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Scand
J
Infect Dis
26:
623-626,
1994
CASE
REPORT
Cellulitis
as
First Clinical Presentation
of
Disseminated
Cryptococcosis
in Renal Transplant Recipients
ALPHONS
M.
HORREVORTS,
FRANS
T.
M.
HWSMANS~,
ROLAND J. J.
KOOPMAN)
and JACQUES
F.
G.
M. MEIS'
From the Deparrmenls
of
'Medical Microbiology, 'Internal Medicine and 3Dermatology,
University Hospital Nijmegen, The Netherlands
Two renal transplant recipients with
cellulitis
due to Cryptococcus
neoformans
are described. The
patients were treated empirically for a presumed bacterial erysipelas, but without response.
Examination of skin biopsies revealed C. neoformans
as
the causative organism. In both patients
the
cellulitis
was
the presenting clinical manifestation of disseminated cryptococcosis. Therapy
with antifungal agents was successful. Disfeminated cryptococcal
disease
occurs
mainly
in
immunocompromized patients. When left untreated, it nearly always has a fatal course. Early
diagnosis and appropriate therapy are therefore essential.
A.
M. Horrevorts,
MD,
Department
of
Medical Microbiology, University Hospital Nijmegen,
P.O.
Box
9101,
6500
HB Nijmegen, The Netherlands
INTRODUCTION
Disseminated infection by Cryptococcus neoformans is observed mainly in immunocompro-
mized patients and cutaneous involvement occurs in
10-
15%
of cases
(1).
Primary crypto-
coccosis
of
the skin is very rare and cryptococcal skin disease should therefore
be
interpreted
as a sign of systemic cryptococcal infection
(2).
Cryptococcal skin disease can manifest itself
in
a variety
of
ways, each
of
which is uncharacteristic
for
C.
neoformans
(3).
Cellulitis is a
very uncommon
form
(I).
We describe
2
patients, both renal transplant recipients, with
cellulitis caused by
C.
neoformans.
CASE REPORTS
Case
1
A
31-year-old woman was admitted to the hospital with fever and a lesion of the right lower leg that
resembled erysipelas. The general practitioner had prescribed erythromycin, but without improvement.
She had in the past had
2
unsuccessful renal transplants, followed by periods of long-term intermittent
hemodialysis and peritoneal dialysis because of a terminal renal insufficiency due to an anti-GBM
glomerulonephritis. She then underwent a third. successful renal transplantation. Her medication
consisted of prednisone
10
mg and azathioprine
100
mg daily. Four days prior to admission she had felt
feverish, without rigors, and had noticed a dry unproductive cough. On examination she appeared
moderately
ill
with a pulse rate of
80
per min and a blood pressure of
120/90
mmHg.
Her
temperature
was
39.0C.
Examination of heart, lungs and abdomen was unremarkable. On the skin of the right lower
leg, there were a few painful, slightly elevated, erythematous patches (Fig.
I).
Laboratory findings:
hemoglobin
90
g/l; leukocyte count
5.2
x
109/1;
platelet count
285
x
109/l;
serum
creatinine was stable at
86
pmol/l. The chest X-ray showed pleural fluid on the left side and
2
circular infiltrates, each with a
diameter of IScm, in the right upper lobe. Because the disorder on the right lower leg resembled
erysipelas. erythromycin was changed
to
oral penicillin.
The
patient became subfebrile and started to
complain of headache. A broncheoalveolar lavage and a skin biopsy were performed. Microscopic
examination of both showed
small
yeast cells and
cultures
yielded
C.
neoformans. Cerebrospinal fluid
(CSF)
and urine cultures both grew
C.
neoformans, whereas blood cultures remained sterile. The
cryptococcal antigen titres in the CSF and blood were
4
and
32,
respectively. Combination therapy with
amphotericin
B
and 5-fluorocytosine was started. However, as the isolate was resistant to 5-fluorocy-
tosine in vitro, therapy was changed to fluconazole 400 mg/day intravenously. Follow-up cultures of
0
1994
Scandinavian University
Press.
ISSN
0036-5548
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624
A.
M.
Horreuorts
et
al.
%and
J
Infect
Dis
26
Fig.
1.
Cutaneous skin lesion in a
renal transplant recipient.
The
biopsy revealed Cryptococcus
neoformans.
CSF, urine and skin biopsies remained sterile, although cryptococci were still visible in smears of skin
biopsies even after
5
weeks of treatment. Combination therapy was given for
7.5
weeks after which
amphotericin
B
was stopped (cumulative dose 1.6 g), but fluconazole was continued in a dose
of
100
mg
orally twice daily
for
6 months.
11
weeks after admission, the patient was discharged in good condition
with healed skin lesions. Cryptocmal antigen titres in CSF and blood had become negative. However,
the abnormalities on the pulmonary X-ray were unchanged.
Three months after stopping medication, a control pulmonary X-ray showed that the infiltrates
in
the
upper right side of the lung had progressed. Therefore blood CSF, urine and bronchoalveolar lavage were
taken for culture, but none yielded C. neoformans. Eventually a dorsal segment of the upper
lobe
of the
right lung was removed. Histopathological examination revealed
no
abnormalities other than fibrotic
consolidation and cultures proved negative for
C.
neoformans.
Case
2
A 66-year-old woman was admitted to the hospital because
of
repeated episodes
of
high fever.
A
few
months prior to admission she had been given antibiotics repeatedly by her general practitioner for an
erysipelas-like skin lesion
on
the left lower leg. Several weeks prior
to
admission she had begun to complain
of
headache. During the last days, vomiting and fever
>
39°C developed. Her medical history recorded
a double-sided hydronephrosis due
to
junctura stenosis
for
which she underwent nephrectomy in 1939
(left) and again in 1982 (right). In 1982 a period of long-term, intermittent hemodialysis followed.
In
1985
she received a cadaveric renal transplant. She was receiving maintenance immunosuppressive therapy with
prednisone
10
mg and azathioprine
150
mg daily. She also suffered from diabetes mellitus type
11.
On physical examination, a moderately ill, slightly somnolent and dehydrated patient was seen with
a temperature of 38.4"C, a pulse rate
of
108 per min and a blood pressure
of
14/85 mHg. Meningeal
signs were absent and fundoscopic examination showed no papilledema. The skin of the left lower leg
displayed erythema
(5
by
5
an).
Laboratory findings: hemoglobin 152 g/l; leukocyte count 10.6
x
109/l;
platelet count 392
x
I09/l; serum creatinine was stable at
84
pmolfl. The pulmonary X-ray showed no
abnormalities.
Blood,
CSF, urine and skin biopsies were taken for culture. CSF examination revealed a
leukocyte count
of
800
x
106/1,
an increased albumin concentration
of
3
g/l, and
a
decreased glucose
concentration of 3.8
mmol/l
(blood glucose of 14.6 mmol/l). An India ink preparation of the CSF proved
positive for yeasts and C. neoformans was isolated from CSF, skin biopsies and urine, while blood and
sputum remained negative. Cryptococcal antigen titres in CSF and blood were
64
and
512,
respectively.
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Scand
J
Infect
Dis
26
Cryptococcal
celluiitis
in
renal transplants
625
Therapy was started with fluconazole 400 mg administered
i.v.
once a day. After
10
days, ampho-
tericin
B
was added at a dose of 0.6mg/kg/day, because the patient was deteriorating and follow-up
cultures of
CSF,
skin biopsies and urine still yielded growth of
C.
neoformans.
CSF
and urine cultures
became sterile
I
week after adding amphotericin
B,
and the skin biopsies after
3.5
weeks’ treatment. The
condition of the patient improved slowly as did the skin lesion. Amphotericin
B
was administered for
4
weeks
to a cumulative dose 1.2 g. After 2 months of
i.v.
administration, fluconazole was given orally at
a dose of 200 mg/day. Cryptococcal antigen titres
in
CSF
and blood had then decreased to
0
and 256,
respectively. The patient was discharged 10 weeks after admission. The administration of fluconazole was
continued for
6
months and
up
until now, 4 years later, she is well, with no recurrence of the
cryptococcosis.
DISCUSSION
Human cryptococcosis was first described by the German dermatologist Buschke in
1895
(4).
It is caused by C. neoformans and is seen mainly in immunocompromized patients. Skin
involvement
occurs
in some
10-15%
of the cases and includes
ulcers,
acneiform papules
or
pustules, ecchymoses, granulomata, gummas, abscesses, vesicles. Cellulitis is the rarest
presentation
(3).
In renal transplant recipients, infections caused by C. neoformans occurs
almost exclusively in the late post-transplant period from about
4
months after transplanta-
tion and onwards
(5).
The reported incidence varies from
0.8
to
5.8%
and use of high doses
of immunosuppressive drugs leads to a higher risk of infection
(6,
7).
C.
neoformans is
considered to be the main cause of subacute
or
chronic meningitis
in
these patients.
Meningitis is often preceded by several weeks of headache and fever
(5,
8).
In about a third
of
the patients a period of coughing is noted and some also suffer from pulmonary infection
(5).
Other predilection sites of C. neoformans include the urinary tract, bones and the skin
(5,
6).
Some
20-30%
of
transplant recipients with cryptococcal infection will have skin
lesions weeks to months prior to the development of central nervous system (CNS) disease
(5).
Any renal transplant patient with a documented cryptococcal infection at any site should
undergo lumbar puncture to exclude CNS involvement, since CNS involvement determines
the intensity and duration
of
treatment
(5).
In addition to
our
2
cases,
11
other recipients
of
renal transplant with cellulitis caused by
C.
neoformans have been reported
(1-3, 9-12).
Inclusive
of
our
2
patients, it concerns 10 male and
3
female patients varying in age from
31
to
66
years,
all
taking immunosuppressive drugs.
11
patients had received
a
transplant from
a deceased donor. The time
of
manifestation of the disease varied from
1
to
10
years after
transplantation.
Two
patients developed cellulitis after a trauma
(
10,
12).
The cellulitis
appeared to be restricted mainly to the extremities, especially the legs. One patient also
suffered from cellulitis on the skin
of
the abdomen
(12).
In
8
patients C. neoformans was also
recovered from more than
1
site, most commonly from CSF and sputum. Cryptococcal
antigens were detected in the blood of
8
and in the CSF of
3
patients.
11
patients had been
treated initially with antibacterial agents, without improvement, when specific examination
revealed
C.
neoformans. Disseminated cryptococcosis appeared to be present in
8
patients,
whereas cellulitis alone was present in
2
renal transplant recipients
(2, 12).
Five patients were
treated with amphotericin
B,
6
further
in
combination with 5-fluorocytosine and
2
(our
2
cases) in combination with fluconazole. The cumulative dose and duration
of
treatment with
amphotericin B varied from 570
to
1,970 mg and from
16
days to
8
weeks, respectively. Five
patients died,
1
as a direct result of the cryptococcal infection
(12).
In
the treatment of acute AIDS-related cryptococcal meningitis, fluconazole has been as
effective as amphotericin B and, as maintenance therapy, even better than amphotencin B
(13,
14).
Our
second case was initially treated with fluconazole alone, but because follow-up
cultures of CSF still demonstrated growth of
C.
neoformans, amphotericin B was added.
Maintenance therapy did not seem necessary, since none of
our
patients and none of the
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626
A.
M.
Horrevorts
et
al.
Scand
J
Infat
Dis
26
renal transplant patients described before
(1-3,
9-12)
had had a relapse
of
cryptococcal
disease after cessation of treatment, in contrast to patients with
AIDS
in whom a high
relapse rate is observed
(3,
IS).
However, it
is
advisable to monitor the patient for at least
a year after completion of the antimycotic therapy
(3).
Untreated disseminated cryptococcosis is almost invariably a fatal disease. Timely diagno-
sis and appropriate treatment are therefore of the utmost importance. Cryptococcal cellulitis
can be mistaken for a bacterial erysipelas and a delay in appropriate diagnosis can lead to
high morbidity and mortality rates.
As
the cellulitis may be the first manifestation of a
disseminated rather than a localized disease, an exhaustive examination (including a lumbar
puncture) is indicated in any renal transplant recipient who presents with cellulitis.
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Submitted March
2.
1994; accepted May
1,
1994
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