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VOLUME ONE HUNDRED AND FIFTEEN
ADVANCES IN
PARASITOLOGY
SERIES EDITOR
D. ROLLINSON J. R. STOTHARD
Life Sciences Department Department of Tropical
The Natural History Museum, Disease Biology
London, United Kingdom Liverpool School of Tropical
d.rollinson@nhm.ac.uk Medicine, Liverpool, United Kingdom
russell.stothard@lstmed.ac.uk
EDITORIAL BOARD
T. J. C. ANDERSON K. KING
Department of Genetics, Texas Department of Zoology,
Biomedical Research Institute, University of Oxford,
San Antonio, TX, United States Oxford, United Kingdom
M. G. BASÁÑEZ M. G. ORTEGA-PIERRES
Professor of Neglected Tropical Professor of the Department of Genetics
Diseases, Department of Infectious and Molecular Biology,
Disease Epidemiology, Faculty of Centro de Investigación y de
Medicine (St Mary’s Campus), Estudios Avanzados IPN,
Imperial College London, Mexico City, Mexico
London, United Kingdom
D. L. SMITH
D. D. BOWMAN Johns Hopkins Malaria Research
Director Cornell CVM MPS—Veterinary Institute & Department of Epidemiology,
Parasitology, Professor of Parasitology, Johns Hopkins Bloomberg School
C4-119 VMC, Dept Micro & Immunol, of Public Health, Baltimore,
CVM Cornell University, Ithaca, MD, United States
NY, United States
R. B. GASSER R. C. A. THOMPSON
Head, WHO Collaborating Centre
Faculty of Veterinary and Agricultural
for the Molecular Epidemiology
Sciences, The University of Melbourne,
of Parasitic Infections, Principal
Parkville, VIC, Australia
Investigator, Environmental
A. L. GRAHAM Biotechnology CRC (EBCRC),
Professor of Ecology & Evolutionary Biology, School of Veterinary and Biomedical
Co-Director of the Global Health Program, Sciences, Murdoch University,
Princeton University, Princeton, Murdoch, WA, Australia
NJ, United States
X.-N. ZHOU
J. KEISER Professor, Director, National Institute of
Head, Helminth Drug Development Unit, Parasitic Diseases,
Department of Medical Parasitology and Chinese Center for Disease Control
Infection Biology, Swiss Tropical and Public and Prevention, Shanghai,
Health Institute, Basel, Switzerland People’s Republic of China
VOLUME ONE HUNDRED AND FIFTEEN
ADVANCES IN
PARASITOLOGY
Edited by
DAVID ROLLINSON
Life Sciences Department
The Natural History Museum,
RUSSELL STOTHARD
Department of Tropical
Disease Biology
Liverpool School of Tropical
Medicine, Liverpool, United Kingdom
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Contents
Contributors vii
1. An update on female and male genital schistosomiasis and

a call to integrate efforts to escalate diagnosis, treatment and
awareness in endemic and non-endemic settings: The time is now 1
Amaya L. Bustinduy, Bodo Randriansolo, Amy S. Sturt, Seke A. Kayuni,
Peter D.C. Leustcher, Bonnie L. Webster, Lisette Van Lieshout,
J. Russell Stothard, Hermann Feldmeier, and Margaret Gyapong
1. Introduction 3
2. Pathogenesis and clinical manifestations 9
3. Immunology 12
4. Diagnosis of genital schistosomiasis 13
5. Co-infections and co-morbidities 21
6. Immigrants and returned travellers 24
7. Management of FGS and MGS 25
8. Disability, stigma and community awareness 29
9. Programme integration 30
10. Conclusions and way forward 33
Acknowledgements 33
References 33
2. Vertebrates as uninfected disseminators of helminth

eggs and larvae 45
Neil J. Morley
1. Introduction 46
2. Terminology and definitions of helminth zoochory 48
3. Features of different vertebrates that affect their ability to disseminate
parasites 49
4. Endozoochory 54
5. Ectozoochory 127
6. Long-distance dispersal 138
7. Conclusion 143
References 146
v
vi Contents
3. Anthelmintic resistance in ruminants: challenges and solutions 171

J. Charlier, D.J. Bartley, S. Sotiraki, M. Martinez-Valladares, E. Claerebout,
G. von Samson-Himmelstjerna, S.M. Thamsborg, H. Hoste, E.R. Morgan,
and L. Rinaldi
1. Concerted action for combatting anthelmintic resistance in ruminants 173
2. Prevalence and impact of anthelmintic resistance 175
3. Gastrointestinal nematodes: current and future diagnosis 179
4. Diagnosis of anthelmintic resistance 185
5. Towards a sustainable use of anthelmintics 193
6. Prospects of new anthelmintics 197
7. Complementary control approaches 198
8. Facilitating behavioural change 206
9. Conclusions 210
Acknowledgements 211
References 211
Further reading 226
Contributors
D.J. Bartley
Disease Control, Moredun Research Institute, Penicuik, United Kingdom
Amaya L. Bustinduy
Department of Clinical Research, London School of Hygiene & Tropical Medicine,
J. Charlier
Kreavet, Kruibeke, Belgium
E. Claerebout
Ghent University, Faculty of Veterinary Medicine, Laboratory of Parasitology, Merelbeke,
Belgium
Hermann Feldmeier
Charite University Medicine Berlin, Institute of Microbiology, Infectious Diseases and
Immunology, Berlin, Germany
Margaret Gyapong
Institute of Health Research, University of Health and Allied Sciences, Ho, Ghana
H. Hoste
INRAE, UMR 1225 IHAP INRAE/ENVT, Toulouse University, Toulouse, France
Seke A. Kayuni
Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool,
United Kingdom; MASM Medi Clinics Limited, Blantyre, Malawi
Peter D.C. Leustcher
Centre for Clinical Research, North Denmark Regional Hospital, Hjoerring; Department of
Clinical Medicine, Aalborg University, Aalborg, Denmark
M. Martinez-Valladares
Instituto de Ganaderı́a de Montaña (CSIC-Universidad de León), Departamento de Sanidad
Animal, León, Spain
E.R. Morgan
Institute for Global Food Security, Queen’s University Belfast, Belfast, United Kingdom
Neil J. Morley
School of Biological Sciences, Royal Holloway, University of London, Egham, Surrey,
United Kingdom
Bodo Randriansolo
Association K’OLO VANONA, Antananarivo, Madagascar
L. Rinaldi
University of Naples Federico II, Unit of Parasitology and Parasitic Diseases, Department of
Veterinary Medicine and Animal Production, CREMOPAR, Napoli, Italy
vii
viii Contributors
S. Sotiraki
Veterinary Research Institute, Hellenic Agricultural Organisation ELGO-DIMITRA,
Thessaloniki, Greece
J. Russell Stothard
Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool,
United Kingdom
Amy S. Sturt
Section of Infectious Diseases, Veterans Affairs Palo Alto Health Care System, Palo Alto,
United States
S.M. Thamsborg
Veterinary Parasitology, University of Copenhagen, Frederiksberg C, Denmark
Lisette Van Lieshout
Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands
G. von Samson-Himmelstjerna
Institute for Parasitology and Tropical Veterinary Medicine, Veterinary Centre for
Resistance Research, Freie Universit€at Berlin, Berlin, Germany
Bonnie L. Webster
Natural History Museum, London, United Kingdom
CHAPTER ONE
An update on female and male

genital schistosomiasis and
a call to integrate efforts
to escalate diagnosis, treatment
and awareness in endemic
and non-endemic settings:
The time is now
Amaya L. Bustinduya,∗, Bodo Randriansolob, Amy S. Sturtc,
Seke A. Kayunid,e, Peter D.C. Leustcherf,g, Bonnie L. Websterh,
Lisette Van Lieshouti, J. Russell Stothardd, Hermann Feldmeierj,
and Margaret Gyapongk
a
Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, United
Kingdom
b
Association K’OLO VANONA, Antananarivo, Madagascar
c
Section of Infectious Diseases, Veterans Affairs Palo Alto Health Care System, Palo Alto, United States
d
Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom
e
MASM Medi Clinics Limited, Blantyre, Malawi
f
Centre for Clinical Research, North Denmark Regional Hospital, Hjoerring, Denmark
g
Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
h
Natural History Museum, London, United Kingdom
i
Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands
j
Charite University Medicine Berlin, Institute of Microbiology, Infectious Diseases and Immunology, Berlin,
Germany
k
Institute of Health Research, University of Health and Allied Sciences, Ho, Ghana
∗
Corresponding author: e-mail address: amaya.bustinduy@lshtm.ac.uk
Contents
1. Introduction 3
1.1 Selection criteria 3
1.2 Epidemiology and geographical distribution of genital schistosomiasis 3
1.3 Life cycle and transmission 4
1.4 FGS and MGS in less common Schistosoma species 7
1.5 The importance of different hybrids of S. haematobium group species
(including minor species contributing to FGS/MGS) 8
2. Pathogenesis and clinical manifestations 9
2.1 Female genital schistosomiasis (FGS) 9
2.2 Male genital schistosomiasis (MGS) 11
Advances in Parasitology, Volume 115 Copyright #2022 Elsevier Ltd 1

ISSN 0065-308X All rights reserved.
https://doi.org/10.1016/bs.apar.2021.12.003
2 Amaya L. Bustinduy et al.
3. Immunology 12
3.1 Vaginal environment in FGS 12
3.2 Immune activation during pregnancy 13
4. Diagnosis of genital schistosomiasis 13
4.1 FGS diagnostics 13
4.2 Molecular diagnostics (nucleic acid amplification tests) 17
4.3 MGS diagnostics 19
4.4 Immunopathology in MGS 20
5. Co-infections and co-morbidities 21
5.1 Human immunodeficiency virus (HIV) 21
5.2 Human papillomavirus (HPV) and FGS 22
6. Immigrants and returned travellers 24
7. Management of FGS and MGS 25
7.1 FGS treatment 25
7.2 Treatment of MGS 28
7.3 Pregnancy 28
8. Disability, stigma and community awareness 29
8.1 Case study: Ghana 29
9. Programme integration 30
10. Conclusions and way forward 33
Acknowledgements 33
References 33
Abstract
The last decades have brought important insight and updates in the diagnosis, man-
agement and immunopathology of female genital schistosomiasis (FGS) and male
genital schistosomiasis (MGS). Despite sharing a common parasitic aetiological agent,
FGS and MGS have typically been studied separately. Infection with Schistosoma
haematobium manifests with gender-specific clinical manifestations and consequences
of infection, albeit having a similar pathogenesis within the human genital tract.
Schistosoma haematobium is a known urinary bladder carcinogen, but its potential caus-
ative role in other types of neoplasia, such as cervical cancer, is not fully understood.
Furthermore, the impact of praziquantel treatment on clinical outcomes remains largely
underexplored, as is the interplay of FGS/MGS with relevant reproductive tract infections
such as HIV and Human Papillomavirus. In non-endemic settings, travel and immigrant
health clinics need better guidance to correctly identify and treat FGS and MGS. Our
review outlines the latest advances and remaining knowledge gaps in FGS and MGS
research. We aim to pave a way forward to formulate more effective control measures
and discuss elimination targets. With a growing community awareness in health prac-
titioners, scientists and epidemiologists, alongside the sufferers from these diseases,
we aspire to witness a new generation of young women and men free from the
downstream disabling manifestations of disease.
An update on female and male genital schistosomiasis 3
1. Introduction
As a neglected tropical disease (NTD), interventions against schisto-
somiasis are featured within the recently outlined WHO 2021–30
Roadmap (WHO, 2021a). Preventive chemotherapy against urogenital
and intestinal schistosomiasis-related morbidity is strongly encouraged and
disease-specific control targets are also defined. However, the detection
and management of disease sequelae within the female and male genital
tracts due to urogenital schistosomiasis, remain unaddressed. In this review,
we seek to highlight the importance and often overlooked connections
between female genital schistosomiasis (FGS) and male genital schistosomi-
asis (MGS), addressing disease-specific needs and challenges in endemic and
non-endemic settings, respectively. Our review presents a comprehensive
summary of the recent published evidence about FGS and MGS to ulti-
mately inform policy makers to support integrative approaches for disease
management.
1.1 Selection criteria

References were searched in PubMed and Medline databases using the key
words ‘female genital schistosomiasis’, ‘male genital schistosomiasis’, ‘genital
or urogenital schistosomiasis’, ‘praziquantel’, for the last 10 years (2011–21)
with the terms ‘AND’, ‘OR’. A total of 324 articles were identified.
Abstracts were reviewed for suitability and were included in this review if
they pertained to any discipline related to FGS and MGS. A total of 123 arti-
cles related specifically to FGS published in the last decade were screened
and 85 were reviewed. No clinical trials were identified. For MGS, 56 arti-
cles were retrieved and only 32 were found to be related to the topic. A sea-
rch for articles covering both FGS and MGS retrieved 29 results but only
3 studied both diseases jointly. Historical articles were included where
relevant
1.2 Epidemiology and geographical distribution of genital

schistosomiasis
The global distribution of FGS is estimated to be around 50 million people
limited to S. haematobium endemic areas in sub-Saharan Africa (SSA)
(Christinet et al., 2016). Urinary schistosomiasis (viz. S. haematobium eggs
in urine) and FGS often co-exist, and are commonly referred to as urogenital
schistosomiasis. For example, a Tanzanian study reported concurrent FGS
diagnosed by histopathology in 62% of 543 women with urinary schistoso-

miasis (Poggensee et al., 1998). Overall, there are fewer studies evaluating
FGS compared with the broader disease definition of urogenital schistoso-
miasis, including urine-based diagnostics with and without genital involve-
ment. Thus, accurate geographical estimates for FGS are lacking and remain
an extrapolation from the broader disease manifestations. Estimates for
MGS are scarce and also rely on extrapolation of a wider range of clinical
manifestations attributed to S. haematobium (Kayuni et al., 2019a).
Genital schistosomiasis is an inflammatory parasitic disease caused when
eggs from the waterborne blood fluke S. haematobium, are lodged within the
reproductive organs. Genital schistosomiasis affects both females and males
(Colley et al., 2014; Kjetland et al., 2012; Yu et al., 2013). FGS and MGS are
not yet included in the global burden of disease estimates of 1.44 million
disability-adjusted life years (DALYs) attributed to schistosomiasis, despite
the well-known disabling morbidities associated with FGS (DALYs and
Collaborators, 2018). Control efforts for schistosomiasis, noting urogenital
and intestinal manifestations, broadly focus on decreasing heavy intensity
infections leading to severe morbidity in school-aged children in the urinary
tract, and in the liver and spleen, respectively (Savioli et al., 2017; WHO,
2020). This approach neglects to recognize manifestations related to genital
disease that are often difficult to quantify such as infertility, ectopic pregnan-
cies, sexual dysfunction and menstrual disorders (Bustinduy et al., 2017;
Helling-Giese et al., 1996a; Kjetland et al., 2008; Stothard et al., 2020b).
WHO has recognized the hidden manifestations of FGS as a public health
problem whereas MGS remains unacknowledged, not only by its sufferers
but also overlooked in health statistics captured across the continent of
Africa and other schistosome endemic locations (WHO, 2020). Fig. 1 shows
the limited number of countries with reported FGS and MGS studies.
The recognition of gender differences is necessary, as they may impact
exposure, transmission, manifestation and treatment for genital schistosomi-
asis (Ozano et al., 2020). Importantly, there are several differences in disease
awareness and social stigma for each disease manifestation (Mazigo
et al., 2021).
1.3 Life cycle and transmission

The life cycle of the waterborne Schistosoma species is complex but can be
highly efficient when certain temperature and humidity environmental
conditions are met; this can result in universal exposure and infection in
Fig. 1 Countries with FGS (A) and MGS (B) case reports and studies in S. haematobium
endemic areas in sub-Saharan Africa published to date. Panel (A) is adapted from
Sturt, A.S., Webb, E.L., Francis, S.C., Hayes, R.J., Bustinduy, A., 2020a. Beyond the barrier:
female genital schistosomiasis as a potential risk factor for HIV-1 acquisition. Acta
Trop. 209, 105524 and Panel (B) is adapted from Kayuni, S., Lampiao, F., Makaula, P.,
Juziwelo, L., Lacourse, E.J., Reinhard-Rupp, J., Leutscher, P.D.C., Stothard, J.R., 2019b. A sys-
tematic review with epidemiological update of male genital schistosomiasis (MGS): a call for
integrated case management across the health system in sub-Saharan Africa Parasite
Epidemiol. Control 4, e00077.
communities that have unsafe water contact (Satayathum et al., 2006). In

Africa, two main Schistosoma species infect humans, S. haematobium and
S. mansoni (Lai et al., 2015). While cross-specific worm pairings occur
within a co-infected host, it is likely that successful mating between these
two species is very rare although such mixed worm pairs may lead to ectopic
egg deposition (e.g. S. mansoni eggs in urine) and associated pathology
(Stothard et al., 2020a) (Fig. 2).
Schistososoma mansoni primarily causes hepatosplenic and intestinal
disease, while S. haematobium is strongly associated with urogenital manifes-
tations. In mixed heavy infections, S. mansoni eggs can be excreted in the
urine (mansonuria), contributing to urinary tract disease. This is most likely
resultant from mixed worm pairings between S. haematobium and S. mansoni,
with S. mansoni females being carried by S. haematobium males to the uro-
genital system (Doehring et al., 1986). Schistosoma haematobium infections
are endemic in Africa, the Middle East, and now also in Corsica (France)
(WHO, 2020), while S. mansoni is distributed in Africa, the Middle East
and also the Americas (Colley et al., 2014). While co-infection with both
Fig. 2 The life cycle of S. haematobium. Adapted from Countdown (https://countdown.

lstmed.ac.uk).
parasites is common, its epidemiological occurrence is only rarely reported,

even by WHO. In 2012, for example, 163 million men and women in Africa
were infected with either of these two Schistosoma species with about a quar-
ter having dual infections. Some 57 million (35%) are school aged children
(Lai et al., 2015). Much of the pathological description of S. haematobium’s
related disease has focused on urinary abnormalities, ignoring the less obvi-
ous genital complications of the disease (Bustinduy et al., 2021).
FGS is defined by the detection of parasite eggs or DNA in genital tissue
or in secretions. Schistosoma eggs (also referred to as ova) are immunogenic,
and once tissue-entrapped they invoke granulomatous inflammation. The
accumulation of eggs in genital tissues over time results in subsequent mor-
bidity and organ dysfunction (Kjetland et al., 2014). Worm migration pat-
terns of adult schistosomes and the accessibility of genital organs via the
pelvic venous plexus explain why genital manifestations are so common
in S. haematobium infections and their disease sequelae more noticeable in
sexually active adults. Signs and symptoms therefore overlap with many sex-
ually transmitted infections (Poggensee et al., 2000). Depending on where
Fig. 3 Schistosoma haematobium egg deposition in the female and male genital tracts
causing female and male genital schistosomiasis. Graphic components courtesy of
https://smart.servier.com/.
eggs are released, clinical pathology develops in the vulva and vagina, cervix,
uterus, fallopian tubes and the ovaries (Kjetland et al., 2012) (Fig. 3). All gen-
ital organs may be affected simultaneously, and their dynamics change
through time concurrent with administration with praziquantel, the only
available deworming medication that is active against Schistosoma spp.
(WHO, 2020).
Male genital schistosomiasis (MGS) is a specific chronic manifestation of
schistosomiasis, associated with presence of Schistosoma eggs and pathologies in
male genital fluids and organs of men inhabiting or visiting schistosomiasis-
endemic areas. Of the 54 countries in Africa, only 20 of them have formally
reported FGS and 17 countries have MGS reported cases in the literature
(Kayuni et al., 2019b; Sturt et al., 2020a).
1.4 FGS and MGS in less common Schistosoma species

Although uncommon, genital manifestations of the disease are not always
directly related to infections with S. haematobium alone. In a Tanzanian
study, 5% (19/359) of women who underwent gynaecological exam had
S. mansoni eggs detected in cervical tissue and 52.6% (10/19) had both
S. haematobium and S. mansoni eggs present in genital samples (Poggensee
et al., 2001a). In S. mansoni endemic areas in Brazil there are reported
FGS cases affecting the fallopian tubes (Faria et al., 2010) and presenting
as ovarian tumours (Cavalcanti et al., 2011; Feldmeier et al., 1998).
There are several reports of MGS caused by species other than
S. haematobium; for example, a case of testicular schistosomiasis leading to

secondary infertility was reported in a S. mansoni endemic area in Nigeria
(Adisa et al., 2012) and prostate involvement reported in a patient with
Schistosoma japonicum living by the Yangtze river in China (Yu et al., 2013).
1.5 The importance of different hybrids of S. haematobium

group species (including minor species contributing
to FGS/MGS)
There are currently 23 Schistosoma species, 13 of which are found in
sub-Saharan Africa, which are split into three species groups.
S. haematobium resides within the S. haematobium species group, which con-
sists of nine closely related species all of which share the characteristic of ter-
minal spined ova. Apart from S. haematobium two other species within this
group are considered to be human pathogens S. guineensis and S. intercalatum,
both of which cause intestinal schistosomiasis in specific foci in central
African regions. Other species within the group are considered pathogens
of mammalian livestock and/or wildlife. Of note is the occurrence of
S. haematobium hybrids; S. haematobium-guineensis, S. haematobium-bovis,
S. haematobium-curassoni, S. haematobium-mattheei, the latter three involve
livestock Schistosoma species and raise concerns over zoonoses and animal
reservoir hosts. Mixed species combinations are likely to result in ectopic
egg excretion and/or deposition, though there is still much to learn about
these hybrid forms, together with their potential impact on schistosomiasis
control. This has been observed for co-infections between S. haematobium
and S. mansoni where the species are urogenital and intestinal forms,
respectively.
Schistosoma intercalatum and Schistosoma guineensis have not been specifi-
cally reported to be involved FGS or MGS, either alone or in combination
with an underlying S. haematobium. However, this association has never
actually been investigated. This absence, together with that of any morbidity
impact of S. haematobium hybrid forms is more likely to represent a deficit in
application of precise species-specific diagnostic methods per se rather than
these species’ inability to colonize veins surrounding the genitalia and
deposit eggs therein.
The same molecular genetic markers that have been used to characterize
these species and hybrid forms collected from their human hosts, could be
applied for a more in-depth analysis of clinical materials associated with FGS
and MGS. This could involve the evaluation of ejaculate or cervicovaginal
samples with molecular diagnostics, to gauge the extent to which existing
S. haematobium-hybrids contribute to genital schistosomiasis. A further

research need is an improved understanding of not just the epidemiology
of S. haematobium-hybrids, but also their role in inflammation, and
organ-specific responses, including FGS and MGS (Baay et al., 2004;
Kayuni et al., 2019a; Leutscher et al., 2009).
2. Pathogenesis and clinical manifestations

2.1 Female genital schistosomiasis (FGS)
FGS was specifically recognized in the medical literature over 100 years ago
(Madden, 1899), but it is still often incorrectly reported and seldom treated.
This is partly due to overlapping symptoms with sexually transmitted infections
(Christinet et al., 2016; Kjetland et al., 2012). As a neglected gynaecological
condition in SSA, FGS is not frequently considered in clinical practice, with
both patients and practitioners alike unaware of the disease and its downstream
sexual and reproductive health consequences (Ngwenya, 2016).
The pathogenesis of FGS is the result of a complex inflammatory
immune response driven by the antigens released from both viable eggs,
which have been entrapped in genital tissue, and adult worms located in
small veins of the pelvis (Fig. 3). Inflammation occurs in all strata of the gen-
ital tissue including the small blood vessels ( Jourdan et al., 2011a, 2013).
Schistosomiasis related inflammation extends beyond egg-deposition site
eventually affecting entire organs (Ramarokoto et al., 2014; Schanz et al.,
2010). Lesions in the vulva, vagina and the cervix are easiest to detect
and can be identified with a colposcope (Yirenya-Tawiah et al., 2011).
Deeper lesions in the uterus, the Fallopian tubes and the ovaries are challeng-
ing to assess (Andrianjafitrimo et al., 2019) but the ensuing pathology is asso-
ciated with chronic morbidity and can sometimes be life-threatening
(Kjetland et al., 2010; Norseth et al., 2014; Schanz et al., 2010; Swai
et al., 2006) and often negatively impacts women’s reproductive health
(Laroche et al., 2016; Laxman et al., 2008).
Studies in Niger, Malawi and Zimbabwe have found that up to 75% of
women with urinary schistosomiasis also have S. haematobium eggs distrib-
uted in the genital tissues (Kjetland et al., 1996, 2005; Poggensee et al., 1998;
Renaud et al., 1989). However, just as importantly, at least 20% of women
with Schistosoma genital involvement did not have eggs present in the urine
(Poggensee et al., 1998). These data highlight the non-linear relationship
between egg detection by different diagnostic methods and established
genital morbidity.
Vulvar or vaginal ulcerations and papillomata have been associated with

FGS (Goldsmith et al., 1993; Laven et al., 1998; Yirenya-Tawiah et al.,
2011). These may lead to stigmatization if the findings are misinterpreted
as being caused by a sexually transmitted infection (Goldsmith et al.,
1993). Consequences of FGS may include post-coital pain and bleeding
which are not uniquely identifiable as associated with schistosomiasis. Of
special concern, women with FGS in rural Zimbabwean had a twofold
greater odds of prevalent HIV infection (Kjetland et al., 2006).
Recent population-based and ecological studies have linked FGS with
female infertility and sub-fecundity in endemic communities (Kjetland
et al., 2010; Miller-Fellows et al., 2017; Woodall and Kramer, 2018).
More recently, the Bilharzia and HIV (BILHIV) study in Zambia (Sturt
et al., 2020b), found a twofold increase in delayed conception in women
with FGS as diagnosed by DNA-based detection methods (Mills, 2021).
FGS occurs in women of all age groups, including young girls, and is
associated with important, frequently debilitating and stigmatizing morbid-
ity. Women with FGS report spontaneous or post-coital bleeding, vaginal
discharge, pain during sexual intercourse, pelvic pain, irregular menstruation
and infertility (Kjetland et al., 2008, 2010). Across studies in Zambia and
Zimbabwe, a higher proportion of young women were found to have more
detectable Schistosoma DNA in their genital tract than older women
(Kjetland et al., 2009; Sturt et al., 2020b). Additionally, young girls with uri-
nary S. haematobium may present with gynaecological symptoms prior to
their sexual debut, in particular bloody or foul-smelling vaginal discharge
(Hegertun et al., 2013). These symptoms are frequently attributed to STIs
by health care providers, contributing to the associated stigma. As a conse-
quence, many women are not encouraged to pursue medical help at health
centers and are seeking help from traditional healers (Madagascar KAP study,
Randriansolo, B, personal communication). Vagino-vesical fistulae in
women are unlikely to heal if concomitant schistosomiasis is left untreated
(Richter et al., 2008).
2.1.1 Pregnancy and placental involvement

The placenta may also be involved during chronic Schistosoma infection,
however foetal outcomes of prematurity or lower birth weight are primarily
due to the effect of schistosomiasis on the mother, in conjunction with pro-
tein loss and anaemia (Schleenvoigt et al., 2014). Maternal iron deficiency
during pregnancy is also associated with iron deficiency among infants

(Abioye et al., 2019; Friedman et al., 2007; Mombo-Ngoma et al., 2017;
Siegrist and Siegrist-Obimpeh, 1992). Importantly, the effect of underlying
FGS on pregnancy outcomes has not been explored.
2.2 Male genital schistosomiasis (MGS)

The first case of MGS was reported in 1911 (Madden, 1911). This was
followed by several case reports, post-mortem and histopathological research
studies in the subsequent decades (Corachan et al., 1994; Gelfand et al., 1970;
Leutscher et al., 2000). Like FGS, MGS is underreported and often not rec-
ognized by medical providers in endemic areas. Schistosome eggs passing
through or being entrapped in the tissues of prostate, seminal vesicles, vas
deferens, epididymis and testis, trigger immune reactions and granulomata
formation (Kayuni et al., 2019b). In addition to granulomatous inflammation,
post-mortem and histopathological studies have shown egg-induced lesions
such as fibrosis and calcifications which can also be detected on radiological
examinations (Al-Saeed et al., 2003; Ramarakoto et al., 2008; Vilana
et al., 1997).
In MGS, changes of sperm consistency or blood in semen
(haematospermia) are often presenting symptoms (Corachan et al.,
1994). A particular observation in retuning travellers, haematospermia can
present in the early stages of MGS (Barlow and Meleney, 1949; Feldmeier
et al., 1999; Schwartz et al., 2002) and in some instances at a young age
(Rambau et al., 2011). Symptoms associated with semen quality and outflow
include, coital or ejaculatory pain, abnormal ejaculates, and occasional spe-
rmaturia (presence of spermatozoa in urine). Additionally, orchitis, prostatitis,
dyspareunia, and hydrocele are also associated with MGS. Other potential
symptoms include pelvic pain, erectile and ejaculatory dysfunction or para-
phimosis. To date, the epidemiology, diagnostic testing, specific clinical man-
ifestations and case management of MGS are not well or widely described.
There are little data regarding the current burden of and morbidity among
local inhabitants in endemic areas of SSA.
The aetiology of symptom underreporting in MGS is likely multi-
factorial including stigma associated with genital tract infections and the
potential impact on fertility-despite the quality of the semen being
preserved (Leutscher et al., 2009). Studies in Madagascar and Malawi have
demonstrated resolution of symptoms after anti-schistosomal therapy
(Kayuni et al., 2019a,b; Leutscher et al., 2000, 2009). This finding has
increased interest in including men-at-risk of schistosomiasis during mass
drug administration campaigns in endemic areas.
3. Immunology
3.1 Vaginal environment in FGS
Chronic egg deposition in genital tissues results in the clinical manifestations
associated with FGS (Kjetland et al., 2005). However, studying the natural
history of S. haematobium egg deposition in human genital tissue through to
the formation of cervicovaginal lesions is not ethically permissible and there
are no well described clinical manifestations during acute infection in
humans (Odegaard and Hsieh, 2014). These limitations restrict the current
knowledge to an extrapolation r from animal models. A murine FGS model
has been created through the microinjection of viable S. haematobium eggs
into the vaginal walls of female BALB/c mice (Richardson et al., 2014).
Eight weeks after vaginal egg injection, mice developed egg-associated
granulomata surrounded by eosinophils, neutrophils, and lymphocytes.
Both Schistosoma infection and subsequent egg patency stimulate
immune responses, though divergent in character. Acute schistosomiasis,
also known as Katayama Syndrome is thought to occur in response to the
migration of the immature schistosomula and evokes an initial T helper type
1 (Th1) response (Ross et al., 2007). As the schistosomes mature and pro-
duce eggs, a T helper type 2 (Th2) response prevails, stimulated primarily by
antigens present on schistosome eggs (Pearce and MacDonald, 2002). Both
Th1 and Th2 responses can be associated with morbidity (Fallon, 2000),
while granuloma formation (Pearce and MacDonald, 2002) and clinically
detected hepatic fibrosis in S. mansoni are associated with a Th2 response
(Mutengo et al., 2018). However, a carefully orchestrated balance between
Th1 and Th2 responses is required as an unopposed Th1 response has been
associated with mortality in murine hosts (Fallon, 2000; Fallon et al., 2000).
Studying local cytokines and chemokines can provide additional infor-
mation regarding downstream biological processes associated with
Schistosoma egg deposition. Murine studies emphasize the importance of
studying the immune environment local to egg deposition (Fu et al.,
2012; Richardson et al., 2014). For example, a Luminex multiplex
bead-based immunoassay was used to evaluate cytokine responses in a study
of mice with urinary S. haematobium infection highlighted a Th2 cytokine
bias (interleukin [IL]- 4, IL-13, and IL-5) in the local bladder environment
(Fu et al., 2012). However, when similar techniques were used to evaluate
cytokine concentrations in systemic circulation of mice with FGS, only

differences in RANTES were detected (Richardson et al., 2014).
While the immunology of human Schistosoma infections has been widely
explored, data regarding the immunologic microenvironment in FGS are
limited. In human studies, women with S. haematobium infection, in the
absence of evaluation for genital involvement, have also been shown to have
altered levels of IL-15 in cervicovaginal lavage as well as differences in the
expression of genes associated with regulating extracellular matrix deposi-
tion, angiogenesis, and protease activity in the cervical mucosa (Dupnik
et al., 2019). Recent data on the immunology of FGS suggest the impor-
tance of an evaluation stratified by a measure of the burden of schistosome
infection. In the BILHIV study in Zambia when participants with a medium
to high Schistosoma DNA concentration was detected in any genital speci-
men (cervical or vaginal swab or cervicovaginal lavage (CVL)), higher con-
centrations of Th2 (IL-5) and pro-inflammatory (TNF-α) cytokines were
detected in CVL after adjusting for multiple comparisons and potential
confounders (Sturt et al., 2021a).
3.2 Immune activation during pregnancy

There are currently no studies on pregnancy outcomes or placental involve-
ment in women infected with S. haematobium (Bustinduy et al., 2017).
Studies in the Philippines have shown elevated inflammatory cytokines
(Kurtis et al., 2011) and high levels of endotoxin, a systemic immune activa-
tion marker, in pregnant women whose placentas were concomitantly
infected with Schistosoma japonicum compared to non-infected women
(McDonald et al., 2014). Furthermore, women with high levels of endotoxin
had adverse pregnancy outcomes including prematurity (McDonald et al.,
2014). Despite clear differences in the pathophysiology of S. haematobium
and S. japonicum, which target different organ systems there appears to be
common pro-inflammatory pathways. Further research is needed in women
with FGS to understand gestational issues and in the case of pregnant women
infected with S. haematobium pre-gestational female genital schistosomiasis.
4. Diagnosis of genital schistosomiasis

4.1 FGS diagnostics
Conventional FGS diagnosis is challenging, as it relies on costly equipment
and high-level specialized training seldom available in resource-limited set-
tings. This hinders the accurate estimation of disease burden and challenges
study comparisons due to differences in FGS case definitions. For example,

egg visualization in the genital mucosa is sufficient but not necessary for FGS
diagnosis. Concerns of increasing the risk of HIV acquisition have
preempted the routine use of biopsies for FGS diagnosis (Kjetland et al.,
2012). As a consequence, well conducted histopathological studies are
scarce. Recently, the wider availability of molecular diagnostic assays
allowed methods like PCR to aid in the diagnostic accuracy of FGS, as well
as for MGS, by identifying Schistosoma DNA within samples acquired from
the genital tract (Downs et al., 2013; Kjetland et al., 2009; Kayuni et al.,
2019a; Pillay et al., 2014; Sturt et al., 2020b, 2021a).
4.1.1 Traditional colposcopy

A visual FGS diagnosis involves using a colposcope to obtain a magnified and
illuminated view of the cervix and vaginal walls and fornices (Norseth et al.,
2014). FGS-associated lesions in the vulva/vagina and the cervix are the
most visible and have therefore been described in detail (Norseth et al.,
2014). Characteristic clinical findings associated with FGS include grainy
sandy patches, homogenous sandy patches and rubbery papules (Kjetland
et al., 2014; Norseth et al., 2014; Randrianasolo et al., 2015). Abnormal
vessels have also been described in FGS ( Jourdan et al., 2013) (Fig. 4).
The grains of the sandy patches are approximately 0.05 mm 0.2 mm
long, are shaped like grains of rice, they may be single Schistosoma ovum
or exist in clusters of up to 300 (Randrianasolo et al., 2015). These individual
grains (viz. eggs) are deep or superficially situated in the mucosa, with a char-
acteristic yellow, off-white or golden colour. The deeply situated grains
merge into sub-mucosal plaque-like formations with uneven edges and sha-
des of texture. Sometimes, the mucosa is mottled beneath the surface. The
mucosal surface over the deeply grained patches is smooth and grains are not
mobile. The superficial grains have a distinct shape and colour. Grains can
Fig. 4 FGS atlas of visual diagnosis (WHO, 2015). From left to right: Grainy sandy pat-
ches, homogeneous sandy patches, abnormal vessels and rubbery papules.
often be distinguished easily from each other even when they are clustered
together (WHO, 2015).
The homogeneous yellow sandy patches are defined as sandy looking
areas with no visible grains when using the 15 times magnification setting
on the colposcope, appearing as homogenous, yellow areas (Kjetland et al.,
2005). Rubbery papules were initially found and described in Madagascar
(Randrianasolo et al., 2015), but have been described elsewhere (Ekpo
et al., 2017). They are spheroid, pustuloid, firm (hence rubbery), beige papules
that may give the cervicovaginal mucosa an irregular surface. The rubbery
papules may stand alone, or can be found concurrently with sandy patches.
They are often surrounded by various degrees of vascularisation at their base
(Randrianasolo et al., 2015).
Traditional colposcopes are expensive pieces of equipment that are sel-
dom available in resource-constrained settings, where access to electricity
and adequate infrastructure is limited. Furthermore, they require specialist
training to operate. Where colposcopy is not possible, The Female Genital
Schistosomiasis Pocket Atlas has been developed by the WHO as a visual aid
and is free of charge. This resource was created to raise awareness about
FGS and to facilitate clinical diagnosis by clinical health-care professionals
working particularly in rural areas where schistosomiasis is endemic (WHO,
2015) (Fig. 4).
Alternative means of visual diagnosis in-lieu of colposcopy or medical
expertise are urgently needed to increase FGS surveillance at scale. There
are attempts to develop artificial intelligence visual reading algorithms based
on a computer colour analysis (Holmen et al., 2015b). The computer anal-
ysis identifies the region of interest (the ectocervical mucosa) and splits the
image in multiple colour channels, based on the characteristic colour prop-
erties of the FGS lesions (yellow sandy patches). This method shows prom-
ising results in terms of accuracy, but the specificity needs to be refined
(Holmen et al., 2015a).
4.1.2 Hand-held colposcopy and other hand-held devices

The use of simple electronic devices such as handheld cameras, mobile
phone cameras, or other can be an alternative to document FGS lesions with
acceptable results and have been used in an ongoing study in Madagascar
(Randriansolo, B. Personal communication).
Handheld colposcopy has been widely used for the diagnosis of cervical
cancer in remote settings. A recent systematic review of different available
handheld devices for the diagnosis of cervical cancer screening included
Fig. 5 Images obtained by hand-held colposcopy from women in Zambia and Malawi.
They were all PCR positive for Schistosoma haematobium from genital samples. Outlined
areas highlight homogeneous sandy patches (A, C, D), grainy sandy patches (E, F) and
clusters of eggs (B).
smartphones, a digital camera and several handheld colposcopes, their avail-

ability, price and image quality. The study concluded that two handheld
colposcopes, the Gynocular and Mobile ODT could be potentially useful
for FGS diagnosis (Softeland et al., 2021). In two studies in Malawi and
Zambia, hand-held colposcopy (Mobile ODT) enabled the detection of
FGS lesions as shown in Fig. 5 (Bustinduy, AL. BILHIV study, Personal
communication).
4.1.3 Ultrasound scans and other radiological imaging

The role of advanced imaging modalities such as ultrasonography, CT scan,
and MR scan can aid in assessing the severity and complications of schisto-
some infection (Sah et al., 2015). Ultrasound is a non-invasive imaging
method that cannot detect schistosome infection but rather is used to assess
Schistosoma-induced pathology (Skelly, 2013). Despite the use of more sen-
sitive transvaginal probes, specific schistosomiasis related lesions of the
female reproductive tract are difficult to diagnose by ultrasound
(Ramarakoto et al., 2008). Ultrasound may be helpful in diagnosing com-

plications related to genital schistosomiasis such as sterility, vesico-vaginal
fistulae (Ben-Chetrit et al., 2015; Richter et al., 2008; Schanz et al.,
2010; Schleenvoigt et al., 2014) and gestation issues such as ectopic pregnan-
cies due to granulomatous tubal obstruction (Laroche et al., 2016; Laxman
et al., 2008; Sheorey et al., 2004).
4.1.4 Parasitology diagnosis

It is possible to identify eggs upon microscopy of genital samples through
wet preps or pap smears. However, this technique is not frequently used,
as several studies have demonstrated its low sensitivity ( Jourdan et al.,
2011b; Pillay et al., 2016; Poggensee et al., 2001b).
4.2 Molecular diagnostics (nucleic acid amplification tests)

4.2.1 Real time PCR
Due to their high specificity and sensitivity, DNA detection methods have
become a feasible option for the diagnosis of schistosomiasis (Hoekstra et al.,
2021; Utzinger et al., 2015). Specifically, for FGS, parasite DNA detection
from cervicovaginal lavage has been postulated as a highly specific diagnostic
method with potential to monitor treatment effect (Downs et al., 2013;
Randrianasolo et al., 2015; Sturt et al., 2020b). Although specificity was high,
some studies reported low sensitivities in the detection of Schistosoma DNA in
cervicovaginal lavage samples, ranging from 15% to 53% using visual methods
as the diagnostic reference for FGS (Galappaththi-Arachchige et al., 2018;
Kjetland et al., 2009). More recently, the BILHIV study in Zambia reported
a sensitivity of 80% when Schistosoma PCR was performed on vaginal and cer-
vical swabs obtained through home-based self-sampling and were compared
with detectable Schistosoma DNA in any positive genital sample as a composite
reference. The sensitivity increased to 89% when women with active schis-
tosomiasis, as defined by a positive circulating anodic antigen, were included
(Sturt et al., 2020b). Vaginal and cervical self-sampling at home for FGS
screening was well accepted by participants and can offer a scalable option
for FGS screening and surveillance (Rutty Phiri et al., 2020).
4.2.2 Isothermal diagnostics

Novel molecular diagnostics specifically isothermal (low constant tempera-
ture) molecular diagnostics such as Recombinase Polymerase Amplification
(RPA) (Archer et al., 2020b; Rosser et al., 2015; Rostron et al., 2019) and
Loop Mediated Isothermal Amplification (LAMP) (Gandasegui et al., 2018)

offer an alternative to PCR-based amplification. These assays are better suited
for use in resource-limited settings as they require only minimal equipment,
can be performed using a crude DNA extraction process that can be easily
prepared under field conditions. Results can be rapidly obtained in less than
1 h (Archer et al., 2020a; Lodh et al., 2017).
A previously developed RPA assay (the RT-ShDra1-RPA (Sh-RPA)) has
been used to detect trace levels of Schistosoma ova-derived DNA within
egg-spiked laboratory samples (able to detect a single S. haematobium egg
within 100 μL ddH2O), as well as in clinical urine samples from patients
with very low infection intensities (1–3 eggs per/10 mL) (Archer et al.,
2020b; Frimpong et al., 2021; Rosser et al., 2015; Rostron et al., 2019).
The method is simple, quick (<20 min), portable, low-footprint (can run
at temperatures from 25 to 42 °C) and can be performed using crude sample
preparations.
The Sh-RPA assay has also been piloted to detect S. haematobium DNA
in FGS samples collected as part of BILHIV study in Zambia (Sturt et al.,
2020b). The rapid and portable Sh-RPA assay was able to reliably detect
and amplify S. haematobium DNA within vaginal self-swab samples and pro-
vider obtained cervicovaginal lavage (CVL) using two crude extraction
methods that can be easily and rapidly carried out in field settings. Based
on RT-PCR as the reference test (Sturt et al., 2020b), the Sh-RPA assay
proved to be highly sensitive and specific for self-swab samples, 93.3%
and 96.6%, respectively (Archer, J et al. manuscript under review).
LAMP also has the potential for field-based/point-of-care diagnosis and
assays have been developed for the three main Schistosoma species,
S. haematobium, S. mansoni and S. japonicum. LAMP performs at tempera-
tures between 60 and 65 °C and takes from 30 to 60 min. Its set up can
be simple with low equipment requirements although its design can be com-
plex, needing up to six primers. An assay for urogenital schistosomiasis
proved sensitive and specific, 100% and 86.7%, respectively (Gandasegui
et al., 2018) but has not been tested for FGS diagnosis.
The ease of use, low-resource needs, simplicity and feasibility demon-
strated by LAMP and RPA in field conditions together with the acceptable
level of reproducibility achieved in a reference laboratory, support the use of
these isothermal assays as effective molecular diagnostics for urogenital schis-
tosomiasis in remote endemic areas. These assays have great potential for
field-based point-of-care diagnosis of FGS using self-swab samples.
4.2.3 Histopathology
Direct examination of cervical tissue obtained by biopsy from a suspicious
lesion can be promptly examined by crushing the biopsy specimen between
two glass slides. This technique, known as quantitative crushed biopsy allows
examination for S. haematobium eggs at 100 and provides indisputable evi-
dence of FGS (Poggensee et al., 2001b). However, since eggs may cluster in
the cervix, biopsy and the subsequent histopathology may miss eggs
(Helling-Giese et al., 1996b; Randrianasolo et al., 2015).
4.3 MGS diagnostics

To date, optimal MGS diagnosis remains largely undefined (Kayuni et al.,
2019b). Currently, semen microscopy is considered the standard technique
for diagnosing active MGS. Since Schistosoma eggs can be visualized and
quantified in semen, microscopy can also assess MGS infection intensity.
However, sensitivity and cultural misgivings around the submission and
handling of semen in most rural endemic areas pose challenges for MGS
diagnosis (Kayuni et al., 2019a).
Fig. 6 S. haematobium egg in semen at 400 magnification. Photo credit. S. Kayuni.

4.3.1 Parasitology and molecular diagnostics in MGS

As in FGS, the diagnosis of urinary schistosomiasis is often used as a proxy for
the presence of MGS (Downs et al., 2011). However, this practice lacks sen-
sitivity, as there are reports of schistosome eggs detected in the semen of
patients with no eggs present in the urine (Schwartz et al., 2002; van
Delft et al., 2007) (Fig. 6).
Semen samples need to be processed within 2–3 h of submission and
technicians must allow the semen to liquefy. Thereafter, a drop of well-
mixed semen can be placed on a glass slide with coverslip and light micros-
copy using 40 and 100 magnification can be used to visualize for schis-
tosome eggs. Results can be recorded as eggs visualized per ml of ejaculate
(Kayuni et al., 2019a). Different preservation techniques have been devel-
oped to increase the sensitivity of the assays (Kenguele et al., 2014).
If available, molecular tests can be performed on semen for the detection
of Schistosoma DNA (Kayuni et al., 2019a). Alternative diagnostic methods
for MGS include the detection of soluble egg antigen (SEA) and eosinophil
cationic protein (ECP) in urine and semen and circulating anodic antigen in
serum. The concentration of these proteins correlates with urinary schisto-
some egg excretion but are still not available for clinical diagnosis (Leutscher
et al., 2008).
4.4 Immunopathology in MGS

A single study in Madagascar has explored the immune activation through
seminal egg-induced inflammation in individuals with MGS (Leutscher
et al., 2005). Elevated cytokines (IL-4, IL-6, IL-10 and TNF-α) and
increased leukocytes (eosinophils, lymphocytes) were significantly elevated
in the semen of men with MGS compared to those with no Schistosoma
infection, controlling for sexually transmitted infections (Leutscher et al.,
2005). MGS infection intensity, defined by seminal egg count, was strongly
associated with elevated seminal cytokine concentrations including Th2
(IL-4), regulatory (IL-10), Th1 (IFN-γ) and pro-inflammatory (TNF-α)
immune proteins. Local inflammation is hypothesized to increase viral shed-
ding in the ejaculate from co-infected HIV positive men with MGS, hence
putting the female partner at additional risk of being infected with HIV in
particular if this woman also suffers from egg-induced lesions in the lower
genital tract (Leutscher et al., 2000; Midzi et al., 2017), but longitudinal
studies are needed to confirm this.
5. Co-infections and co-morbidities

5.1 Human immunodeficiency virus (HIV)
Two-thirds (67%) of people living with HIV-1 currently live in SSA
(UNAIDS, 2021). Despite recent advances in HIV prevention and treat-
ment, there continues to be a gender-specific HIV vulnerability, with
new HIV infections disproportionately affecting women and girls. A plau-
sible association between HIV and female genital schistosomiasis was postu-
lated at the height of the HIV pandemic (Feldmeier et al., 1994), with a
cross-sectional study showing an association between HIV-1 and FGS
(Kjetland et al., 2006b).
There is biological plausibility for an association between FGS and HIV.
HIV acquisition occurs at mucosal surfaces where an intact cervicovaginal
epithelium provides a barrier to invading pathogens (Sturt et al., 2020a).
This intact barrier can be disrupted in FGS. The heightened HIV-1 vulner-
ability seen in women with schistosome infection but not in men (Downs
et al., 2017) may suggest a role of the cervicovaginal mucosa. The organs
most commonly involved in MGS are the prostate and seminal vesicles,
internal structures not exposed during sexual contact (Kayuni et al.,
2019a,b) and therefore additional potential mechanisms for HIV-1 vulner-
ability in men with MGS are more likely due to increased viral shedding in
the ejaculate, following similar pathways as in men with sexual transmitted
infections (Cohen et al., 1997; Moss et al., 1995). In females, potential addi-
tional mechanisms include effects on granuloma vascularity ( Jourdan et al.,
2011a) and HIV-1 target cell composition ( Jourdan et al., 2011b) as well as
modulation of HIV-1 co-receptors (Kleppa et al., 2014).
A recent systematic review reported an odds ratio [OR] of 1.85 for the asso-
ciation between prevalent HIV-1 and urogenital schistosomiasis (Zirimenya
et al., 2020). A further metanalysis including both S. haematobium or
S. mansoni infection reported a slightly higher pooled OR 2.3 (95% CI
1.2–4.3) (Patel et al., 2021). Additionally, modelling data suggest that each
S. haematobium infection is association with a 2.9% (95% CI 0.2–5.8%) increase
in HIV-1 prevalence in endemic areas (Ndeffo Mbah et al., 2013). However,
there are also some data against the association of S. haematobium infection with
HIV-1 (N’Zoukoudi-N’Doundou et al., 1995).
S. haematobium seropositivity has been associated with HIV-1 acquisition
in women (Wall et al., 2018). Additionally, in a cross-sectional study in
Zambia, women with FGS were twice as likely to acquire HIV, but with
no statistical evidence for a difference likely due to and a small sample size
and thus limited power (adjusted rate ratio 2.16; 95% CI 0.21–12.30,
P ¼ 0.33) (Sturt et al., 2021b). A subsequent exploratory analysis of women
with a higher burden of Schistosoma infection suggested a potential dose-
response relationship between FGS burden and incident HIV-1 (Sturt
et al., 2021b). Larger, longitudinal studies will be needed to strengthen
the association between FGS and HIV incidence. However, to prevent
life-long complications of both diseases, programmatic integration should
not be delayed.
5.1.1 Interactions with vertically transmitted HIV

To date, there are no longitudinal studies in children with vertically acquired
HIV that evaluate the early development of schistosomiasis-associated mor-
bidity including FGS and MGS (Bustinduy et al., 2014). In this unique sce-
nario, HIV acquisition would precede Schistosoma infection, an intrinsically
different mechanistic pathway to that of adult HIV exposure (where FGS is
hypothesized to precede HIV acquisition). The differences in immunopath-
ological responses in children with vertically acquired HIV may have a role
in shaping schistosomiasis (and HIV) disease manifestations, even if the child
is receiving successful antiretroviral therapy (Bustinduy et al., 2014).
Children’s response to egg excretion and entrapment in the presence of
HIV is also not known. Abnormal egg deposition and subsequent organ
involvement leading to early FGS and MGS is plausible, and should be
explored longitudinally in a cohort of vertically infected HIV positive infants
and children (Bustinduy et al., 2014).
Children born to pregnant women with HIV, S. haematobium and other
helminth co-infection, have a higher likelihood of being HIV positive after
their first year of life (Gallagher et al., 2005). However, the effect of HIV
infection in women with underlying FGS on the mother-to-child transmis-
sion of HIV during delivery is not yet known.
5.2 Human papillomavirus (HPV) and FGS

Human papillomavirus (HPV) is the etiological agent of cervical cancer that
is preceded by cervical dysplasia. Cervical cancer is the fourth leading cause
of death in women worldwide, with an estimated 341,800 deaths/year
(Sung et al., 2021). Despite the recognition of S. haematobium as a urinary
bladder carcinogen (Humans, 2012), few studies have looked at the role
of HPV and S. haematobium co-infection as potential synergistic agents in
cervical cancer pathophysiology.
A plausible pro-neoplastic association between HPV and S. haematobium

has been hypothesized from earlier studies (Feldmeier et al., 1996). Case
reports and cross-sectional studies have used heterogeneous methodology
and FGS definitions, making cross-study comparisons challenging (Coelho
et al., 1979; Dzeing-Ella et al., 2009; Savardekar et al., 2010; Schwartz,
1984; Slavska et al., 2011; Youssef, 1957).
Histopathological studies are limited by the tendency of Schistosoma eggs
to cluster in genital tissue yielding conflicting results. In Malawi, a review of
174 cervical biopsies in women with FGS found no association with dyspla-
sia or cervical cancer (Wright et al., 1982). A larger study analysing 10 years
of cervical cancer and nearly 7000 biopsies in Tanzania did not find an
association between FGS and cervical carcinoma, but found that women
with FGS were younger at time of diagnosis of cervical cancer (A, 1994).
This finding was replicated in South Africa where investigators found that
women with FGS and cervical cancer were 15 years younger than the local
average (van Bogaert, 2011). The women in these series had a clinical indi-
cation for biopsy and furthermore, women accessing healthcare at tertiary
centres are not representative of the population most at risk of FGS, rep-
resenting potential selection bias.
Other gynaecological studies such as Pap smears for the diagnosis of cer-
vical dysplasia have been tested for FGS diagnosis with mixed results and
have been confounded by technical issues. In Zimbabwe, 527 women
underwent visual examination of the vagina and cervix, urine microscopy,
Pap smear and STI testing (Kjetland et al., 2005). No association was found
between FGS diagnosed by visual inspection and cervical dysplasia diag-
nosed by Pap smear. However, a 5-year follow up of a small cohort of
women (n ¼ 37) with high risk HPV serotypes showed that FGS was asso-
ciated with development of cervical neoplasia, but not persistence of
high-risk HPV (Kjetland et al., 2010b). Also, no association was found
between Pap smears for cervical dysplasia and FGS in a study in South
Africa of 394 girls aged 16–23 (Pillay et al., 2016). These results should
be interpreted with caution, as 95–97% of Pap smears from women with
FGS in this study were not interpretable.
Additionally, two case control studies investigated the association
between FGS and cervical dysplasia. The first found no association between
FGS diagnosed by biopsy and HPV diagnosed by PCR, or cervical dysplasia
by Pap smear in 24 women in Ghana from an endemic schistosomiasis area
(cases) compared to women living in a non-endemic area (controls) (Szela
et al., 1993). In a Tanzanian case control study, participants (n ¼ 109) were
compared to 109 German age-matched controls (n ¼ 109). Authors defined

FGS as urine microscopy positive without known genital involvement
(Petry et al., 2003). HPV DNA detection was higher in Tanzanian cases than
in German controls (34.5% vs 26.9%). Prior or current history of schistoso-
miasis was associated with high-risk HPV serotypes (Petry et al., 2003).
A recent study in Zambia, the BILHIV study, was the first study to report a
strong association between women with FGS, diagnosed by genital PCR, and
cervical dysplasia diagnosed by visual inspection with acetic acid (OR 6.8 95%
CI: 1.58–23.37 P ¼ 0.016) (Rafferty et al., 2021). Large longitudinal studies
evaluating HPV DNA persistence and incidence in women with PCR or
biopsy confirmed FGS are lacking and are urgently needed to understand com-
mon pathophysiological pathways in the genesis of cervical cancer. Synergistic
findings would support joint FGS and HPV screening programmes.
6. Immigrants and returned travellers

Among returned travellers, both FGS and MGS diagnosis remain a
rare occurrence and are commonly underreported. Most cases present as
secondary disease manifestations related to overall sexual and reproductive
life changes. Ectopic pregnancies have been reported in female travellers
from Mali (Laroche et al., 2016), Malawi and Tanzania (Sheorey et al.,
2004) and can ensue from tubal obstruction due to bilharziomas (masses of
S. haematobium eggs) that can also be the cause of secondary infertility
(Sheorey et al., 2004). Of note, most clinical disease became patent many years
and often decades after exposure. Some women present with symptoms of
urogenital schistosomiasis such as haematuria and are mistakenly treated for
urinary tract infections (Sheorey et al., 2004). Manifestations similar to those
of sexually transmitted infections (STI), commonly vulvar lesions, can also
confound the diagnosis of FGS as in the case of two returned travellers from
Zimbabwe and Malawi with S. haematobium eggs found in biopsies from
lesions resembling vulvar warts (Carey et al., 2001; Crump et al., 2000).
More extensive manifestations of FGS with ovarian, tubal and endometrial
involvement have been reported after a visit to Malawi (Crump et al.,
2000). Schistosoma serology in these patients confirms parasite exposure
(Carey et al., 2001; Crump et al., 2000) but cannot be used as a marker of
cure since it can remain positive in the long term.
There are few case reports of MGS diagnosed in returned travellers.
Haematospermia was the most common finding in four males returning from
Malawi with two of them presenting with haematuria and testicular
paraesthesia, and one with a tender prostate. All patients had a positive
Schistosoma serology (Schwartz et al., 2002). Semen microscopy can aid in
the parasitological diagnosis of MGS patients presenting with haematospermia
(Torresi et al., 1997) but PCR is likely to increase the yield (Kayuni
et al., 2019a).
Women and men born in endemic areas and migrating to non-endemic
countries are at risk of delayed recognition of the genital manifestation of
schistosomiasis. A large review on schistosomiasis in refugees, immigrants
and returned travellers to Europe reported a large number of individuals
(166/318, 52%) who presented with chronic urogenital symptoms.
However, these symptoms were not distinguished between urinary and gen-
ital complaints (Lingscheid et al., 2017). In a report from an Italian centre,
out of 103 patients, only one patient had FGS as diagnosed by S. haematobium
eggs found in the uterus (Marchese et al., 2018). Other reported cases
include recurrent ectopic pregnancies in a woman born in Zambia and living
in Europe for decades afterwards (Laxman et al., 2008), but many cases
continue to be unpublished and unreported.
7. Management of FGS and MGS

7.1 FGS treatment
Praziquantel (PZQ) is the drug of choice for schistosomiasis and is currently
the only available treatment against human Schistosoma species (Colley et al.,
2014). PZQ is only effective against adult worms with juvenile forms
remaining viable after treatment (Doenhoff et al., 2008). Despite this limi-
tation, cure leads to cessation of egg-deposition (the pathogenic mediator in
host tissues) and this prevents additional organ damage.
PZQ is well tolerated and virtually all trials have confirmed the absence
of toxicity in the liver, kidney, and haematopoietic system. However, minor
side-effects do occur. Praziquantel was initially developed as a sedative due
to its ability to cross the blood-brain barrier. Therefore, it is not surprising
that side effects can include headache, dizziness and somnolence (Bustinduy
et al., 2021). Gastrointestinal side effects related to the gastrointestinal tract
are also common and include epigastric or generalized abdominal pain or dis-
comfort, nausea, vomiting, anorexia or loose stools. The severity of these
side-effects correlates with intensity of infection, but overall, they are generally
mild, transient, lasting between 1 and 3 h, and rarely require intervention.
WHO recommends 40–60 mg/kg of praziquantel in a single dose for
both the treatment and control of schistosomiasis through mass drug
administration programmes in school-aged children (WHO, 2020).

However, this dosing regimen reduces worm load by about 80–90% and
does not guarantee cure, except in very light infections (Downs et al.,
2013) highlighting the need for more frequent dosing. Pharmacokinetic/
pharmacodynamic studies have reported both doses advocated by WHO
to be insufficient in treating children from endemic areas, with modelling
suggesting that at least 80 mg/kg may be needed to achieve cure
(Bustinduy et al., 2020b).
There are inherent flaws in recommending the same dose of PZQ for
public health and clinical outcomes as the indicators of success are different.
In public health campaigns, the desired outcome is to reduce heavy intensity
infections to a prevalence below 1% (WHO, 2006). This approach is thought
to decrease severe morbidity, the ultimate goal of schistosomiasis control
programmes. For WHO, programmes that achieve cure rates of 75% are con-
sidered optimal (World Health Organization, 2010). However, this approach
is likely to leave untreated residual morbidity. Intensified treatments are there-
fore needed and are being evaluated in randomized controlled trials testing
repeated standard dosing of 40 mg/kg of PZQ (Webb et al., 2021). Double
initial dosing is being advocated as the minimum initial treatment needed
in any clinical scenario (Bustinduy et al., 2020a). The rationale for repeated
dosing stems from the assumption that re-infection occurs with maturation
of schistosomula within 4 weeks that become adult worms. High dose-
regimens with a triple dose of PZQ was shown to achieve cure in cases of
travel-associated FGS and is recommended by some medical societies
(Blum et al., 1998; Leslie et al., 1993; Schleenvoigt et al., 2014).
Only a few small studies, evaluating the performance of single dose PZQ
for the treatment of genital schistosomiasis have been conducted (Table 1).
Based on the available data, it is difficult to make conclusions regarding the
efficacy of single dose PZQ given at 40 mg/kg based on the heterogeneity of
methods, study outcomes, and low study power (due to small sample sizes).
None of the studies were randomized controlled trials and did not control
for re-infection. Outcome measures included resolution of infertility
(El-Mahgoub, 1982), reduction of circulating antigen in serum (Richter
et al., 1996), improvement of symptoms (Leutscher et al., 2008c; Richter
et al., 1996), resolution of cervical abnormalities (Kjetland et al., 2006a)
and clearance of Schistosoma DNA in vaginal lavage fluid (Downs et al.,
2013). The clinical pathology present at baseline and follow-up varied con-
siderably from weeks to 12 months. The reduction in the different outcome
measures used varied between zero and 73%.
Table 1 Results of treatment studies on FGS.
Reduction in outcome
Country N Outcome measure Treatment Time interval measures (%) Reference
Egypt 13 Primary infertility Niridazole for 15 months 46% El-Mahgoub
6 days (1982)
Malawi 9 1. CAAa; PZQ 2–9 weeks 1. 80% Richter et al.
2. Complaintsb; single dose 2. 34% (1996)
3. FGS lesions (40 mg/kg) 3. 50
Zimbabwe 1. Presence of FGS lesionsc PZQ 3, 12 months 1. HYSP: 21–36%; Kjetland et al.
260 2. Contact bleeding single dose GSP: 76% (2006a)
(40 mg/kg) 2. 78%
Madagascar 253 Complaintsb PZQ 6 months 52–73% Leutscher et al.
single dose (2008a)
(40 mg/kg)
Tanzania 33 1. Presence of FGS lesions; 6 months 1. 67% Downs et al.
2. Presence of eggs in cervical PZQ 2. 100% (2013)
tissue; single dose 3. 80%
3. Schistosome DNA (vaginal (40 mg/kg)
lavage fluid)
Zambia 32 1. Presence of FGS lesions; PZQ 12 months 1. 0% Samuels (2019)
2. Symptoms single dose 2. 45%
(40 mg/kg)
a
Circulating anodic antigen in serum.
b
Dyspareunia, genito-pelvic discomfort; pain during sexual intercourse, genital itching and others.
c
Homogeneous sandy patches (HYSP) and grainy sandy patches (GSP).
A recently completed RCT for the treatment of FGS in Madagascar

compared five doses of PZQ with the first three doses administered within
24–48 h, a fourth dose at 4 weeks and fifth at 10 weeks compared to standard
of care (40 mg/kg single dose) (Randriansolo, B, Personal communication).
7.2 Treatment of MGS

There are few treatment studies of men with MGS, and only in two coun-
tries; Madagascar (Leutscher et al., 2005) and Malawi (Kayuni et al., 2019a).
Men followed up after 6 months of receiving a single dose PZQ (40 mg/kg)
had a significant reduction in eggs founds in semen and urine as well as lower
levels of pro-inflammatory cytokines and leukocytospermia (Leutscher
et al., 2005). A small case series of five fishermen from Malawi with
MGS were followed up for 12 months after treatment with a single dose
of PZQ 40 mg/kg (Kayuni et al., 2019a). Resolution of symptoms including
delayed ejaculation, reduced semen volume and haematuria, were reported
after 1 year only in one subject. PCR positivity was reported at 3 months
after treatment in two of the subjects. There are currently no randomized
controlled trials comparing different treatment strategies for the treatment
of MGS (Kayuni et al., 2019b).
7.3 Pregnancy
Anti-schistosomal praziquantel treatment of pregnant women is not only
safe, but increases the infant’s iron endowment (Olveda et al., 2016).
Furthermore, it may also prevent pervasive S. haematobium infection in
women of reproductive age who may also have FGS (Bustinduy et al.,
2020b; Friedman et al., 2018; Ndibazza et al., 2010; Olveda et al., 2016;
Tweyongyere et al., 2008). Sadly, despite two randomized controlled trials
in Uganda and the Philippines demonstrating praziquantel safety in preg-
nancy, and revised WHO recommendations, the uptake in endemic settings
is still sub-optimal (Friedman et al., 2018; Ndibazza et al., 2010; Olveda
et al., 2016). In addition, a recent study of PZQ in pregnancy showed a neg-
ligible amount of PZQ is excreted in the breast milk, posing a minimal risk
to the infant and reinforcing the safety and benefits of treating pregnant and
lactating women (Bustinduy et al., 2020b). Special attention must be given
to Schistosoma treatment in pregnant and lactating women during MDA
programmes to decrease disease burden and improve pregnancy and foetal
outcomes (Bustinduy et al., 2017). This approach may prove beneficial
particularly if women have underlying FGS.
8. Disability, stigma and community awareness

Urogenital schistosomiasis is second only to malaria in terms of public
health impact and is one of the most relevant chronic infections among the
world’s poorest people (Hotez and Kamath, 2009; Utzinger et al., 2009;
Yirenya-Tawiah et al., 2016). Few countries in SSA have conducted studies
unveiling the social determinants of FGS and MGS. More specifically, recent
work reported from Cameroon (Masong et al., 2021) and Tanzania (Mazigo
et al., 2021), highlight a worrisome knowledge vacuum on FGS as a treatable
disabling gynaecological disorder. In response to the need to increase FGS
awareness at different levels, a multi-partner initiative has been recently
launched with a focus on Ghana and Madagascar, two endemic countries
for FGS (https://fastpackage.org).
In previous efforts to quantify the global burden of disease attributed
to schistosomiasis, chronic manifestations of disease such as established gen-
ital lesions have been systematically neglected (King, 2010). Disability due to
FGS and MGS will remain unrecognized globally unless the disability-
adjusted life-year (DALY) estimates integrate the disabling consequences
of genital morbidity in their ongoing calculations (DALYs and
Collaborators, 2018).
8.1 Case study: Ghana

Ghana is one of the first five countries to implement the integrated control
program for Neglected Tropical Diseases (NTDs) but with little docu-
mented evidence on FGS (Yirenya-Tawiah et al., 2016). The strategy to
reduce the burden of schistosomiasis in Ghana mainly focuses on children
while neglecting other risk groups, including reproductive-aged women
(Yirenya-Tawiah et al., 2016).
Due to inadequate knowledge about FGS among health workers (Kukula
et al., 2019), community members (Kukula et al., 2019; Yirenya-Tawiah
et al., 2016), and complexities in diagnosis (Engels et al., 2020), obtaining
information about the precise disease burden of FGS is daunting (Engels
et al., 2020). Furthermore, FGS is not included in most textbooks for nurses,
midwives, and medical students worldwide and across sub-Saharan Africa
where the disease is endemic (Engels et al., 2020). This situation further exac-
erbates the poor awareness and diagnosis of FGS and consequently, FGS is
overlooked by national health policymakers (Engels et al., 2020).
Community-based assessment of knowledge and disease burden of FGS

is challenging. For example, studies investigating FGS have been conducted
in a few areas in the country and found that community members and local
health workers had not heard of FGS as a disease entity and were not aware
of the impact of schistosomiasis on women and girls (Kukula et al., 2019;
Yirenya-Tawiah et al., 2016). A common belief was that schistosomiasis
symptoms in girls and women, such as blood in the urine, represented pro-
miscuity as it was believed they could be acquired only by sexual transmis-
sion from males (Kukula et al., 2019).
Many of the health education interventions delivered in schistosomiasis
control programmes do not include information on FGS and its impact on
sexual and reproductive health for both women and men (Yirenya-Tawiah
et al., 2011). Thus, minimal information on this aspect of the disease is avail-
able to endemic communities and the public. A study found that community
members along the Volta Basin did not perceive urogenital schistosomiasis as
an important disease and, therefore, either resorted to self-medication or no
treatment (Yirenya-Tawiah et al., 2011). Other researchers found a lower
level of knowledge for reproductive health implications for urogenital schis-
tosomiasis among females than males (Yirenya-Tawiah et al., 2016).
Stigma associated with FGS was a significant obstacle for girls and
women seeking care at health facilities (Kukula et al., 2019). Health workers
and community members consider boys and men at higher risk of schisto-
somiasis than women and adolescent girls. Because of this misconception,
when younger girls report genital tract symptoms, to the health facilities,
they are often stigmatized by health care workers and are accused of sexual
promiscuity and referred for STI treatment (Kukula et al., 2019). To avoid
stigmatization, adolescent girls prefer seeking home remedies and herbal
medicine to treat symptoms consistent with FGS (Kukula et al., 2019).
9. Programme integration
To achieve integration of FGS and MGS in diagnostic and treatment
platforms, it is paramount to understand if both diseases co-exist in any given
endemic community. Fig. 7 depicts early exposure to S. haematobium
resulting in genital disease at an unknown age, but likely early in childhood.
Exposure to sexually transmitted infections including HPV may lead to ear-
lier development of cervical cancer and increase the risk of HIV and STI
acquisition for both females and males. The role of S. haematobium on the
risk of female and male genital cancers is still largely unknown.
Fig. 7 Natural history of exposure and disease of reproductive tract infections at different
stages of life in a woman and a man. Yellow arrow represents exposure to
S. haematobium, purple arrow depicts the active sexual and reproductive life of a
woman, red arrow marks the exposure to human papillomavirus (HPV). *Not represen-
ted but also important are HIV via sexual transmission and sexually transmitted infec-
tions (STIs) once the woman becomes sexually active.
Opportunities for integration should follow the lead of established,

ongoing programmes that have been rolled out across SSA. As reproductive
tract infections, FGS and MGS can and should be integrated within global
sexual and reproductive health (SRH) efforts without delay. HIV programmes
have gained momentum across SSA and home HIV self-testing is paving the
way to increased testing in communities and access of hard-to-reach
populations and scaling up couples and partner testing ( Johnson and
Corbett, 2016). Policy organization such as UNAIDS has already taken the
lead to raise awareness regarding the important synergies between FGS and
HIV through a seminal report (UNAIDS, 2019).
In November 2020, the World Health Assembly (WHA 73) set forth
The WHO global strategy to accelerate the elimination of cervical cancer
as a public health problem by 2030. It focuses on three key pillars:
prevention through HPV vaccination; screening and treatment of
pre-cancerous lesions; and management of invasive cervical cancer.
Fig. 8 Conceptual framework for integration of FGS and MGS into existing programmes;
schistososomiasis control programmes and sexual and reproductive health routine care.
Absent from this strategy was the potential impact of co-morbidities (like
FGS) that may hinder the success of these efforts if overlooked.
Recent WHO 2021 guidelines for the screening of HPV advocate for
self-sampling as an acceptable technique to increase surveillance followed
by molecular testing (WHO, 2021b). Integrating HPV and FGS screening
through genital self-sampling for the joint detection of DNA could be a
cost-effective strategy at scale to prevent cervical cancer and other adverse
reproductive health outcomes.
In parallel, FGS and MGS diagnosis, treatment and increasing awareness
efforts should be bolstered in control programmes guided by the new
Neglected Tropical Diseases WHO road map 2021–30 and its vision for
the next 10 years (WHO, 2021a). An integrated FGS/SRH approach is
in line with the three pillars of the roadmap that promote accelerating
programmatic action (pillar 1), intensify cross-cutting approaches (pillar 2)
and change operating models and culture to facilitate country ownership
(pillar 3). Fig. 8 summarizes potentially scalable strategies that can be taken
up by countries integrating FGS and MGS screening, diagnosis and treat-
ment within their ongoing control programmes and SRH strategies.
10. Conclusions and way forward

This review is a comprehensive summary of the advances in research
and implementation strategies set forth for FGS and MGS combined. It
describes a clear pathway forward for integration for two diseases that are
found concomitantly with other SRH conditions. A common agenda needs
to be prioritized by affected countries as a holistic approach to health and
wellbeing including both females and males. Early identification of infection
and disease are paramount in delivering treatment to avoid reproductive
complications and severe sequalae. We call for a broad and synergistic
approach to disease surveillance and management. The time is now to inte-
grate efforts and move forward jointly to reach the visionary disease goals for
2030 and beyond.
Acknowledgements
We dedicate this review to all the study participants and disease sufferers that can directly or
indirectly benefit from increasing the knowledge of FGS and MGS.
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consequences; and doing evil to be evil in itself, and evil in its
general and final consequences. In fact, as much is assumed in the
argument.[6]
But, however, if the discussion we have been passing through
supplies a true and complete solution of the interesting question this
chapter propounds, and I cannot but think that it does, then one of its
consequences will be, (though, indeed, it is a consequence in which
the world will not, now, take much interest) that Bishop Warburton’s
much-bruited Theory of the Divine Legation of Moses—as a
schoolboy I rejected it, but could not then answer it—will prove to be
but an Escurial in the air. That the Mosaic Dispensation made no use
of the Doctrine of a future life does not prove that it was upheld by a
daily renewed miracle. With contemporary and subsequent history
before us, we can see that the omission was originally made on
logical and administratively wise grounds.
We ask permission for one remark more. It will be observed that

the foregoing disquisition assumes to some degree that there is a
logical basis for belief in a future life. It is the argument which arises
in the bosom of social development. It is not precisely the same
process of thought as that which appears to have first implanted the
idea in the mind of the Aryan: that was, in some measure, founded
on a sentiment, which arose from the bosom of nature. But, however,
the old Aryan sentiment which, though a sentiment, had its logic,
combined with the distinctly logical argument, founded on the
recognition and eternity of justice, which there is no possibility of
working out on the stage of this world, where the same act carries
one man to the gallows and another to the throne, and which
argument social development makes palpable and intelligible, will
satisfy many minds and must have weight with every mind. That
something, and even that much, can be said on the other side, is a
remark of no weight. It is merely an assertion that, in this respect, the
question before us does not differ from other moral and religious
questions. The same observation may be made of every one of
them; for this is a world, as all must see, in which belief, just like
virtue itself which is the matured fruit of belief, can be the result only
of a right choice, after honest deliberation, between conflicting
considerations. This is of its very essence. The great argument,
however, itself, and everything that depends upon it, are lost to, and
obscured by, those who have persuaded themselves, and are
endeavouring to persuade others, to accept precisely what Christ
overthrew, and which He overthrew precisely that He might establish
belief in the future life.
I have dwelt on the question of this chapter, not on account of its

intrinsic interest, although that is great, but because it is a necessary
part of the survey of old Egypt. The history of Egypt must include
some account of the influence it had upon the world; and a great part
of that influence had to pass through, and be transmitted onward by,
the Hebrews. It was imperative, therefore, in a work of this kind, that
some attempt should be made to obtain a true conception of the
relations of Israel to Mizraim; and the most essential part of those
relations is that which is intellectual, moral, and religious. This
appears to be the only intelligible meaning that can be attached to
the reference ‘out of Egypt have I called my son’: His capital doctrine
was what had been the capital doctrine of Egypt. If, however, the
reference was not intended to have any meaning in the intellectual,
moral, and religious order, this passing comment is non-suited and
must be withdrawn. But, whatever may be the value of the
explanation I have been just attempting to give of the particular
question that has been before us, the fact itself remains, standing
forth on the long records of history as one of the most important they
contain, that, while the belief in future rewards and punishments was
the motive power of morality and religion in Egypt, among a
neighbouring people, who had in some sort been a secession from
Egypt, and always continued to be more or less affected by it,
morality and religion were able, under most adverse circumstances,
to maintain themselves for fifteen centuries without any formal or
direct support from this belief.
Verily we are debtors to the Jew for the great lesson contained in
this fact. Another religion—that one indeed which at the present day
commands the greatest number of believers—does, as some of its
own doctors tell us, leave open, to a considerable extent, this
question of future rewards and punishments, contenting itself with
teaching that virtue is its own sufficient reward; and that should it
have any consequences in a life to come they cannot be evil: and
the bearing of this evidence on the point before us is not
unimportant. Those, however, who are in the habit of passing by
unheeded what more than 300,000,000 of the human family have to
say on such questions, will not think it immaterial what the Jews
believed. And never had any people more unclouded faith in the
eternity and ultimate mundane triumph of truth, of right, and of
goodness than the Jews, although they seldom had any thought, and
then only very dimly; that they should themselves participate in, or
witness that triumph: they lived and died in the faith of it, never
having been supported and strengthened by the sight of it, but only
by the desire to see it: the better condition, which was to make
perfect theirs, having been reserved for other times. Never, however,
were any people more ready to sacrifice everything, even to life
itself, in proclaiming, and endeavouring to carry out, what they
believed. It was this that prompted, and made successful, the
Asmonæan insurrection against Greek domination; and which
afterwards impelled them to challenge single-handed the world-
Empire of Rome. Contemporary history, like much that has been
written subsequently, did not understand, indeed quite
misunderstood, their motives, and what was stirring within them; and
so failed to do them the honour they deserved for their heroic efforts
to prevent the extinction of their religion and morality. We, however,
can now, at the same time, both do them justice, and acknowledge
our obligations to them, for having taught us that the moral
sentiments have such deep root in man’s nature; and can maintain
so vigorous an existence by their own inherent power, without aid
from other-world hopes and fears, and against all of force or
seduction with which this world can assail them. This, I submit,
throws light upon much that, at the present day, and amongst
ourselves, stands somewhat in need of proof and distinctness.
It shows, I think, that there are in our composite mental and bodily
constitution principles, or laws, of morality, which, as they are
indestructible, and capable of maintaining themselves, and of acting
vigorously, under even the most adverse circumstances, must be
regarded as inseparable and essential parts of our being. This fact in
the natural history of morality may be illustrated by an analogous fact
in the natural history of language. A man cannot but use language,
and he cannot but use it in conformity with certain rules and laws. He
cannot alter one law of language any more than he could invent a
new language: he can even hardly add a single word, deliberately
and designedly, to an existing one. And he must not only use
language in conformity with its natural laws, but he must also use
that particular form of it which the working of general laws has
developed, necessarily, both for him, and in him. Just so is it with
morality. Indeed, the parallel is so complete as to lead one to
suspect that morality must to some considerable degree be
dependent upon language. Man seems to invent it; and so he does
in a certain sense. But, however, he cannot help inventing it; and he
must invent it in conformity with certain laws. Over these he has no
control: for though he must use, yet he does not invent, or originate,
them. That falls within the sphere of a Higher Power. In some form or
other, better or not so good, and in some measure, more or less,
morality is a congenital necessity of our being, and if society be fairly
and wisely dealt with (but of this when we speak of the wisdom of
Egypt, and again in our summing up) there are grounds for disposing
us to believe that moral, and not animal instincts, may in any people
be made the lords of the ascendant.
It will be enough to say here that extremes, then, appear in some
sense to have met. We believe just as distinctly as the Jew, or as the
Egyptian, that the law came from God; that in it God speaks within
us, and through us; and that our part is to hearken to, to bow down
before, and obey the Divinity. This involves morality, religion,
responsibility, conscience. They saw this through moral intuition. We
see it also through history and science. The primæval intuition, and
the modern demonstration, constructed out of the materials with
which our hoards of experience and observation have supplied us,
are in perfect accord. Intuition prior to knowledge, and accumulated
knowledge reasoning out the problem, have both arrived at the same
conclusion: and so we have sufficient grounds for believing that no
other conclusion is possible; and that what history has demonstrated
to be inseparable from the working of society, and from the being of
man, will endure as long as society and as man shall endure.[7]
CHAPTER XXVI.
THE EFFECT OF EASTERN TRAVEL ON BELIEF.
Ignorance is the curse of God,

Knowledge the wing whereby we fly to Heaven.—Shakspeare.
The question that I find has been most frequently put to me since
my return home is—What effect travel in the East has on belief?
What the effect may be in any case will, of course, depend on
what were the ingredients and character of the belief. If, for instance,
a traveller makes the discovery that old Egypt was far grander, far
more civilized, and far more earnest than the mention of it in the
Hebrew Scriptures had led him to suppose, he will receive a shock;
or if a man finds the agricultural capabilities of the greater part of
Syria utterly unadapted to English methods of farming, and has no
idea of other methods; and if, furthermore, he is ignorant of the ways
in which commerce can maintain a large population anywhere, he
will receive another shock. We can imagine that such persons will
ever afterwards affirm that the effects are bad. They were bad in
their own minds, and they cannot see how they can be good in any
other mind.
We will take these two instances first. Suppose a different kind of
traveller, one who had previously arrived at some not altogether
inadequate conceptions of the mind, and of the greatness of old
Egypt. He had also observed the fact that these things are not dwelt
on in the Hebrew Scriptures, and had formed some opinion as to the
cause of the omission. Then he will receive no shock from what he
sees in the monuments of the greatness of Egypt, and of the
evidently high moral aims of its religion. Suppose, again, that he had
quite understood that he should not see the same kind of agriculture
in Syria as in Suffolk; and that when he was among the hills he had
found, often to a greater extent than he had expected, that formerly
every rood of ground had been turned to account; it is true, in a very
un-English manner, but still in a manner well adapted to the locality;
that terraces had been formed wherever terraces could be placed;
that corn, figs, olives, vines had been grown on these terraces (on
some hills the actual summit is still a vineyard), and that, where the
ground was not suitable for terracing, it had been depastured by
flocks and herds; and that there is evidence that many hills must
have been clothed from the bottom to the top with olives. And
suppose also that he was quite aware that populous cities could
have been maintained by trade and commerce in Judæa just as
easily, to say the least, as were Palmyra and Petra in the wilderness.
Then he will receive no shock from the un-English agricultural
aspects of Syria. Instead of any disagreeable sensation of that kind,
he will see in the present desolation of the country interesting and
instructive evidence of a change in the channels of commerce, and a
demonstration of the sad fact that where the Turk sets his foot,
although he is a very good fellow, grass will not grow.
But to go on with the discoveries that cause shocks. With many
Jerusalem is the great stumbling-block. If, however, we can imagine
a traveller visiting the Holy City with sufficient historical knowledge to
enable him to recall in a rough way the city of David and of Solomon,
we may be quite certain that he will, as far as that part of the subject
goes, receive no shock from the modern city. The same, too, I
believe, may be said, to a very great extent, even of the city of
Herod. One who can rightly imagine what that city was externally will
not, I think, be disappointed at the sight of modern Jerusalem. I am
not now speaking of the Greek traders, the Roman soldiers, the
Pharisees, and Sadducees, who might have been seen in the
streets, but of the city itself. It must be seen from the Mount of
Olives, and I submit that the grand Mosk of Omar, as beheld from
that point, is a far more imposing structure, architecturally, than the
temple of Herod was likely to have been, which, when seen from a
distance, being in the Greek style of architecture, was, probably, too
much wanting in height to produce any very great effect. The Mosk
combines great height with variety of form, for there are the curves of
the dome as well as the perpendicular lines of the walls and great
windows. The dwelling-houses, too, of the modern city must, with
their domed stone roofs be more imposing than those of the old city.
The cupolas and towers of the churches, and the minarets of the
mosks are additional features. The walls also of the modern city are
lofty, massive, and of an excellent colour; and I can hardly think that
those of old Jerusalem could have added more to the scene. Herod’s
Palace, and the greater extent of his city are probably the only
particulars in which what has passed away was superior to what is
seen now. As looked at from the mount of Olives this day, the city
does not appear to contain a single mean building. History, then, will
again save the traveller from receiving a shock at the sight of the
outward appearance of Jerusalem; or if it must be felt, will much
mitigate its force.
The traveller, however, might be one who had never rambled so
far as the field of history, and was only expecting to find in the
Christians of Jerusalem, that is, in the specimens of the Greek and
Latin communions there, living embodiments of the Sermon on the
Mount; but instead of this, finds littlenesses, frauds, formalism,
animosities, dirt. Of course, he receives a shock; and this is,
perhaps, the commonest shock of all. But the fault was in himself: he
ought to have known better than to have allowed himself to indulge
in such unlikely anticipations.
Every one, then, of these shocks was unnecessary and avoidable.
And now let us look at another order of suppositions. Suppose the
traveller is desirous of understanding something about the efforts
that have been made to interpret, and to shape man’s moral and
spiritual nature under a great, and, on the whole, progressive variety
of circumstances, out of which has arisen, from time to time, a
necessity for enlarging and recasting former conclusions, so as to
include the results of the new light, and to adapt ideas and practices
to new circumstances: then what he sees of the East, and of its
people, will help him mightily in understanding what he wishes to
understand. We are supposing that he has limited his expectations
to certain clearly-defined objects, such, for instance, as the
observation of what now can be seen, that will throw light on the
history of the people, whose record is in the Sacred volume, on what
kind of people they were, and how it came to pass that they became
what they were; and on what it was in the natural order that made
their minds the seed-bed for the ideas, with which, through their
Scriptures, we are all more or less familiar; and on what there was in
the people that made the moral element more prominent and active
in their civilization than in that of Greece and Rome: that is to say, if
his objects are strictly limited to what can be investigated and
understood by what one sees in the East, because it is the
investigation and understanding of what may be seen in the Eastern
man, and in Eastern nature; then I think that travel in Egypt and
Syria will not cause any shocks or disappointments. On the contrary,
I think the traveller will feel, on his return home, that he has brought
back with him some light, and some food for thought, he could not
have obtained elsewhere.
As to myself: for of course I can only give my own experience; and
equally, of course, it is only that that can be of value, should it
happen to possess any, in what I may have to say on this question: I
now feel, as I read the sacred page, that I understand it in a way I
never did before. It is not merely that I can, sometimes, fit the scene
to the transactions—that is something; but that, which is more, I am
better able to fit the people to the thoughts, and even to understand
the thoughts themselves. The interest, therefore, and possibly the
utility, too, of what I read is increased for me. I have seen the greater
simplicity of mind of these oriental people. I have seen that the moral
element in them is stronger, either relatively to their intellect, or
absolutely in itself—I know not which—and obtains more dominion
over them than over our beef-eating, beer-drinking, and indoor-living
people; that the idea of God is more present to them than to us, and
has a more constant, and sometimes a deeper, power over them.
Observations of this kind enable one to see and feel more clearly
what was in the minds and hearts of the old Orientals. This is true of
the whole of Scripture, from the first page to the last; but in an
especial manner is it true of the Psalms and of the Gospels. Before I
visited the East I saw their meaning through the, to a certain extent,
false medium of modern English thought. Elements of feeling and
meaning, which before were unobserved and unknown, now stand
out clear and distinct. I seem to be conscious of and to understand,
in a manner that would have been impossible before, the depth and
the exaltation of feeling of the Psalms, and their wonderful didactic
beauty, the result, clearly, of the feelings that prompted them, rather
than of the amount and variety of knowledge they deal with. The
simplicity, the single-mindedness, the self-forgetting heartiness of the
morality of the Gospel, also, I think, gains much from the same
cause. I think, too, that I understand now, better than I did before, the
fierce tone in which the Prophets denounced existing wrongs, and
their unfaltering confidence in a better future.
And as it is in great matters and on the whole, so is it in small
particulars. For instance, I heard a tall bony half-grey Syrian Arab, in
whose mind I had but little doubt that the thought of God was ever
present, cursing the God of the Christians. It had never crossed his
mind that the God of the Christians was the same as the God of the
Mahomedans. Here was the persistence to our own day of the old
exclusive idea.
A poor native Christian at Jerusalem told me that he believed the
holy places were not known now, because, in these days, men were
not worthy of such blessed knowledge. The old idea again of the
superior holiness of past times. And so one might go on with a
multitude of similar instances.
I will here give a tangible and distinct example of the change in
one’s way of looking at things, and of the consequent change in
feeling, which travel in the East actually brought about in one’s mind,
naturally and without any effort, just by allowing the trains of thought
that spontaneously arose to take their own courses, and, in
combination with pre-existing material, to work themselves out to
their own conclusions.
Formerly I never read the account of the deception Jacob
practised on his father at the instigation of his mother, and at the
expense of his brother; or the imprecations of the 109th Psalm; or
the account of the way in which David, for the purpose of appeasing
God (Who was supposed to be terribly afflicting an innocent people
for the mistaken zeal on His behalf of a deceased king), gave up
seven innocent men, sons and grandsons of Saul, to be hanged by
those whom Saul had sought to injure; without wishing, as I believe
almost everybody does, every time he hears these passages read,
that, by some process of beneficent magic, they could be made to
vanish from the Sacred Volume, and be heard of and remembered
no more for ever. But now they appear to me in quite a different light,
and I regard them with quite different sentiments. Now I am very far
indeed from wishing that they could be made to vanish away. I have
been among people who are, at this moment, thinking, feeling, and
acting precisely in the way described in those passages; and so I
have come to regard them as containing genuine, primitive, historical
phases of morality and religion, and as giving to the record, and just
for this very reason, no small part of its value. This primitive morality,
which has been kept alive all along, or to which men have again
reverted, in the East, belongs to the stage in which subtilty, although
it may, as in the instance before us, palpably mean deception, has
not yet been distinguished from wisdom; when men think they are
serving God by being ready to inflict any and every form of suffering,
and even, if it were possible, annihilation itself, on the man who
rejects, or who does not support, their ideas of morality and religion;
and when the current conception of responsibility is made to include
the family and descendants of the evil-doer. These very
misconceptions and aberrations are in conformity to the existing
sentiments and daily practice of the modern Oriental. With him
deception is a perfectly legitimate means for obtaining his ends; nor,
in his way of thinking, is any infliction too severe for misbelievers and
blasphemers of the Faith; and in the custom of blood-feuds the
innocent descendants of the man who shed blood are answerable
for the misdeed of their forefather. These, then, and similar mistakes,
the contemplation of which is so painful to us, were honestly made,
and were even consequences of deliberate and careful efforts to act
up to moral ideas under the conditions and in conformity with the
knowledge of the times.
I have thus come to see that morality and religion,—and this
includes my own morality and religion—are, in no sense, an arbitrary
creation, but a world-old growth. Thousands of years ago they were
forming themselves, in some stages of their growth, on the hill of
Zion, as they had been previously in earlier stages on the banks of
the Nile, and as they did subsequently in the grove of the Academy,
on the seven hills of Rome, and in the forests of Germany. This has
been brought home to me by actual acquaintance with people whose
morality and religion are different from my own—the difference very
much consisting in the fact that they are still in the early stage to
which the ideas in the passages referred to belong. To associate and
to deal with people who are mentally in the state, which the old
historic peoples were in, is to have the old history translated for you
into a language you can understand. What I now find in myself was
once, in its earlier days, just what I find described in those passages.
My morality and religion, which are my true self, have passed
through that stage; that is to say they were once in the stage of the
Patriarch and of the Psalmist. Virtually, I was in them. My more
perfect condition, therefore, must share the blame which mistakenly
appears—this is a mistake into which unhistorical minds fall—to
belong only to their more imperfect condition. Both are equally parts
of the same growth. I now look upon these earlier stages of my
moral being as I do upon my own childhood. To speak of the ideas,
or of the acts of the Patriarch, or of the Psalmist as, perhaps, I might
have been disposed to speak of them formerly would, I now feel, be
to blaspheme my own parentage. I look with a kind of awe on the
failure—so shocking and so intelligible—of their efforts to find the
right path upon which, through a long series of such efforts, I, their
moral offspring, and heir, have at last been brought. Now I link
myself to the past, and I feel the power and the value of the bond.
Now I know that my religion and morality are not a something or
other of recent ascertainable date; a something or other that has
come hap-hazard; even that might, conceivably, never have been.
They are something, I know, that appertains to man; that came into
being with him, indeed that is of his very being; that has grown with
his growth, and strengthened with his strength; and which
accumulating experience and enlarging knowledge have, all along,
ever been purifying, broadening, deepening. I see distinctly, now,
that they rest on foundations in man himself, which nothing can
overthrow or shake. A conviction is brought home to me that I am
standing on an everlasting rock. Formerly there might have been
some lurking germ of suspicion or misgiving that I was standing on
ground that was not quite defensible. Universal history, rightly
understood, dissipates these enfeebling misgivings, and generates
that invaluable conviction. It is a conviction which nothing can touch,
for it rests on incontrovertible facts and unassailable reasonings; and
which are such as will justify a man in expending his own life, and in
calling upon others to do the same, for the maintenance and
advancement of morality and religion.
And this connexion with the past appears to give a prospective as
well as retrospective extension to my being. If I am in the past, then,
by parity of reason, I am equally in the future. As my moral and
intellectual being was, in this way, forming itself before I was in the
flesh, it will continue, in the same way, the same process after I shall
have put off the flesh. The dissolution of the body will not affect what
existed before the assumption of the body.
These thoughts I did not take with me to the East, or, if I did, they
had at that time only a potential existence in my mind as
unquickened germs. It was what I saw and felt in the East that gave
them life and shape. At all events, I brought them back with me as
recognized and active elements of my mental being.
I am aware that there are some on whom the sight of the
diversities observable among different peoples in moral and religious
ideas has an effect the very contrary to that which I have been
describing. Instead of helping them to bring their knowledge on these
subjects into order, and giving them solid foundations to rest the
structure upon, it appears in them only to make confusion worse
confounded, and to render more incapable of support what had in
them little enough support before. But may not this arise from the
fact that the true idea of history does not exist in the minds of these
persons? For I suppose that just as true science infallibly generates
the craving, and, as far as it reaches, the successful effort, to
harmonize all nature, so does true history the craving, and, as far as
it reaches, the successful effort, to harmonize all that is known of
man. One man observes differences in moral ideas, and thence
infers that it is impossible to arrive at any fixed and certain
conclusions on such subjects. Another man observes the same
differences, but observing at the same time that they are those of
growth and development, thence infers that the principle of which
they are the growth and development must be as real and certain as
anything in the earth beneath, or in the heaven above.
There is no difficulty in understanding the prepotency these ideas
must have in modifying and forming a man’s conceptions of duty and
of happiness.
I have, then, no commiseration for those who receive the kind of

shocks we spoke of at the beginning of this chapter. If a man goes to
the East with anti-historical and unreasonable expectations, there is
nothing in the East, or the wide world, that can, so far as his
expectations go, be of any use to him. Wherever he comes upon
truth it will shock him. Nor do I think that travel in the East will be of
advantage to the man whose minute apprehension is incapable of
taking in anything higher than points of Zulu criticism. This is the
criticism of people who, like those kraal-inhabiting, skinclad
philosophers, are all for small particulars, and who appear to labour
under a congenital incapacity for large views, and for general ideas.
According to their logic, the best established general proposition in
contingent matter is not only utterly false, but even inconceivable, if
they can adduce a single case, or point even, in which it fails. If one
of this sort were to find a burr on your clothes, he would be unable to
see your clothes for the burr; or if he were to go so far beyond the
burr as to form any opinion about your clothes, it would be that they
were bad clothes, because of the burr. I have known a person of this
kind so perverse, that if you had told him that his wife and children
had been burnt to death on the first-floor of a house, the intelligence
would have had no effect upon him, if he chanced to suppose that
you were inaccurate, and were calling the ground-floor the first-floor.
He would be incapable of attending to the intelligence you had
brought him, till this had been rightly understood, and set right. Till
that had been done, he would be unable to think of anything else, or
talk of anything else. Such is the mind of the Zulu critic. Still,
however, there is a place for him, and he is of use in the general
scheme.
But my late excursion to the East not only led to the question
which stands at the head of this chapter having frequently been put
me, and which may be regarded as illustrative of the mental
condition of an educated stratum of society amongst us, but it also
led to my obtaining the following illustration of the mental condition of
the uneducated class amongst us.
Shortly after my return I had the following conversation with one I
knew to be a good specimen of that class—an honest,
conscientious, religious soul.
‘They tell me, sir, you have been a long away off.’
‘Yes, neighbour, I have been to Jerusalem.’
I thought Jerusalem might touch a chord, but was not sure that
Egypt would.
‘What! Jerusalem, sir?’ with great surprise.
‘Yes: Jerusalem.’
‘Now, sir, you have surprised me. I did not know that there was
such a place as Jerusalem in the world. I had always thought that
Jerusalem was only a Bible word.’
CHAPTER XXVII.
THE HISTORICAL METHOD OF
INTERPRETATION.
God who at sundry times, and in divers manners, spake in times past to the
Fathers.—Epistle to the Hebrews.
It belongs very closely to our subject to determine in what sense

the Hebrew Scriptures are to be interpreted, because, if the popular
interpretation is to be maintained at every point, Egyptology, and a
great deal more of what eventually must, and now ought to be, used
in the construction of religious thought, will continue for a time to be
deemed in popular opinion, and to be represented by its guides, as
hostile to religion. I would, then, submit that, if universal history is to
be aided at all by the Hebrew Scriptures, or if they are to be applied
to any historical purpose whatever, they must be interpreted
according to the received canons of historical criticism.
Those who deny this accept, in so doing—if they are logical and
consistent—one or other of two alternative consequences: either that
all contemporary and antecedent history is contained in the
interpretation they put upon the sacred records—that is, in what at
present happens to be the popular interpretation—so that nothing
that is not contained in, or deducible from, or in harmony with, that
interpretation is to be received as history; or else that history has
nothing at all to do with the documents, or the documents with
history.
There are, however, other people, not less learned nor less
desirous of attaining to the truth, who are completely incapable of
accepting either of these two alternatives. They value the Holy
Scriptures too highly to treat them in this way. They believe that,
though their primary object was not historical, they contain much
history of many kinds, and of great value. History of events, of the
human mind, of conscience, of religion—much of the history, in one
word, of man, or of humanity; but, furthermore, they believe—and in
this lies the gist of the controversy—that what they contain on any
one, and on all of these subjects, is to be ascertained only by critical
investigation. The single historical question with them is, when the
documents have been rightly interpreted, what do they really
contain?
They believe that the purpose, the character, and the contents of
the documents, alike, preclude the idea of fraud and deception. The
thought of the existence of any thing of the kind in them had its birth,
naturally and unavoidably, in the popular interpretation. A false and
ignorant interpretation was met by a false and ignorant attack. It
could not have been otherwise; for both belong to the same age. No
one, then, can be deceived by these documents, excepting those
who interpret them ignorantly and wrongly. It is a question of
interpretation. A false interpretation has surrounded them with
difficulties, and in a great measure destroyed with multitudes their
utility and their credit. The true interpretation will remove these
difficulties; and where mischief has been done, restore their credit
and utility.
But there appears to some a preliminary question: that of the right
of interpretation. About this there, however, can be no real question
at all, even among those who support what we call the popular
interpretation. How can they deny to others the right they claim for
themselves, of adopting the interpretation that appears to them most
in accordance with truth and fact? The third, the twelfth, the
sixteenth, and all other centuries, had a right to interpret the
document in the way which at the time seemed true. The nineteenth
century has the same right. The men of other times interpreted it
according to the combination of knowledge, and of ignorance, that
was in them. We must do the same.
Let us see, then, what is the difference between the popular, and
the historical methods of interpretation. Proximately we shall find it
very great; ultimately not much. But the point before us will not be
fully understood until it be seen in a distinct concrete instance. The
popular method goes on the assumption that the modes of thought,
and the modes of expression of early ages, and of other races of
men, must be accepted by us in the sense in which we must take
anything addressed to ourselves by a contemporary author. This, the
historical method tells us, is an impossibility. It has been rendered
impossible by subsequent advances in knowledge, in the
generalization of ideas, and in language through a larger use of
general and abstract terms. The historical method says that archaic
modes of thought, and modes of expression, must be translated into
our modes of thought, and our modes of expression.
I will now give an instance that will include both. In those early
times men had not been trained, as we have been, by ages of
culture, to think abstractedly. They could only think, if we may so
express it, concretely. It was necessary that a palpable image of
what was meant should be before their minds. This was what made
idolatry so attractive to the people Moses led up out of Egypt. It was
so to all the young world, and is so still to all who are in the infancy
of thought. And it was so in a pre-eminent degree with those Moses
had to deal with, for they had been mentally degraded below even
the level of the times, by the hard slavery in which they had been
kept for some generations. Even among our own labouring class this
inability to think abstractedly is very conspicuous. Their want of
intellectual training, their ignorance, their life of toil, their poverty of
language, particularly of abstract and general forms of expression,
are the cause of it. They can never tell you what they themselves
said, or what anybody else said, except in a dramatic form. With
them it is always ‘I said,’ and ‘he said;’ in each case the very words
being given. They cannot indicate the purport of what was said by
the general, or abstract, form of expression that a man consented, or
hesitated, or refused compliance, or remonstrated, &c. General
forms of thought and expression are beyond them. Nor will they, for
they cannot, tell you simply that a thing was done: instead of this
they must tell you every step of the process. That which is very
remarkable, in this nineteenth century, in one class, amongst
ourselves, was a law, a necessity, of thought among those with
whom Moses had to deal.
As a foundation, then, for the theocratic system he was about to
establish, he had to announce the idea, not perhaps altogether new
to some of those who had come out of Egypt, but one to which the
thought of Greece and Rome was never conducted, that God was
the Creator. Suppose, then, that he had contented himself, as we
might, at this day, with stating it in that abstract form. We may be
absolutely certain that the statement would have fallen dead on the
ears of the people, to whom he had to address himself. They could
not have taken in the idea. No effect whatever could thus have been
produced upon them. He was therefore obliged, not as a matter of
choice, but of necessity, to present the idea to them in the concrete.
That is, to give them a series of pictures of creation. This, he had to
say, was the picture of things before creation begun. This was what
was done first. This was what was done next. And so on throughout
the whole. And this was what was said at each act of creation. When
the idea was presented to them in this concrete, dramatic form, they
could understand it, and take it in. It was the only mode of thought,
and the only mode of expression, that were possible then. When
translated into modern modes of thought, and modern modes of
expression, they simply mean God is the Creator. Nothing more.
Those who would press them further, do so because they are not
acquainted with the difference between archaic, rude, uncultured
modes of thought and expression, and those of minds that have
received culture, and been benefited by the slowly maturing fruits of
ages of culture.
This method of historical criticism offers similar explanations of
much besides these first chapters of Genesis. It tells us that good,
and true, and God-fearing men, and who were moved by a holy
spirit, which they described as coming to them ab extra (in which
their metaphysics, if erroneous, were honestly so) could hardly in
those times have thought, or expressed themselves otherwise than
as they did; and that if, through some realization of the Egyptian idea
of the transmigration of souls, they had returned to earth, and were
now amongst us, with precisely the same yearnings for justice, truth,
and goodness they had been moved by in those primitive days, they
would not express themselves now as they did then, but as we do.
Their metaphysics would have become the same as ours. But in
either case there would be no difference in their meaning.
It is evident, by the way, that the historical method of interpretation
differs also, in the effect it has on the feelings and practice, from the
popular interpretation of the present day, and of former times. It is
evident, for instance, that it could not lead a man to denounce the
mythology and religion of Egypt, the aims of which were distinctly
moral, as the invention of devils. The old popular methods of
interpretation, also, naturally sanctioned the persecution of those
who differ from us in religion, as they did at the time of the Crusades;
and of those who differ from us only in interpretation, as in the case
of the treatment of the Vaudois; and in the still more shocking case
of the creation and maintenance of the Inquisition, one of the most
dreadful episodes in human history. The historical method, however,
suggests nothing of the kind. It can regard such extravagancies only
as contradictions of the meaning and purpose of religion.
But to go back to the contrast between the popular and the
historical methods of interpretation as applied to the particular
instance I selected, that of the first chapters of the Book of Genesis.
Some little time back I met with the following illustration of the errors
into which we must fall, if we feel ourselves obliged to take them
precisely in the sense that would belong to their words, had they
been addressed by a living writer to ourselves. There happened to
be an equestrian circus exhibiting in the neighbouring town. The
gardener who was in my service at the time had rather an inquisitive
mind; and the word equestrian, which occurred in the posters that
announced the performance, puzzled him; and as he did not like to
give his money without knowing what it was for, he asked me what
the word meant. I told him it meant an exhibition in which horses
bore a part, and that the word was derived from equus, the Latin
name for a horse.
‘No,’ he exclaimed, ‘that can’t be right.’
‘Yes,’ I rejoined, ‘it is so.’
‘No;’ he continued, ‘it is impossible; because we are told that when
the animals were created they were all brought to Adam, and that

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Advances in Parasitology, Volume 115 -

First edition 2022

Copyright © 2022 Elsevier Ltd. All rights reserved.

For information on all Academic Press publications

Publisher: Zoe Kruze

1. An update on female and male genital schistosomiasis and

2. Vertebrates as uninfected disseminators of helminth

3. Anthelmintic resistance in ruminants: challenges and solutions 171

An update on female and male

Advances in Parasitology, Volume 115 Copyright #2022 Elsevier Ltd 1

1.1 Selection criteria

1.2 Epidemiology and geographical distribution of genital

diagnosed by histopathology in 62% of 543 women with urinary schistoso-

1.3 Life cycle and transmission

communities that have unsafe water contact (Satayathum et al., 2006). In

Fig. 2 The life cycle of S. haematobium. Adapted from Countdown (https://countdown.

parasites is common, its epidemiological occurrence is only rarely reported,

1.4 FGS and MGS in less common Schistosoma species

S. haematobium; for example, a case of testicular schistosomiasis leading to

1.5 The importance of different hybrids of S. haematobium

S. haematobium-hybrids contribute to genital schistosomiasis. A further

2. Pathogenesis and clinical manifestations

Vulvar or vaginal ulcerations and papillomata have been associated with

2.1.1 Pregnancy and placental involvement

during pregnancy is also associated with iron deficiency among infants

2.2 Male genital schistosomiasis (MGS)

cytokine concentrations in systemic circulation of mice with FGS, only

3.2 Immune activation during pregnancy

4. Diagnosis of genital schistosomiasis

study comparisons due to differences in FGS case definitions. For example,

4.1.1 Traditional colposcopy

4.1.2 Hand-held colposcopy and other hand-held devices

smartphones, a digital camera and several handheld colposcopes, their avail-

4.1.3 Ultrasound scans and other radiological imaging

(Ramarakoto et al., 2008). Ultrasound may be helpful in diagnosing com-

4.1.4 Parasitology diagnosis

4.2 Molecular diagnostics (nucleic acid amplification tests)

4.2.2 Isothermal diagnostics

Loop Mediated Isothermal Amplification (LAMP) (Gandasegui et al., 2018)

4.3 MGS diagnostics

Fig. 6 S. haematobium egg in semen at 400 magnification. Photo credit. S. Kayuni.

4.3.1 Parasitology and molecular diagnostics in MGS

4.4 Immunopathology in MGS

5. Co-infections and co-morbidities

5.1.1 Interactions with vertically transmitted HIV

5.2 Human papillomavirus (HPV) and FGS

A plausible pro-neoplastic association between HPV and S. haematobium

compared to 109 German age-matched controls (n ¼ 109). Authors defined

6. Immigrants and returned travellers

7. Management of FGS and MGS

administration programmes in school-aged children (WHO, 2020).

A recently completed RCT for the treatment of FGS in Madagascar

7.2 Treatment of MGS

8. Disability, stigma and community awareness

8.1 Case study: Ghana

Community-based assessment of knowledge and disease burden of FGS

Opportunities for integration should follow the lead of established,

10. Conclusions and way forward

2004. Human papillomavirus in a rural community in Zimbabwe: the impact of HIV

We ask permission for one remark more. It will be observed that

I have dwelt on the question of this chapter, not on account of its

Ignorance is the curse of God,

I have, then, no commiseration for those who receive the kind of