**3. Assessment of morbidity and drug response in community and institutional settings**

solely on microscopy [27]. Lack of egg shedding, one gender-induced infection, and daily variability are some of the causes that directly interfere with the sensitivity of microscopy, thus compromising the detection of *Schistosoma* infection and resulting in the underestimation of "real prevalence" [15, 28]. Moreover, the erratic elimination of *Schistosoma* eggs makes the determination of therapy response uncertain. In addition, some patients may present with severe forms of disease such as neuroschistosomiasis or genital schistosomiasis without any egg excretion detectable [13]. Strategies to overcome the lack of sensitivity of urine filtration and Kato-Katz test include testing replicate samples of urine or stool samples and/or aug‐

**Figure 1.** Schistosomiasis flowchart for clinical management in community and institutional settings. Conventional and new tools to diagnosis, determination of response to therapy, and morbidity assessment are indicated under com‐ munity and institutional settings in hierarchic order. Bellow conventional tests, new tools were depicted according to the strength of literature evidence (red boxes). Approaches still under investigation and/or diagnostic platforms that show debatable results are inside the gray boxes. PM: parasitological method; US: ultrasonography; PCR: polymerase chain reaction; RDT: rapid test (POC-CCA /POC-CAA); FOB: fecal occult blood; CT: computed tomography; MRI:

Other parasitological methods such as sedimentation, centrifugation, flotation techniques, and miracidium hatching were developed and had improved the diagnosis of light infections by increasing sensitivity [26, 32]. In institutional settings, tissue biopsy such as rectal snips and liver biopsy are largely used to diagnose active infection in non-egg excretors despite its invasiveness [31]. Eventually, surgical specimens reveal previously undiagnosed schistoso‐

menting the number of Kato-Katz slides/sample [29].

magnetic resonance imaging.

130 An Overview of Tropical Diseases

Sanitation and community health education in addition to chemotherapeutic intervention are measures that effectively contribute to the control and/or elimination of *Schistosoma* infection in several endemic areas and the resolution or attenuation of progressive forms of disease at individual level [10, 46, 47]. However, the determination of the effects of these measures, in particular, drug intervention, still presents as a challenge (Table 1). Tests like microscopy have low sensitivity and underestimate cure rates especially in non-egg excretors. Day-to-day variations in egg excretion contribute to the misdiagnosis of schistosomiasis elimination after treatment [15]. The evaluation of drug response in individuals previously diagnosed by tissue biopsies is also troubled since the procedures might be invasive like brain or spinal cord biopsies in neuroschistosomiasis [48]. In immunoreactive egg and non-egg excretors submitted to PZQ treatment, it was shown that reactivity against several proteins mostly related to parasite musculature or glycolytic metabolism is enhanced after therapy [49]. Immunoreac‐ tivity might persist for long periods of time despite effective drug response, although sero‐ conversion may occur in some individuals. Nonetheless, in low-endemic areas, immunodiagnosis has proven to be a valuable tool for schistosomiasis surveillance [50]. Changes in immunoreactivity in controlled areas can be used as an indicator of maintained transmission and/or active infection in community settings [51]. Therefore, the assessment of drug response is a hot topic in the schistosomiasis and development of new tools became an urgent matter (Table 1). Investigations have shown a potential role in drug response assess‐ ment with the use of rapid tests and DNA detection assays [14, 52].


in several endemic areas and the resolution or attenuation of progressive forms of disease at individual level [10, 46, 47]. However, the determination of the effects of these measures, in particular, drug intervention, still presents as a challenge (Table 1). Tests like microscopy have low sensitivity and underestimate cure rates especially in non-egg excretors. Day-to-day variations in egg excretion contribute to the misdiagnosis of schistosomiasis elimination after treatment [15]. The evaluation of drug response in individuals previously diagnosed by tissue biopsies is also troubled since the procedures might be invasive like brain or spinal cord biopsies in neuroschistosomiasis [48]. In immunoreactive egg and non-egg excretors submitted to PZQ treatment, it was shown that reactivity against several proteins mostly related to parasite musculature or glycolytic metabolism is enhanced after therapy [49]. Immunoreac‐ tivity might persist for long periods of time despite effective drug response, although sero‐ conversion may occur in some individuals. Nonetheless, in low-endemic areas, immunodiagnosis has proven to be a valuable tool for schistosomiasis surveillance [50]. Changes in immunoreactivity in controlled areas can be used as an indicator of maintained transmission and/or active infection in community settings [51]. Therefore, the assessment of drug response is a hot topic in the schistosomiasis and development of new tools became an urgent matter (Table 1). Investigations have shown a potential role in drug response assess‐

ment with the use of rapid tests and DNA detection assays [14, 52].

For determination of transmission control, elimination or erradication. Inaccurate. no *species* identification; Test does not detect prepatent infections; no assessment of early post-control measures in snail infection rates.

Traditional methods which are simple, cheap and effective for *Schistosoma* detection.

**Community Settings**

**Non-human Hosts**

Parasitological Methods (Egg detection)

**Vector control** Light Exposure Test (Cercarial shedding detection)

132 An Overview of Tropical Diseases

**Traditional Tools Investigational Tools**

**Tests Characteristics/Observations Tests Characteristics / Observations**

Antigen Detection

DNA- based assays

CCA-dipsticks (urine lateral flow test) Serology (IgG/

IgM)

Detection in 2nd week post-infection (pi); secretion by live larvae; group specific. Not commercially available

Detection in 1st week pi; quantitation of parasite load (real -time PCR; specie-specific identification. Mapping foci of vector snails and monitoring transmission. In house

Detection of active infection independent of patent egg-excretion in primate non-humans. Only determination of genus but not

assays.

assays.

species.




**Traditional Tools Investigational Tools**

some control programs by serology which may remain reactive for extended periods post effective drug use. In areas submitted to several rounds of chemotherapy, low and/or absence of reactivity might represent control of infection.Long periods of obsevation are necessary to determine *Schistosoma* infection "real status". Reinfection or incomplete cure may not be

assessed.

coments.

Tissue Biopsy No viable eggs in rectal snips

show good correlation with response to therapy. However, tissue biopsy (rectal snips, liver

biopsies) are invasive procedures. And, lack of ova

Assessment of post-therapy response by parasitological methods in clinical wards has similar advantages and limitations as in community settings. In immigrants (long gone from endemic areas) and recently exposed travelers, absence of egg excretion pretherapy represent an obstacle. Ova detection is inappropriate to determine therapy response in these groups. See above other

**Tests Characteristics/Observations Tests Characteristics / Observations**

DNA-based assays1

methods after PZQ use. However, specificity may be compromised by the presence of persistent low reactivity ( trace positive samples) post-chemotherapy.Cure rates may vary from 23.3 - 26.1 to 40.7- 47.8%

DNA-based assays are a reliable tool to detect response to therapy in distinct clinical specimens. Absence of DNA amplification correlates with response to therapy in individuals treated in Travel

Medicine Clinics

[56].In case of therapy failure, maintained DNA amplification correlate with persistence of clinical signs, symptoms and pathological abnormalities associated to therapy failure [57]. Usefulness of DNAbased assays to detect past infection incomplete cure for non re-exposed individuals has to be established

with large studies [58].

[42, 54]

**Community Settings**

134 An Overview of Tropical Diseases

**Institutional Settings**

**Chemotherapy** Parasitological

Methods (Egg detection)

> **Table 1.** Effectiveness of interventions in surveillance programs and monitoring therapy response in clinical management: use of traditional and investigational tools.

RDTs for antigen detection have been largely used for population studies to evaluate post‐ therapy response and efficacy [42, 43]. In areas of moderate and high endemicity, therapy response represented by decrease or disappearance of antigen detection may represent cure. However, in light infections, rapid test accuracy is reduced with maintained antigen detection in individuals without infection. The use of antigen detection assays is a debatable matter to measure posttherapy response. In contrast, DNA assays seem to be a suitable marker of drug response. Cure is determined by the absence of DNA amplification postchemotherapy use, while persistent DNA amplification correlates with nonresponse to therapy [15].

Schistosomiasis presents as a large spectrum of manifestations and disease severity during acute and chronic phases. Usually, imaging tests and/or biological markers are required to confirm diagnosis, to assess morbidity, and to stage disease progression [21, 22]. Image tests such as ultrasonography became revolutionary to assess urogenital *S. haematobium* infection and *S. mansoni* liver disease [61]. In both community and institutional settings, conventional ultrasound (US) examination is a well-standardized test to assess bladder and liver fibrosis, which is the hallmark of disease progression in urinary and intestinal schistosomiasis, respectively [62-65]. US predicts disease prevalence rates and is a reliable noninvasive indicator of morbidity levels which aloud disease staging [64, 66]. However, morbidity measurement in a multivariate clinical manifestation infection like schistosomiasis is no easy

task. Targeting one compartment to measure schistosomiasis morbidity might not be enough since some clinical presentations can affect a single compartment like in neuroschistosomiasis and others. In intestinal *Schistosoma* infection, independent hepatosplenic forms are the most common clinical presentation after asymptomatic *S. mansoni* infection. However, in contrast to hepatic schistosomiasis, the study of disease progression by using image and/or biochemical markers is still poorly developed [21]. Promising new approaches such as capsule endoscopy have been introduced, but large-scale studies are still necessary to evaluate the usefulness of the method [67]. In hepatosplenic forms, vascular gastropathy and colopathy can be indicators of portal hypertension severity [68]. The assessment of vascular alterations in superior gastrointestinal tract are used to determine schistosomiasis levels of morbidity through the use of upper digestive endoscopy in association with conventional ultrasonography and Doppler imaging [66]. In institutional settings, transient elastography, magnetic resonance, and computerized tomography might give supplementary information regarding fibrosis progression and vascular status, although standardization is necessary especially for disease staging [22, 69]

## **4. Conclusion**

In community settings, concerns have been increasing on the effectiveness of schistosomiasis control interventions like MDA over the years. The low accuracy of the reference test to detect active *Schistosoma* infection and the improper estimates of cure rates jeopardize the truthful analysis of drug intervention, which compromises the effectiveness of surveillance systems. In clinical settings, underdiagnosed schistosomiasis and inadequate morbidity assessment also increase the burden on public and private health systems. In order to change this scenario, new diagnostic tools, markers of treatment response, and morbidity assessment have been developed over the years showing promising results. Nonetheless, efforts still have to be made to find a single cheap and easy-to-do approach that is suitable and reliable for diagnosis, treatment evaluation, and disease staging in community and institutional settings.
