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Programme for ultrasound diagnoses and treatment with albendazole of cystic

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Acta Tropica 117 (2011) 1–5
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Acta Tropica
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Programme for ultrasound diagnoses and treatment with albendazole of cystic
echinococcosis in asymptomatic carriers: 10 years of follow-up of cases
Edmundo Larrieua,∗, Mario Del Carpiob, Carlos Hugo Mercapideb, Juan Carlos Salvitti b,
Jose Sustercicb, Jorge Moguilenskyb, Héctor Panomarenkob, Leonardo Uchiumib,
Eduardo Herrerob, Gabriel Talmonb, Marcela Volpeb, Daniel Arayab, Gabriel Mujicab,
Sergio Mancinib, José Luis Labanchib, Martín Odriozolab
a Facultad de Ciencias Veterinarias de la Universidad Nacional de La Pampa, Argentina
b Ministerio de Salud, Provincia de Río Negro, Argentina

a r t i c l e i n f o
Article history:
Received 1 December 2009
Received in revised form 4 August 2010
Accepted 6 August 2010
Available online 9 September 2010
Keywords:
Cystic echinococcosis
Ultrasound
Albendazol
Follow-up

a b s t r a c t
Cystic echinococcosis is an endemic disease in the Province of Rio Negro, Argentina. Ultrasound surveys
carried out in 1984 found prevalence rates of 5.6% in children between 6 and 14 years of age.
Objective: To describe and to evaluate the results of the strategy applied in school children by hospital
services of the Province of Rio Negro with regard to diagnosis, treatment and monitoring of
cystic echinococcosis and to evaluate simultaneously the results of the control program against cystic
echinococcosis.
Materials and methods: In 1997 ultrasound was chosen to carry out population surveys and the medical
treatment criteria for the detected cases were standardized. The population under study involved 5745
students in the first survey and 22,793 in subsequent studies. The detected cases were classified according
to Gharbi’s scheme. A treatment algorithm was defined based only on monitoring (“watch and wait”),
albendazole, surgery (open or laparoscopic) or mini-invasive procedures, according to type, location and
size of the cyst. Information was also obtained on cases notified to the Health System between 1980 and
2008.
Results: In the first survey, 70 carriers (1.2%) were detected; of these, 25 started albendazole treatment
(35.7%) and only 3 (4.3%) underwent surgery. Ten years after treatment, 60.1% of 42 cases, presented
Types IV and V cysts and 14.5% presented total involution of their cysts. In subsequent studies, 87 (0.4%)
cases were detected, 49 of which started albendazole treatment (56.3%) and 9 underwent surgery (10.3%).
The incidence rate of cystic echinococcosis cases decreased from 38×100,000 in 1980 to 3.7×100,000
in 2008.
Discussion:Astrong decrease in cystic echinococcosiswasobtained although persistent levels of transmission
were maintained. The cases produced under these conditions are diagnosed by means of ultrasound
surveys and are treated using a plan based on albendazole and monitoring by the Health System during
a period of 10 years.
© 2010 Elsevier B.V. All rights reserved.
1. Introduction
Cystic echinococcosis, produced by Echinococcus granulosus, is
an endemic disease in the Province of Rio Negro in the south of
Argentina. In 1980, the number of cases in all age groups was
146 (population incidence rate 38×100,000) (Larrieu et al., 1986,
1993). The control program started, this same year, based on systematic
de-worming of dogs with praziquantel, slaughter control
and health education (Larrieu et al., 2000a; Craig and Larrieu, 2006).
∗ Corresponding author. Tel.: +54 2920 430007; fax: +54 2920 430007.
E-mail address: elarrieu@salud.rionegro.gov.ar (E. Larrieu).
From the beginning, the program included strategies to improve
patient prognosis through early detection and timely treatment,
especially in the young population (Larrieu et al., 1993, 2000a,b;
Frider et al., 1985, 1986). Between 1980 and 1996 it was carried out
through serological screening according to the available technology
(Larrieu et al., 2000a,b), using latex agglutination test, double
diffusion (DD5) and enzyme immunoassay, associated to further
diagnosis of location and early surgical treatment. This strategy led
to a marked decrease in surgical morbidity and mortality and to a
reduction of hospital stay (Larrieu et al., 2000a).
In 1984/85 the first ultrasound survey was carried out in the
Province, resulting in a rate of 5.6% asymptomatic hydatid cyst carriers,
in children of 6–14 years of age (Frider et al., 1985, 1986). Since
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2 E. Larrieu et al. / Acta Tropica 117 (2011) 1–5
1997 abdominal ultrasound scan has become the method of choice
for screening, using Gharbi’s classification (Gharbi et al., 1981). Different
factors support the choice of US as screening method in
abdominal hydatidosis: newly acquired knowledge of the natural
history of the disease (Frider et al., 1990, 1999; Larrieu et al., 2000b;
Larrieu and Frider, 2001), availability of equipment (portable US
scanner) for systematic ultrasound in rural areas and its greater
specificity and sensitivity in relation to serology (Frider et al., 1985,
1986; Mlika et al., 1986; Macpherson et al., 1987; Del Carpio et al.,
2000), highly accessible operative cost for health system and possibility
of hydatid cyst diagnosis in their main anatomic location
(Larrieu and Frider, 2001).
The US surveys for abdominal hydatidosis were carried out
every year in children between 6 and 14 years of age by general
physicians, working in rural hospitals, and trained in courses to
that effect such as FAST (focused abdominal sonography in trauma).
Albendazole was instituted as the first therapeutic treatment of
hepatic hydatid cysts, based on its documented possibilities and
advantages (Horton, 1989, 1997; Gil Grande et al., 1993; Nahmias
et al., 1994; Larrieu et al., 2004; Junghanss et al., 2008). Surgical
treatment or mini-invasive procedures were only applied in those
cases indicated by the location or the size of the cyst (Larrieu et al.,
2004).
These strategies are based on the recommendations by the
Medical Committee of Control Program Against Hydatidosis (established
by Decree 6412/06 of the Ministry of Health of the Province of
Río Negro), which led to Decree 3720/07 of the Ministry which set
the “Standards for Diagnosis and Treatment of Human Echinococcosis,”
updated by Decree 3541/09 of the Ministry. Its implementation
is mandatory throughout the province of Rio Negro.
Therefore, the aim of this study is to make an observational,
prospective and non-randomized study with patients treated
according to provincial standards, describing the strategy applied
in school children by the hospital services of the Province of Rio
Negro with regard to diagnosis, treatment and monitoring of cystic
echinococcosis, with special reference to the systematic use of
abdominal ultrasound in the field and treatment with albendazole
over the 1997–2009 periods. Likewise, our aim is to evaluate the
progress of the infection in those affected with regard to the control
strategies applied.
2. Materials and methods
The study comprises a total of 28,268 ultrasound surveys carried
out in children ages 6–14 attending schools in the endemic area of
the province of Rio Negro.
In 1997 and 1998 the first standardized ultrasound register was
carried out and published (Larrieu et al., 2004). This study included
5475 children between 6 and 14 years of age attending 94 rural
and urban elementary schools in the endemic area. Later on, in the
same age groups, and in schools in the same endemic area, 22,793
ultrasound surveys were carried out in children without previous
diagnosis of cystic echinococcosis corresponding to the following
periods: 4488 (2001/02), 6436 (2003/04), 6051 (2005/06) and 5818
(2007/08).
Cases involved children between 6 and 14 years of age who,
in the abdominal ultrasound register, showed images compatible
with hepatic hydatid cysts according to Gharbi classification
(Gharbi et al., 1981). The categories of this classification were subdivided
according to cyst size. Chest anteroposterior and lateral
radiographs were carried out in all cases.
Ageneral treatment algorithmwasdefined based on Gharbi type
and size of the cyst, and related to the vitality and aggressiveness
of the cyst (Gharbi et al., 1981): Type I up to 3 cm: observation only
and ultrasound monitoring (“watch and wait”, viable cystic but very
low expectancy of complication and usually slow growth); Type
I between 3 and up to 7–10 cm, chemotherapy with albendazol
(viable cysts with low potential for complications). Type II (transitional
cyst, usually fertile, rarely observed in natural evolution,
most frequently observed during treatment with albendazol in our
experience), up to 7–10cm in diameter: albendazol treatment was
started, and in cases of negative response, patients were re-treated
with a new course of treatment with albendazol exactly the same
as the first one, i.e. the same treatment is repeated twice. Type III
(aggressive cysts usually with high complication rate): most type III
cysts are surgical cases. Selected cases in children, with cysts less
than 5–7cm and under strict control, can be treated with albendazol.
In Type IV, observation and ultrasound monitoring without
treatment was carried out (“watch and wait”, most of this type of
cysts are not fertile); and Type V without routine monitoring and
without treatment irrespective of their size (cysts without parasite
activity or dead) (Fig. 1).
Albendazole was administered in a 10mg/kg/day dose during
120 days, together with ranitidine (300 mg/day) or omeprazole
(20 mg/day) to reduce problems associated with gastric intolerance
to the drug. Controls of: haemogram, urea, creatinin, coagulation
and hepatogram are performed prior to treatment and every 30
days. Albendazole tablets were supplied by the official laboratory
of the Health Ministry of the province of Rio Negro, at a cost of 0.10
US$ per 400mg tablet.
The following definitions were applied in the interpretation of
the results from the treatment:
Positive evolutionary changes: modification in ultrasonographic
images signalling hydatid cyst damage or aging, such asmembrane
detachment, decrease in size or calcification, modifications in the
structure and vitality of the cysts;
Total involution: disappearance of all ultrasonographic images
compatible with cystic echinococcosis;
Negative changes: modification in ultrasonographic images
indicative of hydatid cyst growth or appearance of clinical symptomatology
compatible with cystic echinococcosis (Larrieu et al.,
2004).
Surgery was prescribed in symptomatic cases and asymptomatic
carriers with cysts larger than 7–10cm in diameter or with
a dangerous location. All cases were followed using ultrasound
studies to verify qualitative and quantitative changes (modifications
in size and in the state of the membranes and content). These
studies were carried out 30 days after observation or after starting
treatment, then at 60 days and thereafter every 3 months until
completion of the first year of monitoring. In the second year, monitoring
was carried out every 6 months and as from the third year,
every year. In all cases, compliance with the examination and monitoring
was guaranteed by the provincial hospital network.
Group 1, which included cases detected during the first ultrasound
register, was followed initially over 4 years (Larrieu et al.,
2004). In this study, their rural homes were tracked and all possible
cases were monitored by ultrasound. Group 2, on the other hand,
included cases detected in subsequent surveys, and monitoring has
continued since diagnosis to date. A geographical reference of all
cases was obtained.
Likewise, information on all new cases of cystic echinococcosis
was obtained from the National Notification System (SINAVE) as in
Argentina it is compulsory to notify the appearance of symptomatic
cases of this disease.
3. Results
In the first study (Larrieu et al., 2004), 70 carriers (average 8.7
years of age) were detected (Group 1: screening prevalence rate
1.2%) with 85 hydatid cysts (84 hepatic).
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E. Larrieu et al. / Acta Tropica 117 (2011) 1–5 3
Fig. 1. General treatment algorithm, based on Gharbi type and size of the cyst. Río Negro, Argentina, 2008.
Initially 40 (57.1%) were put in the observation only protocol, 25
(35.7%) were treated with albendazole, 2 (2.9%) were subjected to
puncture, aspiration, injection and re-aspiration (PAIR) and 3 (4.3%)
had surgery (in all of this cases, albendazol was used as prophylactic
treatment).
The results of using albendazole after an average of 29 months
of monitoring showed that in 56% of the carriers treated with the
drug either a positive modification of the evolution of the cyst or a
total involution was observed; while in untreated cases (observation
only) a positive evolution was observed in 35.9%. These results
were not significantly different (p: 0.2) (Larrieu et al., 2004).
After 4 years of observation, the positive effect increased to
76.0% in carriers treated with the drug, while in untreated carriers
the positive effect was placed at 40.1%. These differences were
statistically significant (p: 0.00, OR 0.07, 95% CI 0.0–0.6) (Larrieu et
al., 2004). Spontaneous disappearance of the cysts was observed in
10 (14.5%) cases.
In the studies carried out in 2008 (10 years of monitoring) on
44 cases (55 cystic) of Group 1 no new hydatid cyst was diagnosed
(0%), while 3 (7.1%) required surgery. Of the total, only 6 (16.2%) of
the cysts remained Type I or II, without modifying their size, and 31
(83.8%) resulted in non-viable Type IV or V cysts (p: 0.00, OR 0.02,
95% CI 0.007–0.07). Total cyst involution was observed in 9 (20.9%)
of the cases.
Related to the type of treatment, in the observation only group,
at the beginning, 14 (87.6%) cases were cysts Type I or II, and 2
(12.6%) Type IV and V, while 10 years later the type of cysts were in
3 cases (18.8%) cysts Type I or II and in 8 (50.1%) Type IV or V. Total
cyst involution was observed in 4 cases (25.0%) and 1 (6.3%) was
surgically treated. 81% of cases (in cysts less than 3 cm) had positive
evolutionary changes and 6% negative changes. In patients treated
with albendazol, at the beginning 22 cases (88.0%) were cysts Type
I or II and no cases (0.0%) were Type IV and V, while 10 years later 2
cases (8.0%) were cysts Type I or II and 17 (68.0%) Type IV or V. Total
cyst involution was observed in 5 of the cases (20.0%) and 1 (4.0%)
was surgically treated; 92% of cases (cysts between 3 and 10 cm)
had positive evolutionary changes and 4% negative changes. These
results were not significantly different (p: 0.12) (Table 1).
In subsequent studies (Group 2), a total of 87 carriers (screening
incidence rate 0.4%) of 8.9 years of age were diagnosed with 94 cysts
(91 hepatic) corresponded to the 2001/02 period (0.4%), 36 to the
2003/04 period (0.6%), 20 to the 2005/06 period (0.3%) and 12 to
the 2007/08 period (0.1%) (Fig. 2).
In Group 2, 49 cases (average 8.9 years of age) entered in the
protocol of albendazole (56.3%) and 29 in the protocol of only observation
(watch and wait) (33.3%).
At the last control and with an average of 12.1 years of global
analysis of the Clinical Guidelines for the Diagnosis, Treatment of
Human Hydatidosis in the Province of Río Negrono new hydatid
cyst was diagnosed (0%), 9 of the cases (10.3%) were surgically
treated, based on the size of the cyst, its location, the symptoms
or its evolution (changes in the hydatid cyst growth or appearance
of clinical symptoms related to cystic echinococcosis). Of the rest
of the cases controlled, 23 of the cysts (42.6%) remained Type I or II,
without modifying their size and 4 (7.4%) are Type III and 27 (50.0%)
resulted in non-viable Type IV or V cysts, the differences with initial
diagnoses were statistically significant (p: 0.00, OR 0.09, 95%
CI 0.03–0.24). Total cyst involution was observed in 6 (8.7%) of the
cases.
Since the beginning of the standardized programme, a total of
157 cases were diagnosed and placed on the protocol (Table 2 and
Fig. 1).
In 2008, the total number of cystic echinococcosis cases notified
to the SINAVE of the Province of Rio Negro, for all age groups, was 33
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Table 1
Ten years of monitoring asymptomatic hydatid cyst carriers diagnosed in ultrasound surveys carried out in children between 6 and 14 years of age in the Province of Rio
Negro, Argentina, 2008.
Treatment Time Type cystic, no. (%) Total involution Surgery Total cases
I II III IV V
Observation Initial 13(81.3) 1(6.3) 0(0.0) 1(6.3) 1(6.3) 16(100)
10 years 2(12.5) 1(6.3) 0 (0.0) 3(18.8) 5(31.3) 4(25.0) 1(6.3)
Albendazol Initial 17(68.0) 5(20.0) 3(12.0) 0 (0.0) 0(0.0) 25(100)
10 years 0(0.0) 2(8.0) 0(0.0) 8(32.0) 9(36.0) 5(20.0) 1(4.0)
PAIR Initial 1(100) 1(100)
10 years 1(100)
Surgery Initial 1(50.0) 1(50.0) 2(100)
Total Initial 32(72.7) 7(15.9) 3(6.8) 1(2.3) 1(2.3) 9(21.4) 2(4.5) 44(100)
10 years 2(4.8) 3(7.1) 0(0.0) 11(26.2) 14(33.3) 3(7.1)
Fig. 2. Results of ultrasound surveys carried out in children between 6 and 14 years
of age in the Province of Rio Negro, Argentina, 1985–2008.
(population incidence rate 3.7×100,000), this being significantly
different (p: 0.00) from the 146 cases notified at the beginning of
the programme (population incidence rate 38×100,000).
4. Discussion
The control program was successful in reducing considerably
the number of cases of cystic echinococcosis in the population. This
can be verified both by the decrease in the population incidence
rate of the disease estimated by the number of new symptomatic
cases notified at the Health System (38×100,000 in 1980 vs.
3.7×100,000 in 2008) and by the percentage of asymptomatic
carriers detected in the ultrasound surveys in children between
6 and 14 years of age (screening prevalence rate 5.6% in 1984/85
vs. screening incidence rate 0.1% in 2007/08) and is consistent with
Table 2
Number, type and cyst localization in hydatid cyst carriers diagnosed in ultrasound
surveys carried out in children between 6 and 14 years of age in the Province of Rio
Negro, Argentina.
Group 1 Group 2
Studies 5475 22,793
Cases 70(1.3%) 87(0.4)
No. cysts 85(1.2/patients) 94(1.2/patients)
Large 1–6cm 68(79.3%) 67(71.3%)
7–>10cm 19(20.7%) 27(28.7%)
Type cysts Tipo I 55(64.7%) 76(80.0%)
Tipo II 15(17.7%) 8(8.9%)
Tipo III 7(8.2%) 4(4.4%)
Tipo IV 5(5.9%) 5(5.6%)
Tipo V 3(3.5%) 1(1.1%)
Localization Liver 84(98.8%) 91(96.8%)
Others Splen 1(1.2%)
Kidney 3(3.2%)
the significant decrease in prevalence in dogs and sheep that has
been reported in previous papers (Larrieu et al., 2000a; Perez et al.,
2006; Craig and Larrieu, 2006).
Thus the strategy applied, based on the systematic deworming
of dogs which was used in extensive rural areas with difficult
access, was efficient in limiting transmission to man. Nevertheless,
the control programme showed limitations regarding eradication
of the parasite from the environment, due to the above mentioned
geographical difficulties and to limitations in the infrastructure
required to de-worm 100% of the dogs every 45 days over a prolonged
(10–20) period of years (which is the only strategy possible
for successful elimination). This generates a certain number of new
cases in children every year.
The strategy used by the health services to solve this situation
was therefore based on carrying out massive annual programmes,
in urban and rural schools of endemic areas, to actively search for
cystic echinococcosis cases produced despite the existence of a
control programme. This was facilitated by the sensitivity, specificity
and low operative cost of ultrasound coupled with follow-up
monitoring strategies that make the most of the infrastructure of
rural health outposts and treatments based mainly on the use of
albendazole.
The specificity and sensitivity of the rural ultrasound screening
was determined in the Province of Río Negro by Del Carpio et al.
(2000) using CT scan, MRI and an ultrasound imaging made by a
radiologist of a tertiary referral center as the gold standard (with a
specificity 97% and sensitivity 100%). Other studies, however, have
indicated a lower sensitivity of ultrasound (Torgerson et al., 2009)
indicating that some early cases will also be missed by ultrasound.
The present study confirms the applicability and efficiency of the
US when used systematically in rural areas both for early detection
of cases and for surveillance.
The control program against cystic echinococcosis permitted
provision of timely medical attention for the cases detected in the
surveys. In addition it proved to be accessible for the health services,
preventively solved health problems and minimized additional
social costs and up-rooting of rural settlers by eliminating the need
for travelling to tertiary referral centers (usually located hundreds
of kilometres from the home of the patient) for surgical treatment.
With regard to the effects of albendazole, its use in treating cystic
echinococcosis was confirmed (Horton, 1989, 1997; Gil Grande
et al., 1993; Nahmias et al., 1994; Larrieu et al., 2004; Junghanss
et al., 2008). An increase in its effects was observed over time (in
children with cysts between 3 and 10 cm, 56% showed positive evolutionary
changes at 29 months, 68% at 44 months and 92% at 10
years). Therefore in individual cases, an extended monitoring over
time is required to precisely evaluate the effect of the drug on the
carrier before applying new treatments.
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E. Larrieu et al. / Acta Tropica 117 (2011) 1–5 5
The need to avoid surgical removal of a hydatid cyst in an asymptomatic
carrier, without prior confirmation of its speed of growth
and evolution (“watch and wait”), was also confirmed (Frider et
al., 1985, 1999; Larrieu et al., 2000b, 2004). Patients monitored by
watch and wait (cysts in children up to 3 cm) presented negative
evolutionary changes in 28.2% of cases at 44 months and only 6%
at 10 years, which would confirm that in a number of cases the
relationship host-parasite is to evolve quickly towards the onset of
symptoms, while in the majority of cases (81% in this study) the
relationship is stable, and these percentages are similar to the ones
notified by Frider et al. (1999).
Observation of 25% of total involution of hydatid cysts in 10
years confirmed previous reports: in Romig et al. (1986) observed
in Turkana, Kenya, at 12 months’ follow-up, 13.6% of cysts disappeared;
while Larrieu et al. (2004) observed 11.4% of cysts that
evolved into the disappearance of 4-year follow-up. This confirms
the need to verify the evolution of the parasite before indicating
surgical treatment. On the other hand, in this study, appearance
of new hydatid cysts in treated carriers or those being observation
only (“watch and wait”) was not verified. This fact leads to
an important difference with regard to operated cases, where reinfection
and/or recurrence of the disease in many cases lead to
a second surgery years later. The possibility that non-operated
treated cysts may act as immunization against future re-infections
or recurrences of the disease needs to be specifically evaluated in
future studies.
The strategies for diagnosis and treatment in this study for cystic
echinococcosis does not differ largely from the recommendations of
the informal group of the WHO-JWGE (Brunetti et al., 2010) including
the use of albendazol in cysts Type I and not treatment for cysts
Types IV and V. The “watch and wait”, raised originally by Frider et
al. (1985, 1986, 1999) and Larrieu et al. (1993) and applied in this
study in Type I cysts up to 3 cm, is not challenged in that consensus.
We recommend to apply this strategy for evaluation.
In relation to the frequency of case follow-up, the consensus
of experts (Brunetti and Junghanss, 2009) noted: “follow-up visits,
including US examination should be done every 3–6 months initially
and every year once the situation is stable”. This is widely
covered in the present work. Surgery, which had been previously
accepted as the treatment of choice, was only needed in 17 cases
(8 of Group 1 and 9 of Group 2; 10.8% of the diagnosed cases), a
fact which provides a drastic change with regard to the history of
cystic echinococcosis treatment and confirms promising reports on
the effectiveness of albendazole (Horton, 1989, 1997; Gil Grande et
al., 1993; Nahmias et al., 1994; Larrieu et al., 2004; Junghanss et
al., 2008; Brunetti and Junghanss, 2009). It also confirms the possibility
of applying “watch and wait” to small hepatic cysts in those
cases that allow ultrasonographic follow-up over time (Frider et al.,
1985, 1986, 1999; Larrieu et al., 1993, 2000b).
Recent published reviews and meta-analysis (Junghanss et al.,
2008; Brunetti and Junghanss, 2009; Brunetti et al., 2010) are concerned
with the need of more series of longitudinal studies to assess
more accurately the effect of albendazole and to take the decision to
“watch and wait” in asymptomatic patients. The application of Clinical
Guidelines for the Diagnosis, Treatment of Human Hydatidosis
in the Province of Río Negro, Argentina, and the follow-up every 4
years (Larrieu et al., 2004) and every 10 years (present work) are,
thus, a small contribution towards the knowledge of the natural
history of the disease and the evaluation of the best strategies for
diagnosis and treatment of asymptomatic echinococcosis.
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