Hepatic Candidiasis: An Increasing Problem in lmmunocompromised Patients ELIANE HARON, M.D.* RONALD FELD, M.D. PETER TUFFNELL, M.D. BRUCE PATTERSON, M.D. RICHARD HASSELBACK, M.D. ANNE MATLOW, M.D. Torotito, Ontario, Canada Prom the Princess Margaret Hospital and the Wellesley Hospital, Toronto, Ontario, Canada. Requests for reprints should be addressed to Dr. Ronald Feld, Princess Margaret Hospital, 500 Sherbourne Street, Toronto, Ontario, M4X lK9 Canada. Manuscript submitted September 19, 1986, and accepted January 28, 1987. l Current address: M. D. Anderson Hospital and Tumor Institute, 6723 Bertner Street, Houston, Texas 77030. Hepatic candidiasis has been increasingly recognized as a variant of disseminated candidiasis in immunocompromised patients Five leuke- mic patients with antemortem diagnosis of hepatic candidiasis are described, and 32 additional cases reported in the literature are re- viewed. Cultures of the liver and/or spleen and blood cultures usually give negative results; histopathologic demonstration of Candida organ- isms in tissue specimens is necessary for a definitive diagnosis. Re- sponse to conventional therapy with amphotericin B is poor, and 34.4 percent of the patients died with evidence of active fungal disease. Liposome-encapsulated amphotericin B, which has been successfully used in a limited number of patients with invasive fungal disease, may be an effective and relatively nontoxic drug. The past two decades have witnessed a dramatic increase in the fre- quency of fungal infections in cancer patients [I], which can be attributed to many factors. Impairment of cellular and humoral host defenses due to the underlying disease and/or treatment, use of more aggressive chemo- therapeutic regimens in which both prolonged neutropenia and damage to mucosal surfaces might be expected, routine use of central venous lines for administration of chemotherapy and/or hyperalimentation, wide- spread use of prophylactic and therapeutic broad-spectrum antibiotics, and the frequent requirement for steroid administration in these patients all can be implicated [I]. Candida species, especially Candida albicans, account for the majority of serious fungal infections in immunocompro- mised patients, although Candida tropicalis, Candida parapsilosis, and Aspergillus species have also become frequent pathogens [2-51. The organs most often affected in disseminated candidiasis are the lungs, kidneys, gastrointestinal tract, heart, liver, and spleen. The incidence of liver involvement in disseminated candidiasis varies from 4.8 to 59 percent in various series [4-61. Hepatic candidiasis is usually part of a systemic infection, but there are some instances in which the infection is almost confined to the liver and/or spleen [6]. Hepatic candidiasis has been increasingly reported in the literature [6,7]. The more frequent recognition of this entity must be, at least in part, attributed to improved diagnostic techniques, especially ultrasonography and computed tomog- raphy [8-l I]. However, the diagnosis of hepatic candidiasis during life is still a challenge, and despite appropriate treatment, the outcome is often poor [6,7]. In this report, we present our experience with five patients with hepatic or hepatosplenic candidiasis seen between 1979 and 1985 and review the patients with antemortem diagnosis described in the literature. The clinical, biochemical, and radiographic characteristics are presented. July 1987 The American Journal of Medicine Volume 83 17
Transcript
Hepatic Candidiasis: An Increasing Problem in lmmunocompromised Patients
ELIANE HARON, M.D.* RONALD FELD, M.D. PETER TUFFNELL, M.D. BRUCE PATTERSON, M.D. RICHARD HASSELBACK, M.D. ANNE MATLOW, M.D. Torotito, Ontario, Canada
Prom the Princess Margaret Hospital and the Wellesley Hospital, Toronto, Ontario, Canada. Requests for reprints should be addressed to Dr. Ronald Feld, Princess Margaret Hospital, 500 Sherbourne Street, Toronto, Ontario, M4X lK9 Canada. Manuscript submitted September 19, 1986, and accepted January 28, 1987.
l Current address: M. D. Anderson Hospital and Tumor Institute, 6723 Bertner Street, Houston, Texas 77030.
Hepatic candidiasis has been increasingly recognized as a variant of disseminated candidiasis in immunocompromised patients Five leuke- mic patients with antemortem diagnosis of hepatic candidiasis are described, and 32 additional cases reported in the literature are re- viewed. Cultures of the liver and/or spleen and blood cultures usually give negative results; histopathologic demonstration of Candida organ- isms in tissue specimens is necessary for a definitive diagnosis. Re- sponse to conventional therapy with amphotericin B is poor, and 34.4 percent of the patients died with evidence of active fungal disease. Liposome-encapsulated amphotericin B, which has been successfully used in a limited number of patients with invasive fungal disease, may be an effective and relatively nontoxic drug.
The past two decades have witnessed a dramatic increase in the fre- quency of fungal infections in cancer patients [I], which can be attributed to many factors. Impairment of cellular and humoral host defenses due to the underlying disease and/or treatment, use of more aggressive chemo- therapeutic regimens in which both prolonged neutropenia and damage to mucosal surfaces might be expected, routine use of central venous lines for administration of chemotherapy and/or hyperalimentation, wide- spread use of prophylactic and therapeutic broad-spectrum antibiotics, and the frequent requirement for steroid administration in these patients all can be implicated [I]. Candida species, especially Candida albicans, account for the majority of serious fungal infections in immunocompro- mised patients, although Candida tropicalis, Candida parapsilosis, and Aspergillus species have also become frequent pathogens [2-51. The organs most often affected in disseminated candidiasis are the lungs, kidneys, gastrointestinal tract, heart, liver, and spleen. The incidence of liver involvement in disseminated candidiasis varies from 4.8 to 59 percent in various series [4-61. Hepatic candidiasis is usually part of a systemic infection, but there are some instances in which the infection is almost confined to the liver and/or spleen [6]. Hepatic candidiasis has been increasingly reported in the literature [6,7]. The more frequent recognition of this entity must be, at least in part, attributed to improved diagnostic techniques, especially ultrasonography and computed tomog- raphy [8-l I]. However, the diagnosis of hepatic candidiasis during life is still a challenge, and despite appropriate treatment, the outcome is often poor [6,7].
In this report, we present our experience with five patients with hepatic or hepatosplenic candidiasis seen between 1979 and 1985 and review the patients with antemortem diagnosis described in the literature. The clinical, biochemical, and radiographic characteristics are presented.
July 1987 The American Journal of Medicine Volume 83 17
HEPATIC CANDIDIASIS-HARON ET AL
Possible reasons for treatment failure and the potential role of liposome-encapsulated amphotericin B in the treatment are discussed.
PATIENTS AND METHODS
The records of patients with focal hepatic or hepatosplenic infection due to Candida species admitted to the Princess Margaret Hospital, a 202-bed facility solely for the treat- ment of cancer patients, were reviewed. Patients fulfilling the following criteria were considered to have focal hepatic candidiasis: (1) febrile illness unresponsive to broad-spec- trum antibiotic therapy with clinical symptoms and signs localized to the liver and/or spleen including right upper quadrant tenderness, jaundice, hepatomegaly, splenomeg- aly; (2) histopathologic demonstration of fungal organisms ‘in liver and/or splenic tissue consistent with Candida spe- cies: (3) abnormal findings on hepatic/splenic imaging (computed tomographic, ultrasound, or technetium 99m studies). Positive culture evidence of Candida species in the liver or spleen were not required. The presence of budding yeasts, accompanied or not by pseudohyphae, at histo- pathologic examination was considered adequate confir- mation of the diagnosis of candidiasis.
Five patients satisfying these criteria were seen at the Princess Margaret Hospital from August 1979 to December 1985. Computed tomographic scanning were performed with a Picker International fourth-generation computed tomographic scanner, ultrasonographic studies were car- ried out with a General Electric RT 3000 Ultrasound, and technetium 99m sulfur colloid liver/spleen scanning was performed with an Ohio Nuclear scanner.
Liver tissue specimens were obtained by open liver biop- sy in two patients, transdiaphragmatic biopsy in one patient, and laparoscopy-guided needle biopsy in one patient. One patient underwent splenectomy. In one patient, although the diagnosis was made on clinical grounds and treatment was started shortly thereafter, definitive histopathologic confor- mation was only possible at autopsy, after the patient had received approximately 1 g of amphotericin B.
Tissue specimens were cultured for fungi on blood-agar (Columbia base plus 5 percent sheep blood) at 21% and 35’C for four weeks and Sabouraud’s agar at 21%. Blood culture media consisted of 10 ml of tryptic soy broth with sodium polyanethole sulfonate and carbon dioxide (BACTO) at 35OC after venting and one bottle of thiol broth (BACTO) incubated without venting, Routine subcultures were per- formed at 48 hours and seven days. Sputum and urine samples were cultured for fungi on blood-agar with genta- micin at 35’C and 2 1 ‘C and Sabouraud’s agar at 2 1 ‘C.
CASE REPORTS Patient 1. Acute myelogenous leukemia was diagnosed in a 37-year-old Caucasian woman in October 1978. From October 1978 until August 1979, she received many che- motherapeutic regimens without a complete remission. In August 1979, she was admitted to the hospital to receive hydroxyurea and cytosine arabinoside. In the neutropenic period following this chemotherapy, fever developed. No focus of infection was identified, but she was treated with
cefazolin and gentamicin. Blood and urine cultures showed no growth. Sputum and stool specimens grew C. albicans. Two weeks after this therapy had been started, she re- mained febrile, and right upper quadrant tenderness, jaun- dice, transient abdominal distention, and diarrhea devel- oped. Shortly thereafter, bilateral basal infiltrates were not- ed on chest radiography, and erythromycin was added to the previous antibiotic therapy. She continued to have spik- ing fever, and administration of amphotericin B was begun. After a total dose of 250 mg of amphotericin B, the patient’s white blood cell count recovered, and all drugs were dis- continued. During the following week, the patient remained febrile with persistent right upper quadrant tenderness. The alkaline phosphatase level was 171.5 units (normal, 3 to 11 units), the serum glutamic oxaloacetic transaminase leve! was 108 units/ml (normal, 23 to 47 units/ml), and the total bilirubin value was 4.5 mg/dl (normal, 0.4 to 1.0 mg/dl). Repeated chest radiography disclosed an irregular consoli- dation In the right middle lobe that was shown to be cavitat- ed on lung tomography. Amphotericin B was again adminis- tered, with prompt reduction of her temperature to normal. Surgical resection of the pulmonary lesion and transdiaph- ragmatic liver biopsy were performed. Histologic examina- tion of lung revealed necrotic areas with granulomatous reaction and the presence of branched septate hyphae. The liver biopsy specimen showed a granulomatous reaction with budding yeasts and no leukemic infiltrates. The lung tissue culture grew C. albicans. Liver tissue culture was not performed. She continued to receive amphotericin B for the following four months, for a total dose of 2,351 mg, along with 4 g of oral 5-fluorocytosine per day. Computed tomo- graphic scanning of the abdomen three months after treat- ment was resumed showed multiple lucencies scattered through the liver suggestive of residual abscesses. One month later, repeated abdominal computed tomographic scanning showed no improvement. Her clinical condition deteriorated significantly over the following weeks, and the patient died. Postmortem examination revealed multiple Candida abscesses of the liver, spleen, lungs, and kidneys. Patient 2. Acute myelogenous leukemia was diagnosed in a 20-year-old man in January 1979. An initial remission was achieved with chemotherapy. In May 1980, his disease relapsed and he was admitted to the hospital for a new course of remission induction chemotherapy with doxorubi- tin (Adriamycin), cytosine arabinoside, and 6-thioguanine without success, In October 1980, he received a course of hydroxyurea and cytosine arabinoside. While he was neu- tropenic, fever developed, with no obvious focus of infec- tion. He was treated with tobramycin, cefamandole, and ticarcillin. Blood, sputum, and urine cultures gave negative results. Culture of a throat specimen grew C. albicans. Since fever persisted, amphotericin B was added empirical- ly. Two weeks later, despite partial recovery of the blood cell counts he continued to have spiking fever. Amphoteri- tin B was discontinued after a total dose of 340 mg, but he continued to receive broad-spectrum antibiotics. Subse- quently, tenderness over the right and left upper quadrant, dysphagia, and hepatomegaly developed. The alkaline phosphatase, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, gamma glutamyl
19 July 1997 The American Journal of Medicine Volume 83
HEPATIC CANDIDIASIS--HARON ET AL
transferase, and bilirubin levels were normal. Abdominal computed tomographic scanning disclosed hepatomegaly with multiple small lucencies scattered throughout the liver. Cultures of throat, sputum, and stool specimens grew C. albicans. Blood and urine cultures continued to show no growth. Hepatic candidiasis was suspected, and amphoteri- tin B administration was resumed. The fever gradually subsided, and amphotericin B was discontinued at this time after a total dose of 625 mg. However, the leukemia re- mained uncontrolled, and the patient received another course of chemotherapy. Over the following weeks, his clinical condition deteriorated and the patient died. Post- mortem examination revealed multiple Candida abscesses in the liver, spleen, and lungs. Patient 3. Acute lymphoblastic leukemia was diagnosed in a 36-year-old male teacher in July 1984. He was treated with L-asparaginase, doxorubicin (Adriamycin) vincristine, and prednisone. During the neutropenic period following induction chemotherapy, fever developed, with no identi- fied focus. Administration of aztreonam and cloxacillin was started, and piperacillin was added to the regimen three days later, as he continued to have temperature spikes to 39’C. Blood and urine cultures gave negative results. Stool cultures grew C. albicans. Sputum cultures showed C. albicans and Aspergillus species. Amphotericin B was add- ed empirically. Chest radiography disclosed bilateral con- solidation. In the following weeks, jaundice and hepato- megaly developed, and the patient remained febrile despite all drugs. Bone marrow aspiration showed his leukemia to be in remission. The alkaline phosphatase level was 1,432 units/liter (normal, 30 to 110 units/liter), the serum glutamic oxaloacetic transaminase level was 172 units/liter (normal, 23 to 47 units/liter), the gamma glutamyl transferase level was 963 units/liter (normal, 0 to 85 units/liter), and the total bilirubin level was 60 ,umol/liter (normal, 1.7 to 17.1 I.lmOl/ liter). Computed tomographic scanning of the abdomen disclosed multiple lucencies scattered throughout the liver consistent with abscesses (Figure 1). Needle biopsy of the liver performed with computed tomographic guidance was nondiagnostic. Open liver biopsy subsequently showed ex- tensive destruction of hepatic parenchyma and the pres- ence of yeasts, budding forms, and pseudohyphae sugges- tive of Candida species. Culture of the liver biopsy speci- men gave negative results. The patient received amphotericin B for four months, for a total dose of 2.5 g, along with 5fluorocytosine for one month. After amphoteri- tin B was discontinued, the patient began maintenance ketoconazole therapy. Follow-up abdominal computed tomographic scanning revealed marked improvement of the liver microabscesses. A very recent computed tomo- graphic study (November 1986) showed no active disease in the liver, with calcifications in the areas of previous abscess formation. He is currently well and continuing to receive oral ketoconazole. Patient 4. Chronic myelogenous leukemia was diagnosed in a 31-year-old housewife in June 1983. She was treated with busulfan, and her disease was under control until October 1984. In November 1984, she was admitted with fatigue, diffuse bone pain, and a weight loss of 17 pounds over the previous two months. Her disease was found to be
Figure I. Computed tomographic scan of liver illustrating multiple lucencies consistent with abscesses (Patient 3).
in an accelerated phase. She was treated with high-dose cytosine arabinoside, and her course was complicated by fever during the neutropenic period. Administration of to- bramycin, cefazolin, and piperacillin was started. Five days later, she still had spiking fever, and chest radiography revealed bilateral diffuse infiltrates consistent with acute pneumonia. Blood, urine, and sputum cultures showed no growth. Stool cultures grew C. albicans. At the same time, left upper quadrant tenderness developed, and computed tomographic scanning of the abdomen disclosed multiple liver and spleen microabscesses. The serum alkaline phos- phatase level was 522 units/liter (normal, 30 to 1 Id units/ liter), the gamma glutamyl transferase level was 266 units/ liter (normal, 0 to 85 units/liter), the serum glutamic oxalo- acetic transaminase level was 51 units/liter (normal, 23 to 47 units/liter) and the total bilirubin level was 44 ~mol/liter (normal, 1.7 to 17.1 PmoVliter). Amphotericin B was start- ed one week later because the patient continued to have high fevers. Subsequently, chest radiography showed cavi- tated irregular lesions in both lungs consistent with fungal disease. Needle biopsy of the liver performed two weeks later was not diagnostic. Fever disappeared 17 days after antifungal therapy was started, and the cavitated lesions in the lungs showed significant improvement after 1.7 g of amphotericin B. Hepatic and splenic lesions remained un- changed on subsequent computed tomographic studies, and the patient continued to have abdominal symptoms. In February 1985, she underwent open liver biopsy and sple- nectomy. Pathologic examination of liver and spleen re- vealed multiple microabscesses with masses of Candida organisms. Tissue cultures were negative. Bone marrow aspiration demonstrated remission. She is currently well receiving oral ketoconazole. Patient 5. Acute lymphoblastic leukemia was diagnosed in a 22-year-old man in September 1974. He received chemo- therapy consisting of vincristine, prednisone, and intrathe- cal methotrexate. He also had maintenance therapy for five years and his remission was maintained without treatment for a further five years. In April 1984, he had a bone marrow relapse without central nervous system involvement. He
July 1987 The American Journal of Medicine Volume 83 19
HEPATIC CANDIDIASIS-HARON ET AL
TABLE I Demographic and Clinical Characteristics in Current Series
received daunorubicin, vincristine, and intrathecal metho- trexate, and this remission was maintained until October 1985 when he had a central nervous system relapse of leukemia. He was admitted to the Princess Margaret Hospi- tal (day 1) and was noted to be febrile. His hemoglobin level was 105 g/liter, and his white blood cell count was 10.8 X log/liter with 90 percent polymorphonuclear neutrophils, 1 percent eosinophils, 1 percent lymphocytes, 7 percent monocytes, and 1 percent myelocytes. He was treated with tobramycin and cefazolin, and he also received the antileu- kemic chemotherapy. His temperature promptly de- creased. All cultures gave negative results. On day 10, while he was neutropenic, his temperature spiked to 39.2’C, and piperacillin was added to the antibiotic thera- py. From day 12 to day 15, the patient had diarrhea. Despite broad-spectrum antibiotic coverage, high fever (4O’C) per- sisted, and administration of amphotericin B was started on day 15. Four days later, blood and stool cultures grew C.
TABLE II Clinical Signs and Symptoms in Current Series and in Patients Described in Literature
*Note that sign and symptom data were not available for all patients in literature review.
albicans. The development of bilateral infiltrates was noted on chest radiography, and antibiotic therapy was changed to tobramycin and ceftazidime. Results of urine and sputum cultures remained negative. On day 30, transient abdominal distention developed, and a blood culture grew Bacteroides fragilis, which was treated with cefoxitin. Five days later, the patient was noted to be jaundiced and to have right upper quadrant tenderness and hepatomegaly. The spleen was not palpable. The serum alkaline phosphatase level was 444 units/liter (normal, 40 to 120 units/liter), the serum glutamic oxaloacetic transaminase level was 100 units/liter (normal, 5 to 35 units/liter), the serum glutamlc pyruvic transaminase level was 381 units/liter (normal, 7 to 56 units/liter), and the total bilirubin level was 87 pmol/liter (normal, 2 to 17 pmol/liter). Computed tomographic scan- ning of abdomen on day 31 showed multiple liver abscess- es and splenomegaly. Bone marrow aspiration on day 49 demonstrated a complete remission. A liver biopsy speci- men obtained during laparoscopy on day 61 contained Can- dida microabscesses in which budding yeasts and pseudo- hyphae were identified. Cultures of the liver tissue grew C. albicans. On day 91, 5-fluorocytosine was added because, of persistent fever. The patient experienced a gradual de- crease in temperature by day 100 and was subsequently discharged from hospital to receive antifungal therapy on an outpatient basis. Two weeks later, he was readmitted with fever. Repeated computed tomographic scanning of abdomen showed no change. Blood, sputum, urine, and stool cultures showed no growth. Bone marrow aspiration showed an early relapse, with 7 percent blast cells. The patient was treated with L-asparaginase, vincristine, and methylprednisolone sodium succinate (Solumedrol) with resolution of his fever. He has received a total dose of 2.0 g of amphotericin B and is currently receiving 30 mg of this agent three times a week.
RESULTS
Clinical Features. The major features of the five patients in our series are shown in Table I. All patients experi- enced a prolonged period of neutropenia (polymorphonu-
20 July 1987 The American Journal of Medicine Volume 83
TABL
E III
Ab
norm
al F
indi
ngs,
Tre
atm
ent,
and
Out
com
e in
Cur
rent
Ser
ies
Resu
lts
of Im
aging
St
udies
Bi
oche
mica
l Co
mpu
ted
Ultra
- Te
chne
tium
Cultu
re Gr
owth
Hi
stop
atho
logi
c Pa
tienl
Abno
rmali
ties”
tomog
raph
y so
nogr
apfty
Sc
annin
g of
Cand
ida
Findin
gs
Trea
tmen
t7 Ou
tcom
e
1 2 No
ne
5
Alk
ph (
15X)
SG
OT
(2X)
Bi
li (5
X)
Alk
ph
(13X
) SG
OT
(3.5X
) Bi
li (3
.5X)
GGT(
11X)
Alk
ph
(5X)
GG
T (3
X)
Bili
(2.5X
)
Alk
ph
(3.5X
) SG
OT
(3X)
SG
PT
(7X)
Bi
li (5
X)
- No
rmal
Thro
at,
sputu
m,
stool,
lun
g
Multip
le he
patic
No
rmal
Hepa
to-
mega
ly Th
roat,
sp
utum,
sto
ol,
Multip
le he
patic
ab
sces
ses
Multip
le he
pato-
sp
lenic
absc
esse
s
Multip
le he
patic
ab
sces
ses
Multip
le bu
ll’s
eye
type
Norm
al Sp
utum
, sto
ol
- -
- -
Stoo
l
Stoo
l, blo
od,
liver
Liver
: one
focal
myco
tic
absc
ess
with
ov
al bu
dding
ye
asts
Liver
, sp
leen,
lungs
(au
topsy
): mu
ltiple
micro
absc
esse
s wi
th
budd
ing
yeas
ts,
pseu
dohy
phae
Liv
er: mu
ltiple
micro
absc
esse
s wi
th
focal
area
co
ntain
ing
yeas
t for
ms,
budd
ing
yeas
ts,
pseu
dohy
phae
Liv
er,
splee
n: mu
ltiple
micro
absc
esse
s wi
th
gran
uloma
tous
reac
tion,
budd
ing
yeas
ts,
pseu
dohy
phae
Liv
er: mu
ltiple
micro
absc
esse
s wi
th
yeas
t for
ms,
budd
ing
yeas
ts,
pseu
dohy
phae
Amp
B (2
.3 g)
Died
Amp
B (9
65
mg)
Died
Amp
B (2
.5 g)
, 5-F
C,
ketoc
ona-
zo
le
Alive
, we
ll
Amp
B (1
.7 sX
ke
tocon
azole
Al
ive,
well
Amp
B (2
.0 g
), 5-F
C Al
ive,
activ
e inf
ectio
n
0,
c “A
lk ph
=
alkali
ne
phos
phata
se;
SGOT
=
seru
m as
parta
te am
inotra
nsfer
ase;
SGPT
=
seru
m ala
nine
amino
trans
feras
e; GG
T =
gamm
a glu
tamy
l tra
nsfer
ase;
Bili
= to
tal
biliru
bin.
P t
Amp
B =
amph
oteric
in B;
5-F
C =
5-flu
ocyto
sine.
A
TABL
E IV
Ab
norm
al F
indi
ngs,
Tre
atm
ent,
and
Out
com
e in
Lite
ratu
re
Rev
iew
Unde
rlying
Cu
lture
Gro
wth
Posit
ive
Hist
opat
holo
gic
Trea
tmen
t?
3 0 Re
fere
nce
Age/
Sex
Dise
ase*
Pr
ior Th
erap
y of
Can
dida
Imag
ing Re
sults
Fi
nding
s (to
tal d
ose)
Ou
tcom
e 0 2
P-31
[121
!I
48/M
4/F
44/F
[I31 II
1 j/2
/M
1 ‘/J
M
1141
I,
25/F
68/F
[151
I!
54/F
60/M
24/M
[I61
44/F
[81
35/F
[91 ,I
[I71
I181
31/F
33/M
38/F
1%/M
U
3/F
AML
AML
AML
ALL
AUL
AML
AML
AL
AL
AL
AML
ALL
AML
ALL
DM, M
D
ALL
ALL
Mult
iple
antib
iotic
s,
chem
othe
rapy
, st
e-
roids
M
ultipl
e an
tibio
tics,
ch
emot
hera
py,
ste-
ro
ids
Mult
iple
antib
iotic
s,
ste-
ro
ids
Mult
iple
antib
iotic
s,
chem
othe
rapy
, st
e-
roids
M
ultipl
e an
tibio
tics,
ch
emot
hera
py,
ste-
ro
ids
Mult
iple
antib
iotic
s,
chem
othe
rapy
, M
ultipl
e an
tibio
tics,
ch
emot
hera
py,
Mult
iple
antib
iotic
s,
chem
othe
rapy
, st
e-
roids
M
ultipl
e an
tibio
tics,
ch
emot
hera
py,
ste-
ro
ids
Mult
iple
antib
iotic
s,
chem
othe
rapy
, st
e-
roids
M
ultipl
e an
tibio
tics,
ch
emot
hera
py,
Mult
iple
antib
iotic
s,
chem
othe
rapy
, st
e-
roids
M
ultipl
e an
tibio
tics,
ch
emot
hera
py,
- - Mult
iple
antib
iotic
s
Live
r, th
roat
, st
ool
Thro
at
Thro
at,
stoo
l
Urin
e, s
pleen
Bloo
d, t
hroa
t
Thro
at,
liver
Urine
Urin
e, p
leura
l ef
fusio
n,
sple
en,
liver
Bloo
d, u
rine,
leg
ab-
sc
ess
- Stoo
l, bil
e
Stoo
lz, l
iver
(asp
irate
)
- Live
r, sp
leen
, kid
ney,
he
art
Urine
Tech
netiu
m
scan
ning
, co
mpu
ted
tom
ogra
phy
Com
pute
d to
mog
raph
y
Tech
netiu
m
scan
ning
, ga
llium
sc
anni
ng,
ul-
traso
nogr
aphy
Ga
llium
sca
nnin
g,
tech
- ne
tium
sca
nning
- - Tech
netiu
m
scan
ning
, ga
llium
sc
annin
g
Tech
netiu
m
scan
ning
, ga
llium
sc
annin
g
Tech
netiu
m
scan
ning
, ga
llium
sc
annin
g
Perc
utan
eous
tra
nshe
pat-
ic ch
olang
iogra
phy
Com
pute
d to
mog
raph
y,
ultra
sono
grap
hy
Ultra
sono
grap
hy,
com
- pu
ted
tom
ogra
phy
Ultra
sono
grap
hy,
com
- pu
ted
tom
ogra
phy
Tech
netiu
m
scan
ning
Tech
netiu
m
scan
ning
, ga
llium
sc
anni
ng,
ul-
traso
nogr
aphy
Te
chne
tium
sc
anni
ng,
galliu
m
scan
ning
, ul-
tra
sono
grap
hy
Live
r: fu
ngal
absc
ess
with
Am
p B
(4 g
), 5-
FC
yeas
ts a
nd p
seud
ohyp
hae,
fa
tty c
hang
e Li
ver:
supp
urat
ive
gran
ulom
a,
Amp
B (1
g)
yeas
ts a
nd g
erm
tub
es i
n on
e in
flam
mat
ory
focu
s Li
ver:
case
atin
g gr
anulo
ma,
ye
asts
not
atta
ched
, ge
rm
Amsp
F;W
O
ms)
, -
tube
s Li
ver:
norm
al;
sple
en:
pseu
do-
Amp
B (2
0 m
glkg
), hy
phae
5-
FC
Live
r, sp
leen
: Ca
ndida
pse
udo-
Am
p B
(20
mgl
kg)
hyph
ae
Live
r: m
icroa
bsce
sses
wi
th n
o Am
p B
(1 g
) or
gani
sms
Liver
(au
tops
y):
micr
oabs
- Am
p B
(560
mg)
ce
sses
with
gra
nulom
atou
s re
actio
n an
d ps
eudo
hyph
ae
Live
r, sp
leen
: bu
dding
ye
ast
Amp
B (1
9)
form
s
Live
r, sp
leen
: bu
dding
yea
sts
Amp
B (N
R)
Live
r: no
rmal
, sp
leen
: bu
dding
Am
p B
(500
mg)
ye
asts
Live
r: ac
ute
chol
angi
tis,
one
Amp
B (2
9)
micr
oabs
cess
wi
th a
cute
in-
fla
mm
ator
y in
filtra
te
and
budd
ing y
east
s NR
Am
p B
(for
3 m
onth
s),
5-FC
Live
r, sp
leen
(aut
opsy
): m
ulti-
Am
p B
(NR)
ple
abs
cess
es
with
fun
gi Li
ver:
mult
iple
absc
esse
s wi
th
Amp
B (N
R)
fung
i Li
ver:
chro
nic
absc
ess,
few
Am
p B
(4,6
35
mg)
ye
asts
and
pse
udom
ycilia
Sp
leen:
Can
dida
NR
Live
r: Ca
ndida
NR
Alive
Alive
Alive
Died
Died
Alive
Died
Alive
Died
Alive
Alive
Alive
Died
Died
Alive
Died
[Ill
L E Y I,
t s
1/2/
M A
UL
15/M
AM
L
25/F
20/M
SLE
AML
21/F
AM
L
15/N
R
12IN
R
AML
ALL
li/NR
ALL
IOIN
R AM
L
2/F
ALL
32/M
AM
L
44/F
AM
L
9/F
AA
5/M
ALL
36/F
AM
L
Multip
le an
tibiot
ics
Stoo
lt, blo
od
Multip
le an
tibiot
ics,
ste-
Bloo
d,
perit
onea
l flu
id,
roids
liv
er
Multip
le an
tibiot
ics,
Bile
ch
emoth
erap
y
- Liv
er
- Liv
er
Multip
le an
tibiot
ics,
Thro
at,
rectu
m ch
emoth
erap
y, ste
- ro
ids
Multip
le an
tibiot
ics,
ste-
Thro
at,
rectu
m,
urine
ro
ids
Multip
le an
tibiot
ics,
chem
other
apy
Thro
at,
rectu
m,
urine
Multip
le an
tibiot
ics,
ste-
Thro
at,
rectu
m,
urine
ro
ids
Multip
le an
tibiot
ics,
- ch
emoth
erap
y
Multip
le an
tibiot
ics,
chem
other
apy
Sput
um,
blood
Multip
le an
tibiot
ics,
ste-
Urine
, liv
er,
splee
n ro
ids
Multip
le an
tibiot
ics,
chem
other
apy
Multip
le an
tibiot
ics,
Thro
at,
urine
, sp
utum
Thro
at,
urine
, sp
utum
Tech
netiu
m sc
annin
g, ga
llium
scan
ning,
ul-
traso
nogr
aphy
Te
chne
tium
scan
ning,
galliu
m sc
annin
g, ul-
tra
sono
grap
hy,
com-
pu
ted
tomog
raph
y NR
intra
veno
us
chola
ngiog
- rap
hy
(non
visua
lized
ga
llblad
der)
Comp
uted
tom
ogra
phy
Comp
uted
tom
ogra
phy
None
Comp
uted
tom
ogra
phy,
techn
etium
sc
annin
g
Comp
uted
tom
ogra
phy
Comp
uted
tom
ogra
phy
Ultra
sono
grap
hy,
com-
pu
ted
tomog
raph
y, tec
hneti
um
scan
ning
Comp
uted
tom
ogra
phy
Ultra
sono
grap
hy,
com-
pu
ted
tomog
raph
y, tec
hneti
um
scan
ning
Ultra
sono
grap
hy,
com-
pu
ted
tomog
raph
y Co
mput
ed
tomog
raph
y
Liver
, sp
leen:
Cand
ida
Liver
, sp
leen:
Cand
ida
NR
Livi;a
micro
absc
ess
with
Ca
n-
Liver
: ne
crotic
gr
anulo
mas
with
hy
phae
Liver
: ne
crotiz
ing
gran
uloma
s wi
th
hyph
ae
Liver
: he
aling
ab
sces
ses,
bud-
din
g ye
asts,
sp
leen:
budd
ing
yeas
ts wi
th
pseu
dohy
phae
Liv
er:
absc
ess
with
su
bacu
te inf
lamma
tion,
bu
dding
ye
asts
with
ps
eudo
hyph
ae
Liver
: mu
ltiple
absc
esse
s, bu
dding
ye
asts
with
ps
eudo
- hy
phae
Liv
er:
multip
le ab
sces
ses,
budd
ing
yeas
ts wi
th
pseu
do-
hyph
ae
Liver
: bu
dding
.yeas
ts
Liver
: ne
crotiz
ing
gran
uloma
s, bu
dding
ye
asts,
an
d hy
phae
for
ms
Liver
: pe
ripor
tal
inflam
matio
n;
splee
n: fu
ngal
forms
co
m-
patib
le wi
th
Cand
ida
Liver
: NR
; sp
leen:
hyph
ae
forms
an
d ye
asts
Liver
: ye
asts
and
hyph
ae
NR
Died
NR
Alive
Amp
B (N
R)
Amp-
B (N
R)
Died
Died
Amp
B (N
R),
keto-
Al
ive
(in-
cona
zole’
co
mplet
e re
solu-
tio
n of
absc
ess-
es)
Amp
B (N
R)
Alive
Amp
B (N
R)
Alive
Amp
B (N
R)
Alive
Amp
B (N
R)
Alive
Amp
B (N
R)
Alive
Amp
B (4
g),
5-FC
Died
Amp
B (4
g),
5-FC,
Di
ed
ketoc
onaz
ole
Amp
B (1
,926
mg),
Alive
5-F
C,
ketoc
ona-
zo
le Am
p B
(300
mg
), Di
ed
5-FC
Amp
B (5
g),
5-FC
Alive
s ch
emoth
erap
y Y 2
* AM
L =
acute
my
etoge
nous
leu
kemi
a;
ALL
= ac
ute
lymph
oblas
tic
leuke
mia;
AU
L =
acute
un
diffe
rent
iated
leu
kemi
a;
AA
= ap
lastic
an
emia;
DM
=
diabe
tes
mellit
us;
MD
= my
elo-
I
B pe
roxid
ase
defic
iency
; SL
E =
syste
mic
lupus
er
ythem
atosu
s. 5
t Am
p B
= am
phote
ricin
6; 5-F
C =
5-flu
ocyto
sine.
P t
C. t
ropic
alis.
Y
M NR
=
not
repo
rted.
?
HEPATIC CANDIDIASIS-HARON ET AL
clear leukocyte count below 0.5 X log/liter) immediately and symptoms of fungal infection after receiving remis- prior to the onset of symptoms of fungal infection. The sion induction chemotherapy. In 11 patients, the underly- mean duration of neutropenia was 33.3 days (range, 18 to ing disease was in remission, and in one, it was in relapse. 50 days). Fever despite broad-spectrum antibiotics was One patient had undergone bone marrow transplantation the most common finding, followed by hepatomegaly, shortly before becoming infected. Most patients had re- jaundice and right upper quadrant tenderness (Table II). ceived previous therapy with multiple antibiotics and mye- Splenomegaly was clinically detectable in only one pa- losuppressive agents and less frequently with steroids. As tient, who also had chronic myelogenous leukemia. The noted in our series, the clinical picture of patients de- biochemical, radiographic, and histopathologic findings as scribed in the literature was characterized by prolonged well as the culture results, treatment, and outcome in fever unresponsive to broad-spectrum antibiotics, right these five patients are summarized in Table Ill. The most upper quadrant or diffuse abdominal tenderness, and hepa consistent biochemical abnormality was an increased tomegaly. These as well as other clinical features are alkaline phosphatase level. Abnormalities in transami- summarized in Table II. It should be noted that the detailed nase and bilirubin levels were usually more subtle. Cam- clinical picture is not available for all patients [ 11,19], and ma glutamyl transferase levels were measured in only the numbers presented in Table II do not necessarily three patients, and they correlated with the increase in reflect accurately the real incidence of every sign and alkaline phosphatase levels. symptom in these patients.
In this limited series of patients, computed tomographic scanning of the abdomen was a very sensitive radiograph- ic method-superior to abdominal ultrasonography and technetium 99m sulfur colloid liver/spleen scanning. Fur- thermore, computed tomographic scanning was useful in four patients in following the efficacy of antifungal thera- PY.
Microbiologic studies demonstrated fungal colonization of the gastrointestinal tract in all patients. Blood cultures showed no fungal organisms, except in Patient 5. Cultures of liver tissue were performed in three patients, and despite histologic demonstration of yeasts in all, C. albi- cans was recovered in only one. Lung and spleen sam- ples were obtained for culture in Patients 1 and 4, respec- tively. C. albicans was isolated from the lung specimen, but the results of the spleen tissue culture were negative.
The most consistent biochemical abnormality was an increase in the alkaline phosphatase level. Increased transaminase, bilirubin and gamma glutamyl transferase levels were less pronounced and less frequent. Positive radiographic imaging results shown in Table IV refer to abnormalities demonstrated by these methods at some time during the Candida infection. Computed tomography was performed in 17 patients and gave positive results in 16. Ultrasonographic results were abnormal in 13 of 19 patients tested, technetium 99m sulfur colloid liver/ spleen scanning demonstrated abnormalities in 14 of 15 patients tested, and gallium 67 scanning gave abnormal results in nine of the 12 patients tested.
Histopathologic findings in these patients consisted of microabscesses with variable degrees of destruction of the hepatic parenchyma and the uniform presence of budding yeasts with or without the presence of pseudohy- phae. All patients had received systemic antifungal thera- py for a mean of 46.8 days (range, 2 1 to 87 days) before tissue was obtained for histopathologic examination. Reg- imens varied from single-agent therapy with amphotericin B to combination antifungal therapy with amphotericin B and 5fluorocytosine. Two patients with response to ther- apy continue to receive maintenance therapy with oral ketoconazole. One patient was still receiving amphoteri- tin B therapy (Patient 5) at the time this report was written. The duration of fever after the start of antifungal therapy varied from 16 days to nine months.
Although histopathologic examination of liver and/or spleen tissue demonstrated the presence of Candida or- ganisms in 29 patients, tissue cultures grew Candida species in only 15 specimens (12 patients). Candida species recovered from various sites in these patients included C. albicans (20), C. tropicalis (three), and C. stellatoidea (one), with the remaining nine cases either not specified (four), showing no growth (three), or not reported (two).
Despite the use of high doses of amphotericin B alone or in combination with 5-fluorocytosine, 11 patients (34.4 percent) died with evidence of active fungal disease, and two (6.25 percent) demonstrated an incomplete resolu- tion of hepatic candidiasis. Seventeen (53.1 percent) of the remaining patients had complete resolution of their infections, and two (6.25 percent) died of their underlying diseases.
Review of the Literature. Thirty-two patients with a diagnosis of hepatic or hepatosplenic candidiasis have been described in the literature and are presented in Table IV [6-201. Twenty-nine patients had acute leukemia, and three had other underlying diseases (one had aplastic anemia, one had diabetes mellitus, and one had systemic lupus erythematosus). Sixteen patients manifested signs
COMMENTS
Our five case reports confirm the clinical, biochemical, and radiographic features of hepatic candidiasis described by others [6,7]. It is well known that fungal infections affect predominantly the population of patients with he- matologic malignancies [ 11. With the exception of three, all the patients with hepatic candidiasis so far described in
24 July 1987 The American Journal of Medicine Volume 83
the literature, including the present series, had leukemia as the underlying disease. Recent data, however, suggest that episodes of fungemia are becoming more frequent in patients with lymphomas and solid tumors and less fre- quent in patients with leukemia [2]. Whether this will translate into an increase in the incidence of hepatic candidiasis in patients with lymphomas and solid tumors is impossible to predict.
An increasing incidence of liver involvement in dissem- inated candidiasis, as well as the antemortem recognition of hepatic candidiasis, has been suggested by recent reviews [4-71. In 1982, Lewis et al [6] reviewed 17 autopsy series of disseminated candidiasis in which 92 cases of hepatic involvement were identified, for a preva- lence ranging from 4.8 percent to 41 percent with a mean of 13.7 percent. De Gregorio et al [5] analysed 32 pa- tients with acute leukemia who died with disseminated fungal infection. Twenty-seven autopsies were per- formed, and 16 patients (59 percent) had liver involve- ment; 14 of the liver infections were due to Candida species. In 1984, Maksymiuk et al [4] reported on a series of 188 patients with candidiasis, 133 of whom had proved deep organ involvement. Fifty-two patients (39 percent) of the 133 patients with disseminated candidiasis had liver and/or gallbladder involvement.
The common characteristics of these patients that could be considered potential risk factors for this infection are: (1) recent treatment with myelosuppressive agents; (2) use of multiple broad-spectrum antibiotics in the pre- ceeding four weeks; (3) recent therapy with corticoste- roid$; (4) prolonged neutropenia (for two weeks or more); (5) colonization of the gastrointestinal tract with Candida organisms. The role played by central venous catheters is difficult to estimate. Three of our patients had a central line for at least two weeks prior to the development of hepatic candidiasis, but cultures of retrograde blood sam- ples and swab specimens from the line sites never grew Candida organisms. In other reports, the presence or absence of a central line is seldom mentioned. Candida fungemia is uncommon in these patients. Blood cultures grew Candida organisms in five patients in the literature and in one patient in our series.
The pathogenesis of hepatic candidiasis is not well understood. Hepatlc candidiasis could result from coloni- zation of the gastrointestinal tract with Candida [21], which locally disseminates following the onset of neutro- penia and mucosal damage. The observations of candide- mia and candiduria in a normal subject who drank a suspension containing a large amount of Candida [22] support the hypothesis that the gastrointestinal tract is the source of dissemination. Fungemia of the portal vein would result in hepatic seeding and the subsequent devel- opment of microabscesses in the liver [7].
Although a definite diagnosis is based on positive re- sults of tissue cultures or the demonstration of Candida
HEPATIC CANDIDIASIS-HARON ET AL
organisms in the liver and/or spleen, a presumptive diag- nosis can be made on the basis of clinical, biochemical, and radiographic findings, It has been suggested that computed tomographic scanning is the most sensitive imaging technique in the diagnosis of hepatic and spienic fungal abscesses [ 1 I]. Percutaneous liver biopsy and needle aspiration have been reported as accurate meth- ods for diagnosing the presence of Candida in the liver [6]. However, a review of the literature reveals that open liver biopsy was the chosen approach in the majority of cases. Twenty-one of the 22 biopsy specimens obtained at lapa- rotomy demonstrated Candida organisms in the liver and/ or spleen. Percutaneous liver biopsy was performed eight times and was diagnostic in five patients. Three patients underwent guided needle biopsy, one by ultrasound (diag- nostic) and two by laparoscopy (one diagnostic and one nondiagnostic). Interestingly, two patients in our current series and a third previously described patient seen at our institution with Rhodotorula liver abscesses [23] had non- diagnostic needle biopsy of the liver, and fungal involve- ment was demonstrated only on open liver biopsy. The lack of sensitivity of needle biopsy in these cases may be related to the small size of the tissue sample and relatively blind procedure even when it is carried out with ultra- sound, computed tomographic, or laparoscopic guidance. These data suggest that negative findings on percutane- ous liver biopsy do not rule out the diagnosis of hepatic candidiasis. We therefore recommend that, whenever possible, open liver biopsy should follow a nondiagnostic needle biopsy.
Early recognition and adequate treatment of hepatic candidiasis are important to the clinical outcome. Despite its toxicity, amphotericin B remains the cornerstone of treatment of invasive fungal infections. However, the mor- tality rate is still very high even with adequate treatment. The reason these patients do so poorly is not clear. One possible explanation for so many therapeutic failures could be inadequate levels of amphotericin B in the liver. However, an analysis of the concentration of amphoteri- tin B in tissues obtained at autopsy from patients who were receiving the drug during life demonstrated that the concentration of the drug was highest in the liver and spleen [23]. It is suggested that the lack of activity in these cases could be due to the limited availability of the drug in vivo because of binding by tissue membranes P41.
It has recently been shown that incorporation of am- photericin B in liposomes can markedly reduce its toxici- ty, with maintenance of its therapeutic effect against fungal infections [25]. The decreased toxicity may be related to alteration in the ability of amphotericin B to interact with mammalian cell membranes [25]. It has been demonstrated that liposome-encapsulated ampho- tericin B is more effective than free amphotericin B in the treatment of C. albicans infection in neutropenic mice
July 1987 The American Journal of Medicine Volume 83 25
HEPATIC CANDIDIASIS-HARON ET AL
[26]. A preliminary study (at the M. D. Anderson Hospital in Houston, Texas) of 12 patients with hematologic malig- nancies complicated by fungal infections and evidence of progression of the fungal disease despite the use of conventional amphotericin B suggested that liposome- encapsulated amphotericin B may be more effective and less toxic in the treatment of fungal infections in neutro- penic and non-neutropenic patients [27]. Preliminary re- sults in patients with hepatosplenic candidiasis are equally promising [28]. Similar results were obtained by Sculier and colleagues [29] in a recent pilot study at lnstitut Jules Bordet in Brussels, treating 11 cancer patients who had mycotic complications with amphotericin-B entrapped into sonicated liposomes.
5.
6.
7.
6.
9.
10.
11.
12.
13.
14.
15.
16.
26 July 1967 The American Journal Of Medicine Volume 63
In summary, hepatic candidiasis is being recognized as an increasing problem in immunocompromised patients. This may be attributed to a better understanding of its clinical and biochemical picture, as well as the use of more accurate diagnostic imaging techniques. Fungemia is rare in these patients. Definitive diagnosis by means of histopathologic examination and cultures of liver and/or spleen should always be attempted, but treament should not be delayed if the diagnosis is suspected on clinical grounds. The prognosis is usually poor, and mortality rates are still very high in patients treated with conventional amphotericin B. Liposome-encapsulated amphotericin B is a new, but promising, nontoxic treatment for invasive fungal diseases as indicated by preliminary studies.
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