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Eur Respir J
1993, 6, 253-257
Treatment of hydatid disease in childhood with mebendazole
A. Go<_;:men,
M.F. Toppare, N. Kiper
Treatment of hydatid disease in childhood with mebendazole. A. Go~men, M.F.
Toppare, N. Kiper.
ABSTRACT: The general characteristics of 56 childhood cases of cystic hydatid
disease were analysed and the results of mebendazole therapy versus surgery
were verified. Pulmonary radiograms and ultrasonography were used in the
diagnosis. The cysts were localized primarily to the lungs.
Twenty seven patients were surgically-treated, with eight having recurrence
after a mean period of 3.6 yrs. Thirty patients received regular mebendazole
treatment, in a dose of 50 mg·kg·• with a mean duration of treatment of 11.7
months. Twenty one patients were cured and discontinued the therapy. Nine
still use the drug, seven of whom have had dramatic improvement, while the
other two have minimal radiographic changes but subjective improvement in
general condition. The lung cysts vanished leaving minimal scars, whilst the
liver cysts turned into inactive forms. The surgically-treated and drug-treated
groups were similar in age, duration and severity of the disease.
The recurrence rate of drug-treated children (1 out of 20) was lower than
that of the surgically-treated children (8 out of 27); however, this was not statistically significant.
Eur Respir J., 1993, 6, 253-257.
Hydatid cyst disease is known to be a dangerous
parasitic disease, endemic in countries where environmental sanitation is poor and cattle breeding is abundant [1, 2]. For a long time, the only available
treatment was surgery. The expensive and risky surgical interventions may result in anaphylaxis or be
complicated by recurrences years later. Operative
mortality is as high as 5% [3]. Consequently, the
need for treatment by drugs has emerged.
Mebendazole, which was proposed as an antiparasitic drug by BRUGMANS et al. [4] in 1971, was successfully used in human echinococcosis by HEATH and
CHEVIS [5], and by CAMPBELL et al. in 1974 [6]. During the last 10 yrs, medical treatment of hydatid cyst
disease had been on trial in many centres, with encouraging results that reported stabilization and/or regression of lesions [7-11].
Material and methods
In this study, the general characteristics of 56 patients, who applied to the Department of Pediatric
Chest Diseases, Hacettepe Children's Hospital, were
analysed. There were 5, 26, 18 and 7 children in the
0-5, 5-10, 10-15 and 15-18 yr age groups, respectively. Two children had only liver cysts, 43 had only
lung cysts, and 11 had lesions in both liver and lungs.
Twenty seven patients were surgically-treated and 30
patients used mebendazole regularly (fig. 1).
Dept of Pediatrics, Division of Pediatric
Chest Diseases, Hacettepe University
School of Medicine, Ankara, Turkey
Correspondence: A Go~men
Dept of Pediatrics
Hacettepe Children's Hospital
061 00 Ankara
Turkey
Keywords: Children
echinococcosis
hydatid cyst
mebendazole
surgery
Received: September 5 1991
Accepted after revision September 12
1992
~~
I
1
S-u-rge-ry-27-.
.-1
Mebndz initially 28
r - - -- - ,
I '\
I
cured
18
died
3.6 yrs
1 recurrence 8
+ 28= 36
Excluded (irregular or lost)
6
7-24 months
4-23 months
Treatment completed
21
IStill on treatment 91
/
'\
I \
cured 20
Improved(+)
2
lost afterwards 1
I~
16-50 months
Healthy
19
Improved(++)
7
8 months
recurrence
Fig. I . - Flowchart of treatment and follow-up.
mebendazole.
Mebndz:
254
A GOt;:MEN, M. TOPPARE, N. KIPER
The patients were questioned about close contact
with dogs, if they had had previous hydatid cyst surgery, and whether their residences were urban. All patients had chest X-rays, abdominal ultrasonography and
hepatic function tests. Patients were given mebendazole, 50 mg·kg- 1 in three divided doses to be
taken with fatty meals. The mean duration of symptoms, the number and diameter of the cysts, were
noted for each child. The patients were examined
every three months and drug therapy was halted when
clinical and radiological cure was achieved. Patients
were followed-up regularly at appropriate intervals.
At follow-up of the patients with hepatic hydatid
cysts, ultrasonography was used. As it was reported
that treated hepatic hydatid cysts do not usually disappear, cases of shrinkage and filling of cysts with cellular debris and/or calcification, were regarded as
inactive (dead) cysts. All of the patients had a complete blood count and hepatic function tests within one
to six months (mean 3.2 months) after starting the
drug.
Statistical analysis
Mann-Whitney U-test was used in comparing the
diameters of lung and liver cysts. Fisher exact chisquare test was used to analyse the significance of
recurrence rates of surgically-treated and drug-treated
patients. Mann-Whitney U-test was used to compare
the mean duration of drug therapy for pulmonary and
hepatic cysts, and to analyse the difference of mean
cyst diameter per child, mean duration of symptoms,
and mean age in the patients treated with or without
drug therapy. Chi-square was used in comparing the
number of cysts in the two groups.
Results
The overall age distribution of the 56 patients revealed that the predominant age group was the 5-10
yr olds, followed by the 10-15 yr group. The mean
age was 9 yrs. All of the patients were under 18 yrs
of age. Thirty five were from non-urban settlements.
Cough (57%) and fever (38%) were the predominant
symptoms (table 1). In 26 of the patients (46%) there
was a history of close contact with dogs. In majority
of the patients physical examination was within normal limits; however, 16 (29%) had diminished breath
sounds and/or tubular breath sounds, five had sonorous
rhonchi-fine rales, five had hepatomegaly, five had
dyspnoea and tachypnoea, and three had signs of
accompanying disease. Two of the patients had neurological deficit due to intracranial cysts.
With the exception of one patient who did not
receive mebendazole, all patients had normal hepatic
function tests. The predominant appearance in pulmonary radiograms was an homogeneous ellipsoidal density in the right lung (table 2). Specific appearances,
such as water lily sign (the cyst membrane floating in
cyst fluid), and setting sun sign (partial appearance of
the cyst on the diaphragm) were relatively rare. Seventy seven cysts were counted in 56 patients.
Table 1. -
Symptoms of the 56 patients
Cough
Fever
Haemoptysis
Chest pain
Expectoration of cyst contents
Weight loss
No symptoms related to cyst
Neurological deficit
Others
(Abdominal pain, headache, etc).
32
21
10
8
6
6
5
2
5
Table 2. - Characteristics of pulmonary radiograms
from 56 patients
L lung
Homogeneous
ellipsoidal
Pleural sign
Air - fluid
levels
Water lily
sign
Setting sun
sign
Normal
radiograms
Total
R lung
Bilateral
Total (%)
13
1
4
14
1
5
6
0
2
33 (59)
2 (4)
11 (19)
2
3
0
5 (9)
2
0
3 (5)
2 (4)
21
25
8
56
(%): % of 56 patients.
Two patients had liver cysts only, 43 had lung cysts
only, while 11 children had lesions in both organs. In
the latter group, two had cerebral and two had splenic
cysts. Cyst diameters in the lungs ranged from 1-18
cm (mean 5.7 cm), and in the liver from 1-8 cm
(mean 5.6 cm), with no significant differences in the
mean diameters.
Twenty seven patients were surgically-treated. Eight
of these patients had recurrences at 8 months to 7 yrs
after surgery (fig. 1). These eight patients were later
given mebendazole. Twenty eight patients were given
only mebendazole treatment. One patient had a history of expectoration of cyst contents and chest X-ray
revealed a perforated cyst. After two years, in which
he could not be followed, he was seen again, on this
occasion chest X-ray was clear and he was presumed
to have had a spontaneous recovery.
Since 1982, a total of 36 patients were give mebendazole, 30 of them receiving the drug in appropriate dosage and duration. Twenty one of these
patients completed the therapy and the drug was
stopped.
Mean duration of drug usage was 11.7
months (range 7-24 months). Nine patients are still
receiving the drug. While seven had dramatic reduction in cyst size, in two patients only minimal changes
were observed. However, these two stated subjective
improvement. The 20 patients who completed the
MEBENDAZOLE IN CHILDHOOD HYDATID DISEASE
therapy were followed for between 16-50 months
(mean 29.9 months). One patient was lost to followup after obtaining a cure of an hepatic cyst. One patient who had regularly used mebendazole for 11
months and was thought to be cured, had recurrence
after an interval of 6 months; after using the drug for
an additional seven months the residual cyst vanished.
A
255
The 27 surgically-treated children were comparable
to the second group of 30 children who used mebendazole regularly: a) mean age 8.3 versus 8.8 yrs
(p>0.05); b) duration of symptoms 2.4 versus 2.2
months (p>0.05); and c) mean cyst diameters 5.8 versus 5.6 cm (p>0.05). The number of cysts (40 versus 39 (p>0.05)) was also similar in the two groups.
However, in the surgically-treated group two patients
had both intracranial and intrahepatic cysts, and one
of them died after successive operations.
All of the patients except one had nearly clear chest
radiograms with a minimal fibrotic band when drug,
treatment was over. The first radiological changes
were evident 15-20 days after starting the drug and
somewhat earlier in perforated cysts (fig. 2). In
13 out of 23 patients with isolated lung cysts, therapy
was completed with a mean drug usage of 11.2
months (range 4-24 months). In ultrasonographic
follow-up of hepatic cysts, it was noted that in
one patient the cyst vanished with a residual
fibrotic scar, and in seven cysts were filled with cellular debris and became ecogenic (inactive) (fig. 3).
c
Fig. 2. - Serial chest radiograms of a case:
A) before treatment; B) three months later; C) after completion of the treatment with mebendazole .
Fig. 3. - A) first hepatic sonogram;
the treatment with mebendazole .
B)
after completion of
256
A GO!;:MEN, M. TOPPARE, N. KIPER
Two inactive cysts had calcifications. Patients with
liver cysts used the drug for an average of 11.8
months (range 8-18 months). No significant difference in the mean time of cure was observed between
lung and liver cysts (p>0.05). The recurrence rate of
hydatid cyst in children treated with mebendazole was
lower than the group treated surgically, although this
difference did not reach a statistically significant level,
1 out of 2 versus 8 out of 27 (p>0.05).
During the therapy, no patient experienced leucopenia or deterioration of hepatic function and no case
of alopecia, urticaria or anaphylaxis was encountered.
Three children had haemoptysis after 2-6 months of
drug therapy; one of them necessitating admission to
the hospital but needed only supportive measures.
Discussion
In hydatid disease surgical treatment carries a high
recurrence rate. WILSON et al. [12] reported that recurrence after surgery of pulmonary cysts may be even
higher. With successive operations, the mortality rate
could be as high as 20% [13]. As the potential dangers of surgical interventions and possible organ
resections are evident with a growing organism, it is
vital to have a non-surgical treatment for this disease
in children. The report of OzTASKENT and AMATO [14]
showed that 32% of the patients are under 20 yrs and
the disease is also significant in childhood.
The epidemiological data in our study are in accordance with the literature in age distribution, symptoms
and physical findings of childhood patients [15, 16] .
In agreement with our results, several reports indicate
that the main localisation in children is in the lungs
[15, 17, 18]. The possible reason for this is that in
children oncospheres are carried through the periduodenal and perigastric lymphatics to mediastinal vessels and through the thoracic duct to the lungs [19].
They are mostly in the right lung. Our finding of
accompanying liver cysts in approximately one fifth of
pulmonary lesions is also in accordance with the classical knowledge [20].
It was surprising that, after an average period of 3.6
yrs, about one third of the surgically-treated patients
had recurrences. In adult series, recurrence rate is
reported to be 1-14% [3, 21, 22]. In the conditions
existing in Turkey, hydatid cyst operations are common and surgical experience is adequate. Therefore,
rather than inadequacy of surgical interventions it
should be considered that the actual recurrence rate
may be higher in children, or that small cysts may be
unnoticed at the time of operation.
There has not been a general agreement on the dosage and duration of mebendazole treatment. W ANGOO
et al. [23] claimed 200 mg·kg-1 dosage to be most
effective in mice, however, comparative studies in
human beings are required. At this dosage gastrointestinal side-effects may occur. Fatty meals enhance
absorption of the drug and raise plasma levels [24],
therefore, patients are advised to ingest mebendazole
with fatty meals. Side-effects and complications, such
as neutropenia, alopecia, hepatotoxicity and fungal
superinfections, have been reported in the adult series
but were not encountered in our patients. This indicates that the daily dose of 50 mg·kg- 1 is safe in
childhood [8, 13, 25].
Duration of treatment in our patients was generally
longer than in the adult series. BEKHTI et al. [7], who
were among the first users of mebendazole, reported
that 30 days of treatment resulted in the loss of vitality of cysts which then regressed completely within 413 months. KAYSER [8] gave mebendazole to his
patients for less than three months. KAMMERER and
ScHANTZ [26] used a six week high dose, followed by
a three month low dose regimen, while KARPATHIOS et
al. [27] gave the drug for 10-12 weeks, and BRYCESON
et al. [9] continued treatment for 4-11 months in inoperable patients. MEssARITAKIS et al. [28] reported the
effectiveness of high dose and short course mebendazole therapy in children with hydatid disease. In our
series, the duration of treatment varied between 7 and
24 months, with a mean of 12 months. This may be
due to failure of parents to give the drug to the child
regularly, or to rapid microsomal inactivation in childhood. RoMIG et al. [29] found that the rate of cyst
growth is faster in the 5-15 yr age group than in other
age groups. This may explain, in part, the long duration of drug treatment. Even in patients with minimal radiographic changes , drug therapy was
accompanied by improvement in general condition and
disappearance of complaints of anorexia and malaise.
Although the treatment period for isolated lung cysts
was somewhat shorter than that of liver cysts, the
difference was not significant. The lung cysts all vanished leaving a minimal fibrotic density, in one patient,
while liver cysts tended to transform from a cystic
structure to a homogeneous one, by filling with cellular debris. This observation was also reported by
BRENDIMARTE et al. [30] and SJNGCHAROEN et al. [31,]
who demonstrated, by histopathological methods , that
the cysts were non-vital. The reason why hepatic
cysts persist, even though inactive, was poorly understood. RICHARDS et al. [32] demonstrated that pulmonary cysts had some structural differences from
hepatic cysts. The high macrophage activity in lung
tissue may also contribute to the process.
Many researchers feel that objective criteria that indicate the success or failure of the treatment in a definite period [9, 33] are lacking. All paediatric patients,
except those with intracranially or paraspinally localised cysts, are recommended to have mebendazole
therapy lasting for 9- 18 months, including those
patients who showed striking objective improvement at
the beginning of the therapy. This long duration of
drug therapy seems to be a prerequisite for precluding recurrences that may occur up to 7 yrs later [34,
35]. Mebendazole is the drug of choice for treatment
in children, due to its lack of side-effects, the low risk
of recurrence, and the fact that all of the patients benefited from the therapy, with the majority eventually
obtaining a cure.
MEBENDAZOLE IN CHILDHOOD HYDATID DISEASE
Acknowledgement: The authors are indebted to E.
Berglund for his meticulous and invaluable comments in
preparation of this paper.
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