Schistosomiasis is one of seventeen neglected tropical diseases (NTDs) listed by the World Health Organization (WHO), and this disease presents a substantial public health and economic burden and is considered a disease of poverty. An estimated 779 million people are at risk of infection, and approximately 252 million people are currently infected.(1, 2) The Global Health Estimates of 2015 attributed 3.51 million disability-adjusted life years (DALYs) and 10.1 million deaths in 2016 to schistosomiasis, which is a mortality figure that has been challenged as a gross underestimate.(3, 4) In the Americas, the only known species of parasite that is associated with intestinal schistosomiasis and continues to be endemic in parts of Brazil, Venezuela, and the Caribbean is Schistosoma mansoni.(5)
Schistosomiasis induces acute, severe, and chronic morbidity among those who are infected. If untreated, it can result in anaemia, splenomegaly, and fibrosis that can cause portal hypertension, esophageal varices, and upper gastrointestinal bleeding; in serious cases, it triggers kidney and neurological complications and death.(6) Three major control strategies have been adopted to combat schistosomiasis, and these include chemotherapy, diagnostics, and improvements in sanitation and hygiene.(7) Since the mid-1980s, the main global strategy to fight schistosomiasis has been treatment with praziquantel (PZQ).(8) PZQ treatment in general has reduced the high levels of prevalence and intensity of infection so that control programs are able to manage morbidity. After decades of extensive PZQ use, however, low-intensity infections exhibiting high re-infection rates remain and transmission persists.(9, 10)
The failure of PZQ to eliminate schistosomiasis has placed new emphasis on the role of diagnostics in the control of schistosomiasis. The plan for 2020 that focuses on “elimination of disease as a public health problem” also now emphasises attainable strategies for accurately diagnosing low-intensity infections.(11, 12, 13) As a result of intensive control strategies, many previously high-endemic areas are now considered low-endemic areas. They are characterised by < 10% prevalence, and the majority of infected individuals harbour low-intensity infections (number of eggs per gram of faeces (EPG) is < 100).(9, 14, 15) Detection of schistosome eggs in stools by microscopic examination using the Kato-Katz technique (K-K) is the recommended method by the WHO for diagnosing an active infection. K-K, however, possesses poor sensitivity for low-intensity infections and therefore cannot be currently considered the gold standard.(16, 17) Improvements in the diagnostic field are strongly supported by control programs in Brazil, which is a low-endemic country where PZQ mass drug administration (MDA) is only indicated in localities with egg-positivity above 25% and the main control strategy focuses on strengthening diagnoses and treatment of infected individuals at the primary care level.(5, 18, 19, 20)
Over the past 40 years, Brazil has developed an extensive history regarding the fight against schistosomiasis. Integrated control measures, such as investments in basic sanitation and hygiene, improvement in the population’s income levels and quality of life, and chemotherapy have yielded considerable success in terms of reducing the prevalence, transmission, and morbidity.(15) The number of severe clinical cases and deaths has decreased significantly.(21) Currently, Brazil has chronic patients living in endemic areas, as well as acute cases derived from migration of populations due to urbanisation and rural tourism.(18, 22, 23, 24, 25, 26, 27, 28, 29) Low parasite loads are persistent among most individuals from endemic areas as a result of consecutive rounds of treatment and frequent exposure to the infective agent.(18, 30) Further, low-intensity infections may occur upon a single exposure to the infective agent, such as exposure during tourism to transmission areas and movement of residents from endemic areas to urban centres.(27, 28, 29)
The prevalence in Brazil was estimated at 1% by the National Schistosomiasis and Soil-transmitted Helminth Infection Survey (INPEG) conducted between 2010 and 2015.(15) When comparing the two last surveys, a large reduction in prevalence was observed, (10.09% between 1949 and 1953 and 9.24% between 1975 and 1979);(15) however, infection persists, and the lack of a diagnostic method that is compatible with the epidemiological scenario presents a concern.(13, 15, 17) Although K-K is affordable and suitable for low-income areas, its sensitivity decreases dramatically in the current conditions of low egg excretion, and it is not as efficient for determining disease prevalence as it was in the past when medium and high parasite loads (> 100 EPG) were predominant.(26) Infected individuals who are not diagnosed correctly and do not receive the proper treatment remain infected and contribute to the maintenance of transmission and the establishment of a new focus.(18, 31, 32)
The INPEG was the major survey that covered all states within the federation of Brazil. A total of 197,564 school-age individuals (7-17 years old) were evaluated in 27 states by an analysis of parasitological method (two K-K slides). Studies in Brazilian areas, however, have recently demonstrated that disease prevalence has been underestimated by a factor of between two and four, likely due to the inability of the K-K to detect low-intensity infections.(18, 32, 33) This failure to determine the accurate disease prevalence led to shortcomings in decisions made during national control programs, and this elevated prevalence remains a major challenge for disease elimination.(26) Given this, the question arises as to whether the low prevalence rate observed indicates that Brazil is moving toward elimination, or whether Brazil is simply underestimating prevalence because of the use of a method that is not sensitive enough to detect low-intensity infections. If the goal of elimination is a priority for the WHO, new and more sensitive methods must be utilised to achieve this purpose.
Significant progress has been made in regard to development of more sensitive tests. Diagnoses using antibodies,(24) antigens,(34) and DNA(18, 35) have been evaluated. These techniques have exhibited high sensitivity, however, their reduced specificity in comparison to microscopy-based methods make them inadequate as single-use tests.(33, 36) Because of the high specificity of egg-based techniques for detecting active infections, new sensitive parasitological methods have been developed, including the saline gradient (SG)(37) and Helmintex (HX).(38) Improvements have also been made to the conventional protocol of K-K, and these include increasing the number of samples and the number of slides to be evaluated.(18, 31, 39)
As an alternative to time-consuming parasitological methods, a rapid diagnostic test (RDT) based on the detection of active parasite-secreted antigen in urine was also developed. The point-of-care circulating cathodic antigen test (POC-CCA®) has been commercially available since 2008, and owing to its higher sensitivity than K-K, it has been suggested as a suitable substitute for K-K in S. mansoni prevalence mapping.(40, 41, 42, 43, 44, 45) The majority of studies validating POC-CCA®, however, were conducted in Africa using K-K as a reference method.(45) As K-K is not sensitive enough to detect low-intensity infections and cannot be considered the gold standard for evaluation of new methods, POC-CCA® performance in low-endemic areas remains to be validated before it is released for general use.(46) Only 10 studies were conducted in Brazil, which has a significantly different prevalence and morbidity profile, and these tests yielded controversial results regarding sensitivity and specificity.(25, 26, 33, 36, 39, 47, 48, 49, 50, 51)
As human schistosomiasis is becoming more of a low-endemic area disease, and the WHO-recommended method K-K has low efficiency for accurately detecting low-intensity infections, certain strategies have been adopted to overcome the current limitations. We review here some strategies that are applied in Brazil, which is a low-endemic country with hard-to-detect individuals targeted to achieve elimination. Our approach focuses on laboratory and field-based parasitological and immunological assays that can be summarised in three steps. The first is improvement of parasitological methods (increased number of samples or K-K slides and addition of other more sensitive egg-based assays), the second is antibody-based detection as an auxiliary tool to parasitological investigations (acute diagnostic and preliminary screening in endemic areas), and the third is antigen-based RDT POC-CCA® as a possible candidate to be part of the control. These methods have been used alone or in combination and have been accepted because of their easy application and accessible costs.
It is important to emphasise that molecular techniques have also been applied in addition to parasitological and immunological methods in Brazilian endemic areas with significant performance.(18, 35, 52, 53, 54, 55) They have been described as a complementary tool for parasitological methods for detecting low burden individuals and during assessment of cure after treatment.(18, 52, 56) Polymerase chain reaction (PCR)-based detection of parasite DNA in stools or urine is more sensitive than parasitological methods and has been employed increasingly for diagnosis in high-resource settings;(57) however, the infrastructure needed and the costs of reagents and equipment remain relatively high, which limits its use in low-resource settings such as Brazil. Some authors have estimated the costs as US $6 and US $8 for conventional and real-time PCR, respectively,(14) and US $17 for PCR-enzyme-linked immunosorbent assay (PCR-ELISA).(53)
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