The Scientific World Journal

Volume 2012, Article ID 593947, 5 pages

doi:10.1100/2012/593947
The cientificWorldJOURNAL

Review Article
Immunodiagnostic Methods: What Is Their Role in Areas of
Low Endemicity?

Rafaella Fortini Queiroz Grenfell, Vanessa Silva-Moraes, Diana Taboada,

Ana Carolina Alves de Mattos, Ana Karine Sarvel de Castro, and Paulo Marcos Zech Coelho
Schistosomiasis Laboratory, Rene Rachou Research Center, Oswaldo Cruz Foundation (Fiocruz), Avenida Augusto de Lima,
1715/201 Belo Horizonte, MG, Brazil

Correspondence should be addressed to Paulo Marcos Zech Coelho, [email protected]

Received 8 November 2012; Accepted 28 November 2012

Academic Editors: S. Amaral Gonçalves da Silva, P. M. L. Dutra, and P. Grellier

Copyright © 2012 Rafaella Fortini Queiroz Grenfell et al. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.

Worldwide Schistosomiasis mansoni continues to be a serious public health problem. Over the past decades, control programmes
have made remarkable progress in reducing S. mansoni infections to a relatively low level in Brazil and African countries.
Endemic regions are currently circumscribed in certain core areas where reinfection and repeated chemotherapy are frequent
and, consequently, are related to residents with low parasite load. At present, diagnosis is predominately a key step for final disease
control although low endemicity area residents are hardly detected by most of the available assays. In this paper, we review the
current status and efforts made aiming at the improvement of diagnostic tools for S. mansoni in low endemicity infections. The
establishment of diagnostic assays—simple, affordable, sensitive, and specific for field diagnosis of S. mansoni—is essential and
should be given high priority.

1. Introduction response. Its clinical manifestations vary depending on the

parasite load and host immune response when chronic phase
Schistosomiasis is a complex of acute and mainly chronic is established.
diseases caused by six Schistosoma species: Schistosoma In Brazil the elimination of the disease is considered but
haematobium, S. guineensis, S. intercalatum, S. mansoni, S. there are areas of low prevalence where elimination could be
japonicum, and S. mekongi [1]. Schistosomiasis occurs in the achieved with adequate resources and political commitment.
tropics and subtropics and is among the most important In some countries, elimination of schistosomiasis is already
parasitic diseases worldwide, with a significant socioeco- the declared goal. Hence, although morbidity control is likely
nomic impact [2]. Seventy-four countries are endemic, to remain the main strategy in most places, it is essential
with roughly 120 million individuals being symptomatically to ensure that adequate tools for transmission control and
infected and 20 million being severely affected [3]. Moreover, innovative surveillance-response mechanisms are in place
schistosomiasis represents an increasing problem in nonen- wherever elimination is to be achieved [8].
demic areas, due to the growing number of immigrants and Since praziquantel was developed in 1970s, it has
tourists [4–6]. The acute symptomatic schistosomiasis may replaced other antischistosomal drugs to become the only
appear 3 to 7 weeks after an exposure and is characterized drug of choice for treatment of human schistosomiasis,
by cough, fever, anorexia, abdominal pain, headaches, and due to high efficacy, excellent tolerability, few and transient
hypereosinophilia when the inflammatory reaction is well side effects, simple administration, and competitive cost [9].
established involving predominantly Th1 biased and elevated Lessons learnt from the successes and failures of past control
immunoglobulin levels in sera [7]. The late acute phase that and elimination programmes must not be ignored. Emphasis
occurs after 40 to 90 days following infection is characterized on the large-scale administration of praziquantel not com-
by the egg laying and a predominantly Th2 inflammatory bined to the individual diagnosis was largely adopted during
2 The Scientific World Journal

the 1970s as part of the Special Program for Schistosomiasis 2. Immunodiagnostic Methods for
Control in Brazil, and it is still in progress in Africa [8]. Antibodies Detection
Although this strategy could have led to an effective control
of parasite transmission, it showed a different scenario in New indirect diagnostic tests based on antibody detection
endemic areas. There is evidence that prevalence and worm have been developed. Indirect methodologies are highly
burden have decreased significantly since the introduction of sensitive even when parasite burden is low, but they are
this program [10–12]. Given this fact, new objectives need to unable to distinguish past from current infections and are
be defined transferring from control programs designed for relatively nonspecific and prone to cross-reactions with other
morbidity reduction to strategies for transmission control antigens [5, 21]. Since it is based on the determination of
the humoral immune response, positive antibody test results
[13].
may take an indefinite period of time to convert to negativity
In a recent review [9] the authors show the absence of after elimination of infection [22] and do not reflect the
exact mechanisms of action of praziquantel, the mechanisms intensity of infection [23].
of drug resistance in schistosomes that remain unclear.
The presence of cross-reactive IgG antibodies in serum
The study evidences the urgent and great importance to samples of schistosomiasis patients was detected by different
strengthen the monitoring of praziquantel sensitivity and authors when tested with antigens of other parasite species
detection of praziquantel resistance in schistosomes and a by ELISA and Western blot [24–26]. Nevertheless, good
development of an effective and rapid detection technique specificity (98.2%) was observed when detection of IgM
that is urgently needed. antibodies to gut-associated antigens by immunofluorescent
Prevalence and egg burden in feces is expected to be test (IFT). This IFT was applied in different areas of the
low in areas either under advanced control of transmission State of São Paulo, Brazil, with no schistosomiasis and high
[14] or with recent introduction [15, 16]. The increasing prevalence for other helminth infections, such as ascaridiasis,
number of individuals showing low parasite load, most trichuriasis, and enterobiasis [27]. There are various studies
of the time with less than 10 eggs per gram of feces that assess the potential of different immunodiagnostic
after extensive examination, turns the diagnosis even harder methods in populations [28–31], and, even when applied in
to be performed. Moreover, the exact definition of the low endemicity areas, these immunodiagnostic assays show a
prevalence of a population, as well as the identification good relation between sensitivity and positivity ratio but still
of asymptomatic carriers, becomes unviable because a cannot discriminate the active infection.
large amount of unnecessary stool examinations has to be Nonetheless, these methodologies have their own advan-
carried out to find a relatively small number of infected tages when leading with low endemicity infections as
individuals. confirmatory diagnosis. That said, schistosome egg antigen
(SEA) enzyme-linked immunosorbent assay (ELISA) can be
Herein, diagnosis plays a crucial role in the monitoring of
used as a complementary field-based method for monitoring
the infection as well as efficacy of treatment. Currently, the
infection. It performs well over a range of endemic settings
“gold” standard remains the detection of schistosome eggs
and would be best applied to monitor the incidence of
in stools. The Kato-Katz technique is the most widely used
“new” infections in young children in environments where
copromicroscopic method in epidemiological surveys [17].
transmission was thought to be interrupted [21]. The most
However, because of low egg production in endemic areas, important point to be considered is that the use of different
the risk of having a large number of individuals who remain antigens in immunological methods can be applied as
undiagnosed is considerable. Consequently, undiagnosed potential tools for the analysis of the chronological evolution
individuals remain infected and contribute to transmission of S. mansoni infection [32]. Recent analysis has shown that
of the disease. Siqueira et al. [18] showed that the prevalence the antigens from different life stages as schistosomula, adult
obtained from the examination of one Kato-Katz slide in a worms, and eggs can be markers for prepatent, acute and
low-transmission area in Brazil (the methodology adopted chronic phases. Results from individual laboratories and,
by the Brazilian control programme) was 8% compared to from multicentre trials, suggest that egg antigens provide
35.8% from the “gold standard” (Kato-Katz method—18 greater diagnostic sensitivity and specificity than worm
slides plus a quantitative commercial test—TF-Test), which antigens for the detection of an infection [33, 34].
was a 4.5-fold difference. It is clear however that diagnostic tests based on egg
Development and implementation of optimal method- antigens should be postponed until egg laying is started. To
ologies for diagnosis is crucial in all aspects of schistosomiasis obtain a positive result, the parasite cycle must be completed
control, and high sensitivity, as well as absolute specificity, within the definitive host with the development of male
will be needed as programmes shift their emphasis from and female adult worms, which reproduce and lead to
control to elimination [19]. Since initial disease surveillance the oviposition [35]. Also, although extracts prepared by
must be enhanced so that drug delivery can be focused [20], homogenizing Schistosoma eggs contain a large number of
research has been mainly focused on the development and molecules, only a minority of the constituents of egg antigen
optimization of improved diagnostic methods in order to might be released by viable eggs in vivo, as demonstrated in
achieve significant diagnosis sensitivity for the detection of vitro [36], which can explain the low detection capability of
infections with low parasite load. an SEA-ELISA assay.
The Scientific World Journal 3

On the contrary, others have shown that during acute 4. Conclusion

phase of the disease there is an increase in anti-worm
antibody titers, and this fact may be due to the production of We are currently in a diagnostic dilemma for S. mansoni—
antibodies specific for glycan epitopes that schistosome lar- the direct parasitological major technique (Kato-Katz) have
vae and adult worms [37] have in common. Since 2004 there become relatively insensitive due to widespread chemother-
has been a remarkable increment in proteomics, especially apy that results in generally low worm burdens, which
for proteins that reside at the surfaces of schistosome in the leads to less efficiency in low transmission settings and
mammalian host. The most important proteins secreted by in post-treatment situations [2, 8, 10, 14, 25, 27, 30, 37].
the cercaria to gain access to the skin have been described Other diagnostic alternatives include detection of antibodies
as well as those from schistosomula [38]. At this manner, or circulating antigens in serum and/or urine samples.
schistosomula tegument antigens have been considered as Antibody detection assays with relatively high sensitivity but
important markers for the diagnosis and, although the generally low specificity, do not differentiate between current
identification of tegument proteins has been the first step and cured infections, which results in the difficulties in
[39–41], it is the glycans that have been real evidence. determining prevalence, identifying true infected individuals
The detailed identification of glycans on the surface of all for selective chemotherapy and assessing the effectiveness
schistosome life stages has announced that some glycans are of intervention including follow-up of chemotherapy. The
preserved on the tegument during all the parasite life, and detection of circulating antigens was turned out to be
most importantly some of the most immunogenic glycans a highly efficient and easy-to-do assay showing same or
are exclusively found in Schistosoma sp. [42]. The application superior results than parasitological assays. Although extra
of these glycans to innovative immunodiagnostic methods validation is needed for CCA detection, these qualitative
has now been strongly recommended. and/or quantitative methods showed far superior results than
available immunodiagnostic assays [20, 21, 28, 43–46].
The diagnosis of schistosomiasis relies on microscopic
3. Immunodiagnostic Methods for Circulating examination of stools or urine, serologic tests, and imaging.
Antigens Detection However, taking into account the unsatisfactory diagnostic
value of most of them in areas with low infection intensity,
Besides indirect immunoassays, the diagnosis of schistoso-
a search for a better diagnostic test that can be applied in
miasis was increasingly improved by the development of
field situations in Brazil and Africa should be given high
new methods aiming at the detection of circulating anodic
priority. The role of immunodiagnosis in low endemicity
and cathodic antigens (CAA and CCA) in blood or urine areas has been repeatedly reaffirmed. The focus now relies
[43]. CCA is regurgitated from worms into the circulatory on the improvement of sensitivity and specificity using
system and later is eliminated in urine. Since CCAs are only new proteomics and, most importantly, glycomics recent
released from living worms, the rapid tests can be used to information on antibody detection methods aiming inno-
monitor the dynamics of existing worm burdens, as well vative confirmatory diagnosis. Nonetheless, immunodiag-
as clearance following treatment [43, 44]. However, these nostic methods for circulating antigens level determination
assays were initially presented as cumbersome and with a should be better validated in order to be able to establish
low rate of sensitivity even for the diagnosis of patients individual parasite load as the primary diagnosis.
with high parasite load. Current studies has confirmed
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