬
tween case patients and controls in the
amount of time spent with the cat of
most frequent exposure (P<.001, MannWhitney U test for two groups). In ad¬
dition, an increasing number of hours
spent per day on average (<1,1 to 8, >8
to 16, and >16) with the cat of most
frequent exposure was associated with
disease (P<.006, 2 test for trend).
Various types of contact with one or
more cats, including a history of being
recently licked by a cat (OR, 2.0; CI, 1.0
to 3.8), scratched by a cat (OR, 3.7; CI,
1.7 to 8.0), or bitten by a cat (OR, 3.9; CI,
1.8 to 8.9), were associated with disease
on univariate analysis (Table 2). In ad¬
dition, a history of a recent cat scratch
that broke the skin (OR, 4.1; CI, 1.8 to
9.3) or a cat bite that broke the skin (OR,
2.9; CI, 1.2 to 7.1) was associated with
disease. Changing the cat litter box and
exposure to a cat outside the home were
not associated with disease. While ex¬
posure to dogs was quite common, no
dog or other pet exposures (excluding
cats) were associated with having BAP.
Exposure to plants, soil, water, and non-
pet-related
cutaneous trauma
was
not
associated with disease.
Detailed Cat Exposures.—An adden¬
dum questionnaire further detailing
household cat exposures was adminis¬
tered to 28 case patients and 54 matched
controls. A matched univariate analysis
of the data further supported an asso¬
ciation between cat exposure and dis¬
ease (Table 3). In addition, this analysis
examined data on the age of household
cats. Case patients were more likely than
controls to have a kitten (a cat ^1 year
of age) living in the home (OR, 3.0; CI,
1.1 to 8.5). There was no association be¬
tween sleeping with a household cat and
disease.
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Table 2.—Cat
Exposures
of
Study Participants
Case Patients
Controls
Odds Ratio
(N=48)
(N=94)
(Matched)
Confidence
Interval
3.2
1.5-6.7
Variable*
Cat ownership, %
No. of cats owned, mean
At least 1 h spent per day with a cat, %
A cat scratch by =: 1 cats, %
A cat scratch that broke the skin, %
A cat bite by a1 cats, %
A cat bite that broke the skin, %
A cat bite
or
scratch
by
1.1
0.7
64.6
34.0
.007t
62.5
3.7
.002
.0008
56.3
26.6
4.1
1.8-9.3
.001
25.0
9.6
2.9
1.2-7.1
.03
1.5-6.5
.003
a1 cats, %
by =:1 cats, %
cat box at least once per month, %
Pi
A cat lick
50.0
30.9
2.0
1.0-3.8
.06
Change
31.3
26.6
1.3
0.6-2.7
.69
*Six months
prior to diagnosis (case patients)
tMantel-Haenszel 2.
or
enrollment
(controls).
JMann-Whitney U test for two groups.
Table 3.—Detailed Household Cat
Exposures of Selected Study Participants
Variable*
A cat lived in the house, %
A kitten lived in the house, %
Scratched at least once by cat, %
A cat scratch that broke the skin, %
Slept with at least 1 cat, %
Case Patients
Controls
Odds Ratio
(n=28)
(n=54)
(Matched)
67.9
39.6
2.7
59.3
22.6
4.8
53.6
18.9
33.3
20.8
*Six months prior to diagnosis (case patients)
or
enrollment
tMantel-Haenszel 2.
Confidence
Interval
Pt
1.1-6.Í
.04
1.1-8.5
.04
1.6-14.7
0.6-4.9
.44
(controls).
ÍMann-Whitney U test for two groups.
Insect Bite and Terrain Exposures.—
Case patients (n=28) and matched con¬
trols (n=54) were asked about recent
insect bites and terrain exposures. No
association was found between insect
bites (fleas, ticks, lice, chiggers or mites,
mosquitoes, bedbugs, and bugs of un¬
known type) or exposure to various ter¬
rains (mountains, rivers, lakes, beaches,
forests, deserts, and parks) and disease.
Analysis Excluding Surrogate Re¬
sponses.—To eliminate possible bias re¬
sulting from the 15 surrogate interviews,
a matched analysis was performed us¬
ing only the data obtained from the 33
case patients who were interviewed di¬
rectly. The associations between cat ex¬
posures and BAP disease were essen¬
tially unchanged. Cat ownership (OR,
2.3; CI, 1.0 to 5.4; P<.08) and a history
of a recent cat scratch (OR, 3.3; CI, 1.3
to 8.3; P<.01), cat bite (OR, 4.9; CI, 1.9
to 12.9; P<.001), or a cat scratch or cat
bite (OR, 3.1; CI, 1.3 to 7.6; P<.01) were
associated with disease. A matched anal¬
ysis of the data detailing cat exposures
and excluding surrogate interviews gave
similar results.
Analyses Excluding Case-Patient In¬
terviews 6 Months or More After Tis¬
sue Diagnosis.—A matched analysis was
performed using only data obtained from
the 27 case patients interviewed within
6 months of their BAP diagnosis. The
associations between cat exposures and
disease were unchanged.
Analyses of Case Patients With Tis¬
sue Specimens.—To investigate the rep-
resentativeness of responses from the
22 case patients for whom case tissues
were available for 16S rDNA sequence
amplification, a matched subanalysis was
performed. The associations between cat
exposures and BAP disease were un¬
changed. Cat ownership (OR, 2.8; CI,
1.0 to 7.5; P<.08) and a history of a
recent cat scratch (OR, 4.3; CI, 1.5 to
12.7; P<.01), cat bite (OR, 3.9; CI, 1.3 to
11.6; P<.02), or a cat scratch or cat bite
(OR, 3.4; CI, 1.2 to 10.0; P<.03) were
associated with disease.
Unmatched
Analyses
Cat Exposures Among Cat Own¬
ers.—When case patients (n=32) and con¬
trols (n=37) who owned cats were com¬
pared,
case
patients
were more
likely
than controls to report a recent cat
scratch (OR, 3.3; CI, 1.0 to 12.6; P<.04)
or cat bite (OR, 3.5; CI, 1.1 to 10.8,
P<.01), but not a cat lick (OR, 1.7; CI,
0.6 to 5.5; P<.28). The amount of time
cat owners spent with household cats
did not differ between case patients and
controls (P>.20, Mann-Whitney ¡7 test
for two groups; overall median, 6 hours
per day). Finally, among cat owners the
number of household cats did not differ
between case patients and controls
(P>.6, Mann-Whitney U test for two
groups; overall median, two cats).
The addendum questionnaire was used
to collect information on the age of cats
(as many as three cats) living in the
home of case patients (n=19) and con¬
trols (n=28). Among cat owners, the me-
dian age of all case-patient-owned cats
(4 years) differed significantly from the
median age (7.5 years) of control-owned
cats (P<.03, Mann-Whitney U test for
two groups). The median age of the
youngest household cat (12 months) liv¬
ing with a case patient differed signif¬
icantly from the median age ofthe young¬
est household cat (42 months) living with
a control (P<.04, Mann-Whitney [/test
for two groups). Finally, among cat own¬
ers, case patients were more likely than
controls to own a kitten (OR, 3.8; CI, 1.1
to
13.2; P<.002).
Cat Exposures Excluding Case Pa¬
tients With Diagnosed CSD.—When
specifically asked, five of the last 13 case
patients enrolled for study were told of
a possible relationship between CSD and
their BAP illness. We compared expo¬
sures of the eight case patients not in¬
formed of a possible relationship with
CSD with those of all 94 controls. Again,
cat ownership (OR, 10.8; CI, 1.2 to 247.0;
P<.01, two-tailed Fisher's Exact Test),
and cat bite (OR, 9.5; CI, 1.7 to 59.0;
P<.005, two-tailed Fisher's Exact Test)
were associated with disease. These eight
cases were also more likely than controls
to have a history of recent cat lick or cat
scratch, but these trends were not sta¬
tistically significant (P<.08).
Bivariate Analyses
A matched bivariate analysis was con¬
ducted to assess confounding between
the various cat exposure variables as¬
sociated with BAP in the univariate anal¬
ysis (Table 4). A history of a recent cat
scratch (OR, 2.8; CI, 1.1 to 6.9) or cat
bite (OR, 2.8; CI, 1.1 to 7.0) was asso¬
ciated with disease after controlling for
cat ownership. In addition, a history of
a recent cat scratch (OR, 2.4; CI, 1.0 to
5.8) or cat bite (OR, 2.3; CI, 0.9 to 5.8)
was associated with disease after con¬
trolling for a recent cat bite or cat
scratch, respectively. Cat ownership was
not associated with disease after con¬
trolling for either a recent cat scratch or
cat bite, and a history of a recent cat lick
was not associated with BAP after con¬
trolling for cat ownership (Table 4).
Tissue Studies
An approximately 300-base pair 16S
rDNA fragment was amplified from ex¬
tracted DNA of all 22 case tissues test¬
ed. This fragment corresponded to the
expected size of amplified product from
Rochalimaea species or a closely re¬
lated organism.ls The 300-base pair frag¬
ment was not amplified from the 22 con¬
trol tissues (including 17 cutaneous le¬
sions of Kaposi's sarcoma) or from DNA
of the Afelis strain. All control tissues
contained amplifiable DNA using
ß-globin primers.20
Downloaded from jama.ama-assn.org at University of California - San Francisco on January 11, 2011
Study Participants
COMMENT
Table 4.—Bivariate
In this study, we found that the newly
described clinical syndrome of BAP was
associated with a history of recent cat
exposure. Exposure to cats has also been
reported in patients with CSD.22·29 How¬
ever, unlike conventional CSD, in which
87% to 99% of cases are reported anecdotally to follow recent cat contact,22·29
one third of the patients with BAP in
our study had no known exposure to
cats, suggesting that BAP may also be
acquired from other sources.
On univariate analysis, several cat ex¬
posures were found to be risk factors for
BAP disease, including cat ownership,
an increasing amount of time spent per
Interval
(Adjusted by)
(Matched)
Pf
Own a cat (any cat bite)
2.8
1.1-7.0
.03
Any cat bite (own a cat)
Own a cat (any cat scratch)_1_6_0.6-3.8_.33
Any cat scratch (own a cat)_2Ü_1.1-6.9_.03
Own a cat (any cat lick)_25_1.0-5.9_ 4
1.2
0.5-2.8
.69
Any cat lick (own a cat)
day (on average) with a cat, and a his¬
tory of a cat lick, cat scratch, or cat bite.
However, after controlling for cat own¬
ership in the bivariate analysis, only hav¬
ing been recently bitten or scratched by
a cat remained significantly associated
with disease. This suggests that trau¬
matic contact with a cat is associated
with BAP disease. A matched analysis
of detailed cat exposure data obtained
from 28 case patients and 54 controls
found that kitten exposure was associ¬
ated with disease. In addition, an un¬
matched subanalysis of the data restrict¬
ed to cat owners found exposure to
younger cats (kittens in particular) to
be a significant risk factor for disease.
Among patients with classic CSD, 78%
reported exposure to a kitten.22
Two hypotheses can be generated re¬
garding the role of the domestic cat as
a vector for the transmission of bacte¬
rial disease by a bite or scratch. The
agent of BAP might be part of the nor¬
mal flora of the feline oral cavity and
pharynx, and therefore might be present
on the pelage, claws, and teeth following
grooming, allowing the transmission of
these bacilli to humans by a bite or
scratch. A second hypothesis, based on
the close genealogical relationship of
Rochalimaea species with agrobacteria
and rhizobacteria,30 suggests that the
agent of BAP might be a saprophytic
plant or soil organism. Although this
case-control study found no association
between BAP and plant or soil expo¬
sures, it is possible that an infectious
agent could be transmitted to humans
following inoculation of human skin by
the contaminated pelage, claw, or bite of
a
cat.
Several investigators have suggested
that an unidentified arthropod vector
may be responsible for the transmission
of BAP bacilli, based on the association
between other members of the family
Rickettsiaceae and arthropod exposures,
and a report of two patients with R
henselae bacteremia within 1 month fol-
Analysis for Cat Exposures
of
Odds Ratio
Confidence
Variable*
*Six months prior to diagnosis (case patients)
tMantel-Haenszel 2.
or
enrollment
tick bite.31 Because physical
a cat was a risk factor for
BAP disease, we were particularly in¬
terested in insects that commonly infest
cats. If cat fleas (or cat mites) harbor
the bacilli responsible for BAP, and if
cat flea (or cat mite) blood or feces were
present on the claws, pelage, and teeth
of cats, cats could inoculate these bacilli
into human skin via a bite or scratch.
Transmission experiments have clearly
shown that R quintana-inîected louse
excrement is capable of infecting hu¬
mans through abraded skin.32 Of inter¬
est, transovarial maintenance of a ty¬
phuslike Rickettsia in cat fleas has been
described recently, but its relationship
to the agent responsible for BAP has
not been evaluated.33
In our study, subjects were queried
in detail regarding bites from a variety
of insects, including ticks, fleas, lice,
mites, and mosquitoes, during the 1 year
prior to enrollment. We found no asso¬
ciation between insect bites and disease,
but several méthodologie issues may ac¬
count for a failure to identify an asso¬
ciation. These include (1) lack of power
due to the small number of case patients
interviewed about insect bites (n=28),
(2) inability to obtain information on re¬
mote exposures (>1 year), and (3) fail¬
ure to query subjects regarding insects
commonly found in the home environ¬
ment. Future studies should query cat
owners about infestation of their cat(s)
or home by insects.
To confirm that our case patients with
a histologie diagnosis of BAP had infec¬
tion with Rochalimaea or a closely re¬
lated species, we performed the PCR on
DNA extracted from available case-pa¬
tient tissues. A DNA fragment of the
expected size for Rochalimaea species13
was amplified from 16S rDNA extract¬
ed from infected tissues of 22 of our case
patients. Although the PCR primers we
used to amplify DNA do not cross-react
with A felis, these primers do not dis¬
tinguish among Rochalimaea species,
bacilliformis, and Brucella abortus.18
However, infection with either of the
latter two organisms was unlikely be¬
cause
bacilliformis has not been re¬
ported outside South America,21 and
lowing
a
contact with
(controls).
abortus infection has not been associat¬
ed with the histologie patterns of BAP.34
Our laboratory studies suggest that
our case-patients were infected with
Rochalimaea species or a closely relat¬
ed organism. Of interest, both R henselae and R quintana have recently been
isolated from cutaneous BA lesions.12
Because BAP can be caused by either R
henselae or R quintana, it is possible
that risk factors for acquiring infection
with these two organisms differ, pro¬
viding an explanation for the one third
of our case patients who gave no history
of prior cat exposure. Finally, the PCR
failed to amplify Rochalimaea species
DNA from 17 cutaneous control tissue
specimens of Kaposi's sarcoma, provid¬
ing evidence that cutaneous lesions of
Kaposi's sarcoma are not associated with
Rochalimaea species infection, despite
their vascular nature and similar clini¬
cal appearance.
Four potential sources of bias may
have been present in this case-control
study. First, one third of case patients
were not interviewed directly (ie, sur¬
rogates provided information), whereas
all controls were interviewed directly.
However, a matched analysis excluding
all 15 surrogate case patients found no
substantial difference in any associations
when compared with the overall matched
analysis. Second, more than one third of
case patients were interviewed more
than 6 months after their BAP tissue
diagnosis, thereby bringing into ques¬
tion the accuracy of their responses. Re¬
sults of a matched analysis excluding
these 21 case patients were unchanged.
Third, case patients enrolled for study
may have been given a diagnosis of CSD,
which may have introduced recall bias.
However, a recent history of cat own¬
ership or cat bite remained a risk factor
for disease in an unmatched analysis of
the eight case patients never given a
diagnosis of CSD (among the 13 que¬
ried) and all 94 controls. This suggests
that recall bias was unlikely to be re¬
sponsible for the association between
traumatic cat exposures and BAP dis¬
Finally, physician-introduced sus¬
picion bias may have been generated by
soliciting a patient history of cat expoease.
Downloaded from jama.ama-assn.org at University of California - San Francisco on January 11, 2011
This fourth potential bias is un¬
likely because (1) all 48 case patients
presented to their physician for an eval¬
uation of clinical symptoms and physical
findings that required a tissue biopsy
regardless of a history of prior cat ex¬
posure, (2) physicians were asked to re¬
fer potential case patients with a tissue
diagnosis of BAP and not a clinical di¬
agnosis of CSD, and (3) one third of our
case patients gave no history of recent
sure.
cat exposure.
This case-control study is the first sys¬
tematic investigation of the relationship
between environmental exposures and
BAP disease, suggesting that BAP is
associated with traumatic cat exposures
and providing further evidence for a
causal relationship between disease and
infection with Rochalimaea or a closely
related species. Of interest, a recent R
henselae-h&seà serological investigation
among patients with suspected classic
CSD,35 as well as PCR-based studies for
the detection of PocAaiimaea-like spe¬
cies in CSD skin test antigen prepara¬
tions,36 suggest that R henselae or a
closely related organism, as opposed to
A felis, may be responsible for most
cases of classic CSD. If infection with
Rochalimaea species is associated with
exposure to cats, preventive strategies
will need to address the risks and ben¬
efits of exposure to cats, particularly
among HIV-infected patients, who may
benefit psychologically from pet com¬
panionship.37 Future studies investigat¬
ing the incidence and prevalence of BAP
disease, as well as vector(s) and reser¬
voirs) for Rochalimaea species, are
needed to determine what specific rec¬
ommendations for disease prevention are
warranted.
This project was supported by funds from a Na¬
tional Research Service Award, AR07175-15, by a
Dermatology Foundation Research Fellowship
(J.W.T.), and by the University of California, San
Francisco, AIDS Clinical Research Center and the
John D. and Catherine T. MacArthur Foundation,
University of California, San Francisco (J.E.K.).
In addition to the listed authors, the members of
the Bacillary Angiomatosis Study Group who con¬
tributed to the studies in this article include Claire
V. Broome, MD, Georgia B. Malcolm, MS, Mary
Ann Lambert-Fair, Brian D. Plikaytis, MS, and
Arnold F. Kaufmann, DVM, Division of Bacterial
and Mycotic Diseases, National Center for Infec¬
tious Diseases, Centers for Disease Control and
Prevention, Atlanta, Ga; Nitin Nanda, MD, and Ali
Moiin, MD, The Department of Dermatology, Uni¬
versity of California, San Francisco; and Clay J.
Cockerell, MD, Department of Dermatology, Uni¬
versity of Texas Southwestern Medical Center at
Dallas.
We are indebted to the following clinicians for
referring their patients for participation in this
study: Elizabeth A. Benish, MD, Samuel A. Bozzette, MD, Francis X. Burch, MD, Richard A. Cazen, MD, Marcus A. Conant, MD, Brian T. Court¬
ney, MD, M. W. Delmer, MD, Toby S. Dyner, MD,
Joshua Fierer, MD, Joan King-Angeli, MD, Jay
Lalezari, MD, Celia Lamke, MD, William A. Lockyer, MD, David J. Looney, MD, William C.
Mathews, MD, Carmen Myrie Williams, MD, Rob¬
ert O'Donnell, MD, Rube J. Pardo, MD, Mark
Reisman, MD, Kent L. Sack, MD, William L. Salzer, MD, Richard M. Tucker, MD, Carol E. Wratten,
MD, and Richard R. Yates, MD.
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