![Figure 4. Left Surgical specimen from internal drainage and unroofing procedure in 1986 after a 43-year-old man presented with a 20 X 12 X 12-cm nonresectable hepatic lesion in 1974, for which he received mebendazole (3 g daily for 12 years [case 4]). The thin (2-3 mm) fibrotic wall of the abscess is held in the forceps. Right, the absence of residual matrix contrasts with the characteristic thick matrix of an untreated lesion (autopsy specimen, case 14).](/figures/figure-4-left-surgical-specimen-from-internal-drainage-and-2k0ielj3.webp)
![Figure 3. Left, PA chest roentgenogram taken in 1971 of a 58-year old Eskimo man with a massive hepatic lesion after 3,600 mL of fluid was aspirated from the lesion and air was injected. Note air-fluid level and elevated diaphragm. Right, flat plate of abdomen after instilling contrast medium (abscess measured 25 X 18 X 17 cm). (Reprinted with permission from 1 12]).](/figures/figure-3-left-pa-chest-roentgenogram-taken-in-1971-of-a-58-2dh9p0vs.webp)
University of Nebraska - Lincoln University of Nebraska - Lincoln
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Faculty Publications from the Harold W. Manter
Laboratory of Parasitology
Parasitology, Harold W. Manter Laboratory of
8-1992
Parasiticidal Effect of Chemotherapy in Alveolar Hydatid Disease: Parasiticidal Effect of Chemotherapy in Alveolar Hydatid Disease:
Review of Experience with Mebendazole and Albendazole in Review of Experience with Mebendazole and Albendazole in
Alaskan Eskimos Alaskan Eskimos
J. F. Wilson
Alaska Native Medical Center
Robert L. Rausch
University of Washington
, rausch@uw.edu
B. J. McMahon
United States Centers for Disease Control
P. M. Schantz
United States Centers for Disease Control
Follow this and additional works at: https://digitalcommons.unl.edu/parasitologyfacpubs
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Wilson, J. F.; Rausch, Robert L.; McMahon, B. J.; and Schantz, P. M., "Parasiticidal Effect of Chemotherapy
in Alveolar Hydatid Disease: Review of Experience with Mebendazole and Albendazole in Alaskan
Eskimos" (1992).
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234
Parasiticidal
Effect of Chemotherapy
in
Alveolar
Hydatid
Disease:
Review of
Experience with Mebendazole
and Albendazole
in
Alaskan Eskimos
J. F. Wilson,
R.
L.
Rausch,
B. J.
McMahon,
From
the
Departments of Surgery
and
Medicine,
Alaska Native Medical
and
P.
M.
Schantz
Center,
Anchorage,
Alaska; the
Department of Comparative
Medicine,
School
of Medicine, University of Washington, Seattle,
Washington;
and
the
Parasitic Disease Division, Centers
for Disease Control,
Atlanta, Georgia
Evidence that
the larval
stage
of
Echinococcus
multilocularis
in
humans
is
killed
by
chemother-
apy
is
presented
in
a review of
our
17-year experience
with treatment of alveolar
hydatid
disease
in
Alaska.
The
efficacy
of
chemotherapy
was
assessed
with
use of
an in
vivo
assay
of
parasite
viability by means
of inoculation
of
voles,
immunohistochemical
tests,
and
histopathologic
find-
ings.
Of
14
tests
performed
for nine
patients,
12 in vivo
assays (86%)
were
negative after
chemo-
therapy,
while
only
two
(17%)
of 12 vole tests
for seven untreated
patients
were
negative. Regres-
sion
or
arrest
of
growth
of metastatic and
primary
hepatic lesions, together
with
their
partial-to-complete
calcification and
prolonged
survival
times
has
been
observed among patients
treated with the benzimidazole
compounds.
For
six who
received appropriate chemotherapy,
treatment
has been discontinued
for an
average
of 4.6
years (range,
3-7
years)
without an
in-
crease
in
lesion
size or other evidence
of
reactivation.
Alveolar
hydatid
disease
(AHD),
caused
by the
larval
stage
of
the cestode
Echinococcus
multilocularis,
is
a
serious
health
problem
among
Eskimos
in northwestern
Alaska,
as
well as
in various
populations
in Eurasia. E.
multilocularis
is
indigenous
to
the arctic
tundra,
where
arctic
foxes
and
small
rodents
(voles
and
lemmings)
serve
as the final
and
interme-
diate
hosts. The disease
has an
extensive
distribution
in
the
northern
hemisphere,
but
in
North
America
most
autochtho-
nous cases
of
AHD
have
been
diagnosed
in
Eskimos
in
north-
western
Alaska.
Although
good
results
have
been
achieved
in
cases
of
resectable
lesions,
before
1986 8 1%
of
patients
in
Alaska
had nonresectable
lesions
at the
time
of
diagnosis.
In
a
report
of
1,41
1
operations
for AHD
performed
in the
Com-
monwealth
of Independent
States,
Zhuravlev [1]
also
found
the
resectability
rate
to be low ( 18%).
These findings
clearly
reflect
the need for
an alternate
method
of
treatment
of
AHD.
E.
mnultilocularis
was first
identified
in the
Western
Hemi-
sphere
on St. Lawrence Island,
Alaska,
in
1951
[2]
(a
few
earlier
cases
of AHD were diagnosed
retrospectively).
Thus
far 70 autochthonous
cases
of AHD have
been
diagnosed
in
North America,
and
all but
two have
occurred
among
Eski-
Received 5 February
1991;
revised
19 December
1991.
The use
of trade names
is for
identification only.
Financial
support:
This work
was
supported
in
part
by
the National
Insti-
tute
of
Allergy
and
Infectious
Disease
(Al
15172);
Smith
Kline
&
French
Laboratories;
and the Indian
Health Service,
U.S. Public Health
Service
(Research
Proposal
1980/90).
Reprints
or correspondence:
Dr.
J. F.
Wilson,
4821 Mills
Drive,
Anchor-
age,
Alaska
99508.
Clinical Infectious
Diseases
1992;15:234-49
? 1992
by
The
University
of
Chicago.
All
rights
reserved.
1058-4838/92/
1502-0003$02.O0
mos
from St. Lawrence Island
and from a
hyperendemic
area
on
the mainland of
northwestern
Alaska.
Clinical evaluations
of patients, surgeries,
and autopsies
were conducted at the
Alaska Native Medical
Center, which,
since its establishment
in
May 1953 in Anchorage,
has been
the location of the
patient-related work concerning
AHD.
This center is a facility
of
the U.S. Public Health
Service and
is the referring
institution for a broad-based
health delivery
system serving
the needs of all indigenous peoples
in Alaska.
The
organization
includes village clinics staffed
by trained
Native American health
aides and supported
by five small,
regional field hospitals.
Biological and epidemiological
in-
vestigations concerning
E.
multilocularis
were
initiated at the
Arctic Health Research
Center of the U.S.
Public Health
Service
in 1950 and later undertaken also at the Arctic Inves-
tigations Program
of the Centers
for
Disease Control
in An-
chorage. Consequently,
the
investigations
concerning
E.
multilocularis
and
AHD have
continued
without interrup-
tion for -40
years,
and some
of
the same
personnel
have
been involved
for all
or
most
of
that
period.
Aside
from
basic
biological studies,
major aspects
of
this study have
included
clinical
chemotherapy
trials and the
development
of screen-
ing and preventive
programs [3].
During
the
early
years
of this
experience,
most of
the
pa-
tients
with
AHD
were
admitted to
the
hospital
with an ab-
dominal mass
or
symptoms
related to the
primary hepatic
lesion.
For some
patients
the initial
diagnosis
was
made on
the basis
of a
positive
screening serology
with use
of the
indi-
rect hemagglutination
method.
In
1985 an improved serolog-
ical
technique
with
use of a
specific antigen
of
E. multilocu-
laris
was introduced
[4, 5];
and in
1988 field trials were
initiated in
which a
portable ultrasonography
(US)
unit was
used
for
screening
in
four
high-risk villages,
which resulted
in
CID
1992;
15 (August)
Chemotherapy for Alveolar
Hydatid Disease
235
the
diagnosis
of
four
active
cases at
an early
stage of
develop-
ment.
Another
result
of the
improved
method
of
screening
was
the identification
of patients
with a
number
of small,
calcified
hepatic
lesions
that
on further
study
were
found to
represent
lesions
in
which
the larval
cestode
had
died [6].
Five
of these lesions
were
resected
to confirm
the
diagnosis
and to permit
testing
for
viability.
Thus far,
26 such
cases
have
been
identified
and the
patients
received
a clinical
diag-
nosis of
inactive
AHD; in
12 cases
serologies
were
positive
and in
14
the diagnosis
was based
primarily
on the
results
of
computed
tomography
(CT)
or US
findings.
All such
inac-
tive
cases
are still under
investigation
and
will not
be consid-
ered
further
here.
The
44 locally
acquired
cases
of active
AHD
diagnosed
in
North America
form
the basis
for this
review.
After publication
of
the
report
of Heath
and Chevis
[7],
widespread
interest developed
in the use
of benzimidazole
compounds
for
the
treatment
of
hydatid
disease.
Clinical
trials of both
mebendazole and albendazole
have been con-
ducted;
however,
the results
have
been
inconsistent.
Some
authors
have
reported
a
poor
outcome with these
drugs
in
the
treatment
of
cystic
hydatid
disease [8-1
1],
while
others
have
obtained
more
optimistic
results with
regard
to
the
treatment
of
this condition
or
AHD
[
12-25].
The
purpose
of this
paper
is to review
in
detail our
17-year
experience
with chemother-
apy
for
AHD in
Alaska
and
to
present
the data
that have led
us to
conclude
that
E.
multilocularis
can be
eradicated
by
treatment
with
compounds
of
the benzimidazole
group.
Methods
The records
of all
44
patients
with active
AHD were re-
viewed. Tissues
were obtained
from 14
patients
on 26 occa-
sions
for
in
vivo
assays
for
viability.
Chemotherapy
has been
offered
to
all
patients
since
1974
(mebendazole
through
1984
and albendazole
since
1985).
Patients
scheduled
for
surgery
usually
received
two or
three
28-day
courses
of al-
bendazole
before resection
or
biopsy
of tissues
that were
to
be
tested
for
viability
was
performed.
After
a
diagnosis
of
AHD was
made and
clinical
and
laboratory
data
were re-
corded,
chemotherapy
was initiated
as
follows:
patients
re-
ceived
40
mg/(kg *
d)
of mebendazole
(microcrystalline
form
[Vermox],
Janssen,
Piscataway,
NJ)
in three doses
with
fatty
meals
[12-14,
26].
Albendazole
(Zentel),
supplied
as
200-
mg
tablets
by
Smith
Kline
& French
Laboratories
(Philadel-
phia),
was used with
the
approval
of the
U.S.
Food and
Drug
Administration
after
informed
consent
was obtained.
An
oral dose
of 400
mg
was
taken b.i.d.
with meals
according
to
a
protocol
in which
28-day
courses
of
therapy
are alternated
with
14-day drug-free
intervals
[27]
(for
convenience,
such
a
course,
although
consisting
of 28
days
of
therapy
given
dur-
ing
a
42-day period,
will be referred
to as
1
month
of chemo-
therapy).
The eficacy
of
chemotherapy
for AHD was assessed
by
a
combination
of methods
in
addition
to
clinical findings. An
in vivo test for viability of the larval cestode has been based
on the intraperitoneal inoculation of membranes from pa-
tients into red-backed voles (Clethrionomys rutilus [Roden-
tia:
Arvicolidae]). More recently, equally good results have
been obtained with northern voles (Microtus oeconomous)
and
Mongolian gerbils (Meriones unguiculatus) (the red-
backed and
northern voles are natural intermediate hosts of
E. multilocularis on St. Lawrence Island and in major regions
of
Europe and Asia endemic for AHD). We examined inocu-
lated
rodents 3-4 months postinoculation to determine re-
sults. The
proliferation of vesicles confirmed that the larval
cestode was viable.
Tissues for
bioassay were obtained by means of surgical or
needle
biopsy
on 14
occasions from nine individuals who
had received at least 2 years of therapy with mebendazole or
2
months
of
therapy with albendazole (table 1). These param-
eters
were based
empirically
on
results of
bioassays per-
formed
before 1985 (for all patients treated for >24 months,
with one exception, the results were negative) [26]. Since
vesicles of the larval cestode in host tissue remain infective
for >
1
week
when stored
under refrigeration, vesicles ob-
tained
at autopsy
2-3
days postmortem
were
suitable for
testing.
Untreated
patients
for
whom
in
vivo tests were
per-
formed
served as historical controls. Patients who
received
insufficient chemotherapy,
as defined
above,
are for
present
purposes described
as
undertreated.
Twelve
tests
were
per-
formed for
10
untreated or undertreated individuals.
The
reliability
of the
in
vivo test
depends
on whether
an
adequate quantity
of
membranes
from
the
patient's
tissues
has been obtained.
Material obtained
by
needle
biopsy
is the
least
reliable,
since
few,
if
any,
membranes
may
be
present.
In
contrast to
tissues
of
E.
multilocularis that are used for
maintaining
isolates
in the
laboratory,
also
transferred
by
intraperitoneal inoculation,
those obtained from
patients
are
difficult
to
quantify
for in vivo
tests.
Fully developed
larval
cestodes
from rodents consist of
a
dense
aggregation
of
mi-
crocysts
with abundant
protoscolices
and
little or
no
host
tissue.
Consequently,
uniform 0.
l-g samples
are
readily
ob-
tainable.
In
humans, however,
sterile vesicles
(lacking proto-
scolices)
that are
usually
of small size
are
dispersed
in
a dense
matrix
of
collagen
that
has
replaced hepatic
tissue.
In
collect-
ing
material
for
inoculation,
slices of
the
lesion are
examined
for
cavities
containing
membranes
(figure 1),
which are
translucent
and
often
folded
[28].
The
membranes are
re-
moved
by
means
of
fine-pointed forceps
and
placed
in
saline,
after
which
aliquots
are
prepared
for inoculation
into the
rodents
(three
rodents
were
routinely inoculated,
unless the
quantity
of
membranes
was
insufficient).
When
normally developed
larval
E.
multilocularis
consists
of
great
numbers
of
closely apposed,
interconnected
vesicles,
each
made
up
of an
external nonviable
layer,
the
laminated
membrane,
and an
internal
layer
of
germinal
tissue
from
which brood capsules and protoscolices arise. When found
236
Wilson
et al.
CID
1992;
15
(August)
Table
1.
Efficacy
of
chemotherapy
determined
by
in vivo
assay
of
parasite
viability
in
voles for
untreated and
treated patients
with
alveolar hydatid disease.
Results
of
assay
(no.
of
voles)
Date No.
of
No. of
Patient
Source
of tissue months of
No
negative
Treatment no.*
tissue obtained chemotherapy
Growth growth tests
(%)
Untreated 26 Resection
10/71
0 2
1
30 Resection
8/73
0 2
1
4
Surgical biopsy 11/74
0 1
2
wt
Resection 10/77 0 3 2
35
Surgical biopsy 11/80
0
0 2
38 Resection
6/84
0
2 0
51
Surgical biopsy 5/87 0 2
0
1
(14)
Undertreated
Mebendazole (<2 y)
5 Needle
biopsy 2/77
6
1
0
5
Surgical biopsy 2/77
6
1
1
34
Surgical biopsy 2/82
15 1 3
1
(10)
Albendazole
(<2 mo)
42
Surgical biopsy 10/85
1
0
2
42
Surgical biopsy 2/88
1
1
1
2
(17)
Treated
Mebendazole
(>2 y)
4
Needle
biopsy 11/78
48
1
1
1
Surgical biopsy 12/78
37
0 1
I
Surgical biopsy 2/80
62 0 3
34
Surgical biopsy 11/82
24
0 1
1
Autopsy 4/84
108
0
2
34
Autopsy 10/84
37
0
2
3
Autopsy 3/85
123
0 3
30
Autopsy 9/85
42
0 3
4
Surgical biopsy 11/86
143 0 2
35
Surgical biopsy -/86
72
0
2
35
Surgical biopsy 3/90
74
0 2
10
(91)
Albendazole
(>2 mo)
39
Surgical biopsy 5/85
2
0 2
42
Surgical biopsy 3/90
9
1 5
60
Surgical biopsy 5/91
3
1 2
11
(79)
NOTE.
For seven
untreated
patients,
seven tests were
performed;
for
nine undertreated
patients
who
received
mebendazole,
10 tests
were
performed;
for
10
undertreated
patients
who
received
albendazole,
12 tests were
performed;
for six treated
patients
who
received mebendazole,
11
tests were
performed;
and for nine
treated
patients
who
received
albendazole,
14 tests were
performed.
*
Patient
no.
corresponds
with that
in
text
[13].
t
Patient
from Wisconsin.
in humans,
however,
the
organism's
germinal layer
is
very
thin
and usually
not discernible
by light
microscopy.
In ac-
tive
lesions
of AHD,
all germinal
tissue
in
the peripheral
zone
of
proliferation
is
presumably
viable; it
is from
that
zone
that
surgical
and
needle
biopsy specimens
are
obtained.
Vesicles
in such
tissues
consist
of laminated
membrane,
pre-
sumably
with
a thin
layer
of
germinal
tissue
which,
when
inoculated
into
rodents,
undergoes
proliferation
and ulti-
mately produces protoscolices.
We
have routinely
inocu-
lated
10-1
5 small
vesicles, judged from experience to be
ade-
quate
for
producing
vesicles in an
individual rodent (figure
2).
The
minimal
number of cells required for proliferation
is
unknown,
but
Furuya
[29] determined that growth occurred
when
107
undifferentiated (germinal) cells from tissue cul-
tures were inoculated
into cotton rats (Sigmodon
hispidus).
The germinal
membrane in paraffin sections is stained
by
CID
1992;15
(August)
Chemotherapy
for Alveolar Hydatid
Disease
237
Figure
1. Cut
surface
of a
typical
lesion of
AHD
in the liver
(case
60).
Arrows
indicate cavities
filled by
membranes
of the
larval
E.
multilocularis.
The scale
bar has a
value of 5 mm.
means
of the
avidin-biotin
immunohistochemical
(ABC)
method
[30].
With
this
technique
active lesions
can
be
distin-
guished
from those
in
which the larval cestode has
died
spon-
taneously,
but
it
appears
to be
of
limited
value
in
assessing
the effect
of long-term
mebendazole
therapy.
In such
cases,
positive
staining
has been observed
for
scattered
vesicles
which,
as indicated
by other
evidence,
were
nonviable
[30].
It is often
difficult
to
determine
whether
the
larval
cestode
in lesions
is dead
or
alive when
it
is
assessed
by
means of the
usual histopathologic
methods.
The laminated membrane
may persist
even
in
totally
calcified
lesions
in
which the
lar-
val cestode
was evidently
nonviable
for
10-30
years
[6].
Nonetheless,
such membranes
in
decalcified
tissues
stain
strongly
when the
periodic
acid-Schiff
method
is
used
and
often
do not
differ
in
staining
characteristics
from mem-
branes
taken
from active
lesions.
The
presence
of the lami-
nated membrane
in nonactive
lesions
may
account
for a
per-
sistent
antibody
response.
Since
protoscolices
are
very
rarely
produced
in
humans
(they
were found
in
a metastatic
lesion
in the brain
in
only
one of
our
cases),
viability
cannot be
established on
the
basis of observation
of flame cells or
by
less
reliable methods
of
staining
[311.
Signs
of degenerative
changes
in
laminated
membranes
and the characteristics of
the cellular
response
are
useful
in
distinguishing
nonviable
vesicles.
Clinical
Experience
The effect
that
chemotherapy
has had on the clinical
course
of the disease
was
also evaluated.
Among
31
patients
for whom
the
diagnosis
was
made
before
1974,
six were
cured
with
surgical
resection
and two
underwent
incomplete
resections.
Twenty-three
patients
with nonresectable disease
initially
received no
chemotherapy.
Early
in this
experience
five
cases
were
excluded
from analysis
because clinical
data
were
insufficient
for assessment
(data
on
these
five cases
were
included
only
with
regard
to
survival).
Two cases
in
which
incomplete
resections
were
performed
and one
recent
case
(case
42 in which
severe
undertreatment
occurred
be-
cause
of
noncompliance
with
therapy)
are added
to
the
re-
maining
18 untreated cases to give
a total of 21
patients
who
had active
untreated or
undertreated lesions
and who
were
observed over
time. They
serve as
the
historical
controls
to
be compared
with 13
patients
who received
chemotherapy
(table 2). (Eleven
active
cases were diagnosed
after 1974
when chemotherapy
trials
were initiated;
of these, data from
three are
not
included
because
the
patients
died of
causes
unrelated to
AHD before
they
had received 2
years
of me-
bendazole therapy.)
Five
patients
in the untreated
group
eventually
received
chemotherapy (cases
1, 2, 3, 30, and
42),
and data from these cases
appear
in
both the treated and
untreated categories,
resulting
in
analysis
of 34
cases.
In this study the sizes
of untreated
hepatic lesions
were
largely
determined during
physical
examination by measur-
ing the palpable
liver edge
or hepatic mass
below the costal
margin. Before
1975 the only means
for
monitoring
the
prog-
ress of
lesions was
by physical
examination,
and thus it was
customary
for the
physician
to conduct thorough examina-
tions and to
record results at the time
of each clinic visit.
Most
of
the
examinations were
performed
by
one of the au-
thors over
the
period
of 1961 to
the
present.
Data from
physi-
cal examinations
represent,
in
nearly
all
cases,
the
average
measurements
derived
from
several
cases. Lesions of treated
cases
were more
precisely
monitored
by CT
and
US, imaging
techniques
not
previously
available. Overall
progression
was
assessed
by
measuring
the
change
in lesion size as deter-
mined
by
physical
examination or
imaging
methods
or
on
the basis of
extension of
disease,
the
development
of end-
stage
disease
or
metastases,
and other
clinical criteria.
a~~~
Figure
2.
Appearance
of vesicles of E. multilocularis
taken from
tissue shown
in
figure
1. The
quantity
shown
was sufficient
for
inoculating
three
voles and
inducing proliferation.
Each
space
has a
value of I
mm.