Acta Tropica 189 (2019) 6–9

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Acta Tropica
journal homepage: www.elsevier.com/locate/actatropica

Progress towards international adoption of the World Health Organization T

ultrasound classification of cystic echinococcosis
⁎
E. Mirabilea,1, N. Solomona,c,1, P.J. Fieldsa,b,c,1, C.N.L. Macphersona,b,c,
a
School of Medicine, St. George’s University, Grenada
b
School of Veterinary Medicine, St. George’s University, Grenada
c
Windward Islands Research and Education Foundation, Grenada

A R T I C LE I N FO A B S T R A C T

Keywords: Cystic echinococcosis (CE) is a global parasitic zoonosis for which ultrasound (US) is the gold standard modality
Cystic echinococcosis for diagnosis. In 2003, the WHO published a standardized US classification of CE, on which WHO treatment
Ultrasound guidelines are based. In 2014, global adoption of the classification was questioned by a publication which
Classification indicated that, between 2004 and 2014, only half of studies utilizing a classification used the WHO classification.
More recent studies have demonstrated that the WHO classification best reflects the natural history of CE, and is
used with high reliability by experts in the field; despite these attributes, the classification’s impact is ultimately
limited by the extent of its adoption. A PubMed search using the terms “Echinococcus granulosus ultrasound,”
“Echinococcus granulosus classification,” “cystic echinococcosis ultrasound,” and “cystic echinococcosus clas-
sification” revealed publications on human CE utilizing a US classification. Classification(s) used, year of pub-
lication, and the country of the first author’s institution were recorded. From 2004 to 2010, the WHO classifi-
cation was used in 50% or fewer of included publications for 6 of the 7 years. After 2011, it appeared in a low of
75% (2013) to a high of 96% (2017) of included publications. Of all included studies published from 2004 to
2017, the WHO classification was referenced in 18% (3 of 17) from Africa, 64% (32 of 50) from Asia, 79% (89 of
113) from Europe, 89% (8 of 9) from North America, and 100% (9 of 9) from South America. Findings suggest
that the WHO classification has been progressively taking preference to other classifications, with rate of
adoption depending on continent of origin of the research. Residual use of the classification developed by Dr.
Hassen Gharbi of Tunisia in 1982, used widely prior to development of the WHO classification (which reversed
two stages in Gharbi’s classification in order to more closely reflect the natural history of CE) suggests that
adoption of a new classification takes time and varies regionally.

1. Introduction There is currently no standard, highly sensitive and specific ser-

Cystic echinococcosis (CE) is a chronic, complex zoonotic disease
resulting from infection with the cestode Echinococcus granulosus
(Symeonidis et al., 2013; Thompson and McManus, 2001). Infection
occurs when humans accidentally ingest E. granulosus eggs, which hatch
into oncospheres and enter the portal circulation via the gastro-
intestinal tract. Oncospheres develop into cysts within the organs and
body tissues, particularly in the liver and lungs (Symeonidis et al.,
2013; Thompson and McManus, 2001; Kern, 2003). In regions where
CE is endemic, 60–75% of patients are asymptomatic (Belard et al.,
2015); but the disease can be complicated if cysts become secondarily
infected, rupture, or impinge on surrounding structures (Pawłowski
et al., 2001).
ological test for CE antibody detection (Pawłowski et al., 2001). Factors
like the high rate of false-negatives, high expense of materials and re-
agents, long processing time, invasive nature of the tests, and ease of
test contamination outside of the laboratory make serology not im-
possible, but difficult to use in field settings (Pawłowski et al., 2001;
Macpherson and Milner, 2003; Macpherson et al., 1987). A 1987 study
on patients with CE in Turkana, Kenya, found ultrasound (US) data
superior to serological data, which identified only 50% of patients with
cysts and could not provide information regarding cyst location, size, or
condition (Macpherson et al., 1987). Serology also cannot be used to
monitor changes in cysts.
US has been used to detect a variety of pathologies, including
parasitic infections, since the 1970s, with the use of portable US

⁎
Corresponding author at: St. George’s University School of Medicine, P.O. Box 7, St. George, Grenada.
E-mail addresses: emirabil@sgu.edu (E. Mirabile), nsolomon@sgu.edu (N. Solomon), pfields@sgu.edu (P.J. Fields), cmacpherson@sgu.edu (C.N.L. Macpherson).
1
St. George’s University, P.O. Box 7, St. George, Grenada.

https://doi.org/10.1016/j.actatropica.2018.09.024
Received 19 August 2018; Accepted 25 September 2018
Available online 27 September 2018
0001-706X/ © 2018 Published by Elsevier B.V.
E. Mirabile et al. Acta Tropica 189 (2019) 6–9

scanners in rural communities starting in 1980s. The advent of portable Table 1

US screening has allowed for more effective mass surveillance and Utilization of the Gharbi classification, WHO classification, a combination, and
evaluation of CE prevalence among asymptomatic human populations others.
(Macpherson et al., 1987; Macpherson, 1992; Solomon et al., 2017a). Publications by Classification(s) Utilized
With high sensitivity (88–98%) and specificity (95–100%) for CE, US
can be used to quickly and easily visualize clear pathognomonic signs of Classification Frequency Percent
the disease (Pawłowski et al., 2001; Macpherson et al., 1987; WHO-
Gharbi 51 25.8
IWGE, 2003), and because is painless and non-invasive US is accepted WHO 130 65.7
by populations in field settings. Gharbi & WHO 11 5.6
The complexity of CE led to the development of numerous classifi- Gharbi & Other 1 0.5
Other 5 2.5
cations, the first of which was a US classification developed by Gharbi
Total 198 100.0
in 1981, which was followed by approximately 30 other classifications
for clinical or epidemiological natural history purposes (WHO-IWGE,
2003). This confusing situation led in 1994 to the World Health Or- Table 2
ganization Informal Working Group on Echinococcosis (WHO-IWGE) US classification utilization by year.
proposing the development of a WHO standardized US classification
Publications by Year
which was agreed upon in 2003 (WHO-IWGE, 2003) and updated in
2010 (Brunetti et al., 2010). Since then, studies on the WHO classifi- Year Frequency Percent
cation have revealed that it both reflects disease natural history, and
can be used by experts in US and CE to reliably classify cysts (Solomon 2004 2 1.0
2005 9 4.5
et al., 2017b, c), findings which support and promote adoption of the
2006 4 2.0
classification by clinicians and researchers working in the field. 2007 11 5.6
A 2014 study evaluating the acceptance of the WHO classification 2008 15 7.6
reviewed papers published from January 1, 2004 through April 30, 2009 7 3.5
2014, and found that, of those utilizing a US classification, 48.8% uti- 2010 15 7.6
2011 16 8.1
lized the WHO-IWGE classification, 47.9% utilized the Gharbi classifi- 2012 28 14.1
cation, and 3.3% utilizing other classifications altogether (Tamarozzi 2013 16 8.1
et al., 2014). 2014 19 9.6
Because the WHO classification has been demonstrated to more 2015 15 7.6
2016 18 9.1
accurately reflect disease natural history than other classifications and
2017 23 11.6
treatment guidelines for CE are based on the WHO system, appropriate Total 198 100.0
and effective treatment relies on the proper application of the WHO
classification by clinicians (Brunetti et al., 2010). This study builds
upon the previous study evaluating international classification use in To demonstrate classification use over time, the percentage of pa-
order to determine whether WHO classification usage has increased pers utilizing each classification (or combinations) each year were
since publication of the prior study, and to identify factors which may graphed (Fig. 1).
be preventing its universal adoption around the world. This data was further evaluated to show classification usage by lo-
cation (specifically, by continent) since the WHO classification was
2. Materials and methods published (Fig. 2).

This study represents a combined secondary evaluation of a data set

from a previous study (Tamarozzi et al., 2014), with the addition of
papers published after the previous study’s publication, through No-
vember 30, 2017. Publications utilizing a US classification to stage CE
were collected in order to analyze classification usage over time and on
different continents. A PubMed (MEDLINE) search was conducted,
using the search terms “echinococcus granulosus ultrasound,” “echi-
nococcus granulosus classification,” “cystic echinococcosis ultrasound,”
and “cystic echinococcosus classification” in order to identify studies
utilizing US and a US classification. Publications focusing on E. granu-
losus infection and utilizing a US classification were included in the data
set, as long as use of a classification and classification type could be
identified within an available abstract or full text (regardless of lan-
guage). Studies on other Echinococcus species and animal studies were
excluded. Classification(s) used, year of publication, and country of the
institution with which the first author was affiliated were recorded.
3. Results
A PubMed search resulted in a data set composed of 198 articles,
published between January 1, 2004 and November 30, 2017.
Evaluation of these 198 articles revealed use of the WHO classification,
the Gharbi classification, a combination of these, and others (Table 1).
The number of articles published each year since 2004 was then
tabulated (Table 2), followed by an assessment of where the articles
originated based on country of first authorship (Table 3).
4. Discussion
Part of the intrigue surrounding CE is the significant variability in
its presentation, and the WHO standardized US classification was de-
veloped to address this variability by reflecting disease natural history
and allowing for standardization of treatment decisions so that the
disease can be most effectively eradicated from affected persons
(Brunetti et al., 2010; Solomon et al., 2017c). According to the WHO
standardized US classification of CE, there are seven cystic stages of the
disease, with each class demonstrating its own distinguishing char-
acteristics. The earliest presumed stage is a cystic lesion (CL), an un-
differentiated simple cyst: thought to be an early, simple cyst, it is
considered active with the potential to grow and develop (WHO-IWGE,
2003). US characteristics of CE1, CE2, and CE3 cysts are pathogno-
monic for infection with E. granulosus. Active stages of CE include CE1
and CE2, which are usually fertile, containing viable protoscoleces
(WHO-IWGE, 2003). CE1 cysts are unilocular, whereas CE2 cysts are
either septated or contain daughter cysts (WHO-IWGE, 2003). CE3 cysts
are transitional: CE3A cysts demonstrate laminated membrane de-
tachment from the cyst wall, and CE3B cysts contain a mixture of intact
and ruptured daughter cysts in a matrix of solid, degenerated materials
(WHO-IWGE, 2003). CE4 and CE5 cysts predominantly contain de-
generated materials and are considered inactive and infertile (WHO-
IWGE, 2003; Gil-Grande et al., 1993).
Given that these disease stages suggest varying levels of parasitic

7
E. Mirabile et al. Acta Tropica 189 (2019) 6–9

Table 3 CE3A cysts. For CE4 and CE5 cysts, the “wait and watch” approach is
US classification utilization by country. recommended (Brunetti et al., 2010). Pharmacological treatment al-
Publications by Country of First Author’s Affiliated Institution ready operates at relatively low success rates and becomes even less
successful as cysts become more complex; as such, providing che-
Country Frequency Percent motherapy in an inappropriate stage of disease further reduces treat-
ment efficacy (Brunetti et al., 2010; Gil-Grande et al., 1993).
Argentina 5 2.5
Austria 1 0.5 Because of the dependence of parasite eradication on proper diag-
Bangladesh 1 0.5 nosis and staging, international adoption of the WHO classification is
Bulgaria 2 1.0 vital for establishing best clinical practices and optimizing patient care.
China 19 9.6 Despite initial concerns that the WHO classification would not super-
Denmark 1 0.5
sede Gharbi’s, present observations suggest that the WHO classification
Finland 1 0.5
France 1 0.5 has been progressively taking preference. From 2004 through 2011,
Germany 16 8.1 Gharbi’s classification appeared to predominate; the past six years,
Grenada 4 2.0 however, have reflected a very different situation. From 2004 to 2010,
India 14 7.1
the WHO classification was used in 50% or fewer of included publica-
Iran 4 2.0
Italy 31 15.7
tions for 6 of the 7 years. After 2011, it appeared in a low of 75% (2013)
Japan 4 2.0 to a high of 96% (2017) of included publications. Of all included studies
Kenya 1 0.5 published from 2004 to 2017, the WHO classification was referenced in
Korea 2 1.0 18% (3 of 17) from Africa, 64% (32 of 50) from Asia, 79% (89 of 113)
Latvia 1 0.5
from Europe, 89% (8 of 9) from North America, and 100% (9 of 9) from
Morocco 8 4.0
Netherlands 1 0.5 South America.
Pakistan 2 1.0 These findings suggest that the WHO classification has been pro-
Palestine 1 0.5 gressively taking preference to other classifications, with rate of
Peru 4 2.0
adoption depending on the continent of origin of the research and/or
Poland 3 1.5
Portugal 2 1.0
researchers. Residual use of the classification developed by Dr. Hassen
Saudi Arabia 2 1.0 Gharbi of Tunisia in 1982, used widely prior to development of the
Spain 6 3.0 WHO classification (which reversed two stages in Gharbi’s classification
Switzerland 3 1.5 in order to more closely reflect the natural history of CE) suggests that
Taiwan 1 0.5
adoption of a new classification takes time and varies regionally.
Tunisia 8 4.0
Turkey 40 20.2 The community of clinicians and researchers studying CE is very
UK 3 1.5 small, even compared to those studying many other parasitic and non-
Ukraine 1 0.5 parasitic neglected tropical diseases. Given the wide geographical dis-
USA 5 2.5
tribution of CE, it is not surprising that these researchers also hail from
Total 198 100.0
around the globe and speak a multitude of different languages. Because
of this, it is enormously important that the few who are investigating
activity and correlate with US appearance, accurate staging is para- this disease are able to communicate their findings clearly and effec-
mount for determining and administering appropriate treatment. The tively. Use of a common classification system facilitates communication
most recent guidelines developed by the WHO Informal Working Group and understanding between these researchers by providing a common
on Echinococcosis (IWGE) suggest surgery for removal of CE2 and CE3B language to discuss important features of CE—including epidemiology,
cysts, puncture-aspiration-injection-reaspiration (PAIR) for removal of diagnosis, and management—and share new findings. In this way, more
large (> 5 cm) CE1 and CE3A cysts, and chemotherapy (typically the efficient communication ultimately allows for more effective clinical
benzimidazole carbamate albendazole) for small (< 5 cm) CE1 and and research practices.
This study’s use of PubMed searches to identify articles is limited in

Fig. 1. Demonstration of individual and combination classification use by year.

8
E. Mirabile et al.
Fig. 2. Demonstration of classification use by year and continent, from 2004 to 2017.
that there may be other articles in journals not listed on PubMed which
use one or any number of these classifications. The PubMed database
was chosen specifically for its high volume of peer-reviewed publica-
tions from national and international journals which are both easily
accessible to the scientific community and receive international atten-
tion purely by nature of being listed within this database. We feel use of
PubMed therefore provides an accurate representation of current trends
within the field.
It remains to be seen if complete adoption in those regions still
showing a degree of allegiance to Gharbi’s classification will eventually
occur, at a slower rate or at all. Given recent studies establishing the
WHO standardized classification of CE as the US classification most
closely following disease natural history, and in the interest of estab-
lishing a universal language to discuss this disease, continued turnover
and widespread adoption of this classification should be promoted.
Future investigations might question what effect adoption of the WHO
classification and the subsequently developed treatment guidelines
have had on treatment outcomes; and whether there is a difference in
treatment outcomes depending on the tool used to classify disease
stage.
Acknowledgments
The authors would like to thank Dr. Francesca Tamarozzi for sup-
porting this study and assisting the authors in commencing it. No
funding was required for this study.
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