Diagnosis and Treatment of Schistosomiasis in Children in the Era of Intensified Control

Stefanie Knopp; Sören L Becker; Katrin J Ingram; Jennifer Keiser; Jürg Utzinger

Expert Rev Anti Infect Ther. 2013;11(11):1237-1258.

Abstract and Introduction

Abstract

In the current era of intensified and integrated control against schistosomiasis and other neglected tropical diseases, there is a need to carefully rethink and take into consideration disease-specific issues pertaining to the diagnosis, prevention, control and local elimination. Here, we present a comprehensive overview about schistosomiasis including recent trends in the number of people treated with praziquantel and the latest developments in diagnosis and control. Particular emphasis is placed on children. Identified research needs are offered for consideration; namely, expanding our knowledge about schistosomiasis in preschool-aged children, assessing and quantifying the impact of schistosomiasis on infectious and noncommunicable diseases, developing new antischistosomal drugs and child-friendly formulations, designing and implementing setting-specific control packages and developing highly sensitive, but simple diagnostic tools that are able to detect very light infections in young children and in people living in areas targeted for schistosomiasis elimination.

Introduction

Schistosomiasis is a chronic neglected disease of poverty caused by blood flukes of the genus Schistosoma.^[1–3] Hence, schistosomiasis mainly affects people who live in deprived or marginalized communities in the tropics and subtropics. According to the Global Burden of Disease Study 2010 (GBD 2010), schistosomiasis ranks third after leishmaniasis and soil-transmitted helminthiasis among the neglected tropical diseases and is responsible for an estimated 3.3 million disability-adjusted life years.^[4] In 2012, the WHO announced the new goals for 2020, namely to eliminate several of the neglected tropical diseases and to intensify control of other neglected tropical diseases, so that they no longer pose public health problems.^[5] WHO gets support from public (e.g., Ministries of Health) and private partners (e.g., pharmaceutical companies) and nongovernmental organizations. These partners collectively signed the London Declaration and are thus committed to tackle neglected tropical diseases including schistosomiasis.^[301] Specifically, the aim for schistosomiasis-endemic countries is to periodically administer the antischistosomal drug praziquantel to populations at risk of infection and hence prevent morbidity. This strategy is phrased 'preventive chemotherapy.' The primary target, as endorsed by Member States in World Health Assembly (WHA) resolution 54.19 in 2001 – but still far from being met – is to treat at least 75% and up to 100% of school-aged children (SAC) who are at highest risk of morbidity.^[6,7] In May 2012, WHA resolution 65.21 has been endorsed, acknowledging progress in schistosomiasis control and hence considering elimination as the next logical step and an attainable goal in some low-endemicity areas.^[8] Hence, Member States are encouraged to work toward the interruption of transmission and to initiate elimination campaigns wherever appropriate.^[8] Additionally, the Schistosomiasis Consortium for Operational Research and Evaluation is currently supporting a multiyear integrated program aiming at schistosomiasis elimination on Zanzibar.^[9] Lessons learnt will be important for shaping the elimination agenda.^[10] Although the primary tool for large-scale schistosomiasis control programs is preventive chemotherapy,^[11] Member States and the international community should not only provide means for treatment, but instead improve the water and sanitation infrastructure, alongside setting-specific hygiene interventions and snail control.^[8,12]

In this review, we summarize the epidemiology of, and morbidity due to, the three main Schistosoma species infecting man. The centerpiece of our review focuses on tools and strategies to diagnose, prevent, treat and control/eliminate schistosomiasis. In view of intensified control efforts, we highlight available drugs and regimens, different control approaches, novel diagnostic tests and the potential impact of schistosomiasis on co-infections and comorbidities due to HIV/AIDS, tuberculosis, malaria and intestinal protozoa infections. Since children are the main carriers and spreaders of schistosomiasis, particular emphasis is placed on this age group with child-related aspects discussed in detail toward the end of each subchapter.

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Table 1. Symptomatology and clinical manifestations of schistosomiasis caused by the three main *Schistosoma* species parasitizing man.
	Schistosoma mansoni	Schistosoma japonicum	Schistosoma haematobium	Clinical presentations and typical symptomatology
Early (hours to days after infection)	+	+	+	Localized maculopapular eruption at the site of cercarial transcutaneous penetration (cercarial dermatitis), pruritus
Acute = Katayama syndrome (2–8 weeks after infection)
General findings	+	+	+	Fever (typically nocturnal, often absent), arthralgia, myalgia (neck pain!), fatigue
Respiratory tract	+	+	+	Dry cough, chest pain, wheezing
GI tract	+	+	+	Abdominal pain, tenderness, diarrhea, hepatomegaly
Central nervous system	+	+	+	Headache, confusion, rarely severe complications (hemiplegia, focal deficiencies, seizures, visual impairment, ataxia, incontinence)
Cardiac involvement	+	+	+	Pericarditis, myocarditis, myocardial ischemia, electrocardiogram: repolarization abnormalities (ST segment, abnormal T waves)
Cutaneous	+	+	+	Urticarial rash, angioedema
Genitourinary			+	Hematuria, dysuria
Laboratory findings	+		+	Eosinophilia, elevated serum liver enzymes (ALT, AST)
Chronic (months to years after infection)				The clinical manifestation depends on the site of schistosome egg deposition.
Respiratory tract	+	+		Remodeling of pulmonary vessels, pulmonary hypertension and related complications (cor pulmonale)
GI tract	+	+		Colitis, intestinal obstruction, ulceration, hyperplasia, (bloody) diarrhea, enteric protein loss
Hepatobiliary system	+	+		Hepatomegaly, periportal fibrosis, portal hypertension and development of related complications (variceal bleeding, splenomegaly, hypersplenism, hepatopulmonary and hepatorenal syndrome)
Central nervous system	+	+	+	Acute transverse myelitis (paraplegia, lumbar pain, altered sensitivity, vegetative dysfunctions), progressive myeloradiculopathy, seizures, alteration of mental state, focal deficiencies
Renal and urological involvement			+	Haematuria, dysuria, suprapubic dyscomfort, calcification, obstruction with consecutive ureteric and renal involvement (nephrotic syndrome [edema, proteinuria, arterial hypertension], megaureter, hydronephrosis, bacterial pyelonephritis, renal colic, membranoproliferative glomerulonephritis), important risk factor for squamous cell carcinoma of the bladder
Genital			+	Genital lesions and ulcers, genital bleeding and pain, vulval involvement, facilitation of HIV transmission
Cognitive and physical morbidity in chronic infections	+	+	+	Impaired growth, anemia, reduced physical fitness, susceptibility to co-infections, impaired cognitive and mental development (e.g., in educational tests for short-term memory)

Table 2. Summary of cure rates determined for antischistosomal drugs against *S. mansoni* and *S. haematobium*.
Drug	Dosage	Cure rates on schistosome species (%)		Ref.
Drug	Dosage	Schistosoma haematobium	Schistosoma mansoni	Ref.
Praziquantel^a	1 × 40 mg/kg	63–100	52–92	[65,66]
Metrifonate^b	3 × 7.5–10 mg/kg	52–81	–	[65]
Oxamniquine^b	1 × 40 mg/kg	–	82	[66]
Artesunate^c	3 × 4 mg/kg/day 4 mg/kg for the first day and 2 mg/kg daily for the next 4 days; total dose 12 mg/kg	27 NA	NA 31	[65] [228]
Mefloquine^c	2 × 15 mg/kg 1 × 25 mg/kg	36–70 21	NA NA	[90] [89]

NA: Not assessed.
a: Current drug of choice against all schistosome species. b: Previously marketed antischistosomal drugs. c: Antimalarial drugs that have been tested against schistosomiasis.

Table 3. Methods to diagnose schistosomiasis at different levels of infection intensity and control.
	Infection intensity				Control				Ref.
	Very light^†	Light	Moderate	High	Morbidity	Prevalence	Transmission	Elimination/surveillance	Ref.
Questionnaire									[148]
Schistosoma haematobium				x	x
Dipstick for hematuria									[151]
Schistosoma haematobium		(x)		x	x	(x)
Direct parasitological methods			*
Urine filtration			*						[158]
Schistosoma haematobium		(x)		x	x	x	(x)
Kato-Katz									[161]
Schistosoma mansoni		(x)	x	x	x	x	(x)
Schistosoma japonicum		(x)	x	x	x	x	(x)
Formalin–ether concentration									[229,230]
Schistosoma mansoni		(x)	x	x	x	x	(x)
Schistosoma japonicum		(x)	x	x	x	x	(x)
FLOTAC									[164]
Schistosoma mansoni	(x)	x	x	x	x	x	(x)
Schistosoma japonicum**
Miracidium hatching test									[183,184]
Schistosoma haematobium				x	x	x
Schistosoma mansoni			x	x	x	x
Schistosoma japonicum			x	x	x	x
Indirect methods
Antibody detection									[190,231]
Schistosoma haematobium							(x)	(x)
Schistosoma mansoni							(x)	(x)
Schistosoma japonicum							(x)	(x)
Antigen detection									[181]
Schistosoma haematobium	(x)	x		x	x	x	(x)	(x)
Schistosoma mansoni	(x)	x	x	x	x	x	(x)	(x)
PCR									[169,171,174,232]
Schistosoma haematobium	(x)	x		x	x	x	(x)	(x)
Schistosoma mansoni	(x)	x	x	x	x	x	(x)	(x)
Schistosoma japonicum	(x)	x	x	x	x	x	(x)	(x)

^† Very light infection intensity is defined as infections that are below the detection limit of a single urine filtration and Kato-Katz thick smear: S. haematobium: >0 and <1 eggs/10 ml urine, S. mansoni and S. japonicum: >0 and <24 eggs per 1 g of stool. *moderate infection intensity for S. haematobium does not exist. **no data on FLOTAC for S. japonicum detection exist to our knowledge. x is defined as method suitable for detection of infection at the given level of intensity. x is defined as method moderately suitable for detection of infection at the given level of intensity.