Personal disease. It has therefore been of great personal

Personal background

During my gap year prior to studying medicine
at University of Dundee, I lived for 12 months in Uganda, spending the majority
of time at Jinja, the source of the Nile on Lake Victoria, and some time
helping with health care on Lingira Island on Lake Victoria. I was involved
with the diagnosis and management of patients with Schistosomiasis and have had
experience of the health care burden inflicted by this disease. It has
therefore been of great personal interest to me researching this topic for my
SSC.

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Pathology

Schistosomiasis
is one of the World Health Organisation’s (WHO) Neglected Tropical Diseases. Schistosomiasis
is a parasitic disease caused by an infection with the blood flukes of the
genus Schistoma (1). There are two types of
schistosomiasis: Urogenital schistosomiasis caused by the species S. haematobium and intestinal
schistosomiasis caused by S. guineensis,
S. intercalatum, S. mansoni, S. japonicum or S. mekongi.
S.Haematobium and S. mansoni are the most frequent causes of
disease in Sub Saharan Africa (1). Schistosomiasis is a water borne
disease in which eggs from an infected individual are passed, in the urine or
faeces, hatch in fresh water and release larvae called miracidia. Miracidia penetrate
the tissue of an intermediate host, a specific snail species, where they
multiply and release cercariae back into the water. The cercariae can survive
for up to 3 days in the water (2). During this time, they can
penetrate the skin of humans who come into contact with water. In the case of
intestinal schistosomiasis, the adult worms mature in the mesenteric veins and
their eggs pass into the intestines to reach the faeces. With urinary schistosomiasis, the adult worms
live in veins surrounding the urinary tract and the eggs are excreted via the
urine (2). The schistosomiasis transmission
cycle requires excrement containing eggs, specific fresh water snails as
intermediate hosts and human water contact. Swimming, washing and walking in
contaminated fresh water is the most common cause of infection. Schistosomiasis
is a disease of poverty, characterized by poor sanitation and a lack of clean
water access (3).

Diagram 1:
A diagram to illustrate the schistosomiasis life cycle (4).

Epidemiology

First
recognized in 1902, schistosomiasis effects around 200 million people globally (5), with 90% of the disease burden
found in Sub-Saharan Africa (6). It is estimated that 4.5 million
disability adjusted life years (DALYs) are lost due to schistome infections worldwide
(7). In Uganda, up to 36 million people
are through to be at-risk and approximately 4 million people are currently
living with the disease (8). Intestinal schistosomiasis is
endemic in 73 of the 112 districts in Uganda but prevalence varies from 92% to
2% in different districts (8,9). A 2013 study in Cameroon suggests
that the geographical distribution of the disease is dependent on water
development schemes, control initiatives, the environment and migration (10).

The annual
number of deaths resulting from schistosomiasis in sub-Saharan Africa is over
200,000, but the greatest burden is due to chronic disease (11). The disease has long term
consequences, including infertility. Chronic intestinal schistosomiasis
progresses from abdominal pain and bloody diahorrhoea to hepatosplenomegaly,
periportal liver fibrosis and portal hypertension. Urogenital schistosomiasis
can result in haematuria, dysuria, hydronephrosis, calcification of the bladder
and is rarely related to bladder cancer (12).

Impact on
communities

Water
contact is part of daily activities for those living in rural Uganda. Men commonly
make a living from fishing for tilapia, commonly found in Lake Victoria (13). This traditionally involves
spearing the fish, therefore fisherman frequently swim in the water. Women use
the lakes for washing and children often bathe in the shallow waters of less
than 1.5m, where the concentration of snails is greatest (14).

Schistosomiasis
has an adverse effect on cognitive development due to anemia (7). This has the largest effect on developing
children and can lead to poor educational performance. This may prevent young
people from reaching their academic potential which is linked to an increase in
poverty (3). Iron deficiency is a serious
threat to the health of pregnant women and unborn children (7). On the basis of a 2003 study, the
WHO now recommends praziquantel (PZQ) is given to pregnant and lactating women (15), the most common schistosomiasis
control measure at present. However, some women are excluded or opt out of Mass
Drug Administration (MDA) programmes during pregnancy and lactation, meaning
those with schistosomiasis may be untreated for over 12 months. The common
practice of not treating pregnant and lactating women suggests women are untreated
for years because in rural communities in Uganda, women are either pregnant or
lactating for a substantial portion of their reproductive years. According to
the World Bank, in 2016 83.5% of Uganda’s population lived in rural areas (16) therefore this factor cannot be
underestimated. Schistosomiasis is a risk of increased HIV infection,
especially in females (1). This risk is thought to be
significantly high as a study in 2013 suggested that MDA of PZQ is a highly
cost effective way, as effective as any other measure currently in place, to
prevent HIV infection (17).

Present control
measures

The most
widely used control initiative for schistosomiasis globally, since the 1990s,
is the periodic MDA with PZQ as preventative chemotherapy (PC) (5). PZQ was developed in the 1970’s
but was initially unaffordable for countries where schistosomiasis is endemic.
PZQ is given at a dose of 40mg/kg body weight (5). Nowadays, PZQ is widely available
at cost of US$0.10 per 600mg tablet (18). The Schistosomiasis Control
Initiative (SCI), an international charity from Imperial Collage London, has
been treating people in Uganda since 2003 after initial funding from the Bill
and Melinda Gates Foundation. The SCI has since partnered with the vector
control division in the Ministry of Health in the Ugandan Government and other
aid organisations. They work in 30 affected districts and have successfully reduced
the prevalence to below 10% in 4 formally endemic districts (8). Although effective in lowering the
prevalence of schistosomiasis and the burden of infection significantly by reducing
the egg replication rate (2), there remain several areas for
improvement with the overall schistosomiasis control programme in Uganda. These
must be considered if schistosomiasis is to be eliminated by 2020 or soon
after, in line with the WHO NTD targets. According to the WHO, 37% of the
population at risk in Uganda received PCT in 2016 leaving over 7 million people
unprotected (19). These areas will be discussed
below.

 

 

Graph
1: A graph to show the distribution of Prophylactic Chemotherapy (PC) in
Uganda between 2010 and 2016 (15).

 

 

Areas for
improvement in present control measures:

Target
age group

The MDA
programme has focused on the prophylactic treatment of school aged children
aged 6-16 years old, as this group has the highest rate of infection (5). Pre-school aged children aged
under 6 have been excluded from the MDA programme as there was previously
little documentation on the safety and use of PZQ in this group. However, studies
have shown that children aged 2-4 are at a greater risk than originally thought
(5). Schistosomiasis infection in
younger children can be the most devastating, as the development of chronic morbidity in childhood before they
are given PC at school may increase the long-term severity of the disease (9). A 2017 study published in
the Lancet, suggests that a standard dose of 40mg/kg is safe and effective in
all children over 2 years old (20).

MDA in
schools is generally considered cost effective although, Brooker et al. suggest
more research is needed on a global scale (17). Teachers are trained to administer
PZQ as there are very few side effects and it is very safe (2). However, this is overseen by a
health clinic. The infrastructure is present therefore, little investment is
needed to implement the programme. If carried out as planned, this is
successful in reducing the prevalence of schistosomiasis in school aged children
(21). However, it should be noted the
proportion of children attending schools is often variable, with children from
poorer families and girls underrepresented and overlooked in this key public
health initiative (22).

A
systematic review in 2013 showed that combing a schools based programme with a
community based programme, where volunteers visit homes to administer PC,
results in a further reduction in prevalence in communities (21). This highlights the need of other at-risk
groups within communities for PC such as, the elderly, pregnant or lactating
women.

It is
difficult to give PC to younger children because PZQ is currently available only
in one tablet strength. The large size and bitter taste of the tablet makes it hard
to swallow, with many children gagging or vomiting. Crushing the tablets is a
possibility but if more time consuming and can alter the dose or efficacy of
the drug (23). The Paediatric Praziquantel Consortium
is a recent initiative to develop and register a PZQ tablet formulation to
treat schistosomiasis in preschool aged children. In December 2017, the
European and Developing Countries Clinical Trails Partnership and the Global
Health Innovative Technology Fund announced they will co-fund the phase 3 clinical
trial for this formulation (24). The aim is to produce a small
orally dispersable tablet, with an acceptable taste for children (25). The tablet may be available by
2020, but there are no plans for distribution or financial resource to make the
tablet available to the populations who require it. This is an initiative
which, if resourced and implemented effectively within the near future, could reduce
the prevalence significantly of schistosomiasis in preschool aged children.

Socioeconomic division in communities

A 2016 study showed that the most frequent non recipients of
MDA were individuals of low socioeconomic status, minority religions, and minority
tribes (26). It is important to ensure
that MDA is provided to these groups in a location that is accessible and
acceptable, that information is provided in a language that they understand and
that PZQ is provided without charge. There are many local languages spoken in
Uganda which provides additional challenges to effective distribution (27).

Frequency
of Administration

PC using PZQ
is effective in destroying the mature adult worms within the human body.
However, it is ineffective in killing the preceding immature eggs (13). PZQ does not prevent reinfection and
treatment must be repeated on a regular basis to protect populations (5). Currently, PC is given annually
through MDA. If the life cycle of a schistosomiasis blood fluke was 12 months,
this would be ideal. However, a 2014 study found that 4-6 weeks after the
cercaria have penetrated the human skin, the female adult worms begin to
produce eggs (28). This suggests if treated, 6 weeks
later an individual may be re-infected with the parasite. A different study of
preschool aged children in Uganda in 2014 looked at the benefits of giving a
second dose of praziquantel 2 weeks after the first dose rather than a single
dose with the aim of killing any remaining eggs which mature into adult worms (5). They found that two doses lead to
a significant reduction in egg excretion compared to a single dose. However,
the cure rates one month post treatment and reinfection rates 8 months post
treatment were equal irrespective of a single or double dose. There is some
evidence to suggest that if the intensity of the infection is initially high, a
double dose can lead to increased cure rates (29).

There is
some research which suggests that after repeated rounds of infections and PZQ
treatment, humans may acquire some immunity to S. mansoni leading to partial resistance to re-infection (30).  PZQ increases adult worm immunoglobulin E (IgE)
antibodies, macrophages and mast cells. These are immune cells that resist re-infection
with the parasite (31). This implies children aged 1–5 would
experience increased re-infection because as they have a lesser cumulative exposure
to S. mansoni which is insufficient
to produce partial acquired immunity. This research has encouraged the
development of a vaccine.

Availability
and Distribution

The SCI was
initially funded using US$34 million from the Bill and Melinda Gates Foundation
in 2002 which was used in 6 sub Saharan countries, including Uganda, to deliver
40 million treatments in the initial 5 years (32). More funding was offered following
publicity from the WHO. In 2007 Merck KGaA pledged 200 million tablets of PZQ
over 10 years and increased their donation in 2012 to 250 million tablets
annually by 2017 (32). This was for use in school based
programmes.

Currently
the government funded health system in Uganda implemented by the Ministry of Health
is not accessible in every village. This means MDA of PZQ is administered by Community
Medical Distributors (CMD) who are selected. They are trained annually by a District
Health Officer who is linked to a District Health Centre. CMD are unpaid
volunteers which reduces the cost of the distribution programme (8,26). They can have a positive effect on
uptake by being familiar to communities, setting an example by taking the PC
with the community and visiting before MDA programme. Some of the volunteers
are poorly motivated or have poor communication skills, which can lead to
reduced distribution in the communities (33). Most are not incentivised and
volunteer work can take them away from paid employment (8). Financial incentives may be
successful in increasing the community’s engagement (33).

Administration

When PZQ is
distributed, it is important the correct dose is given and taken under the
right conditions. The efficacy of PZQ is greatest when taken just after food (18,32). This also helps to minimize the
side effects which include: dizziness, headache, nausea, vomiting, stomach
pain, joint pain and a general feeling of weakness and lethargy. However, the
poorest families may not take the drug with food which may reduce the effectiveness.
If people experience unwanted side effects, they may be unwilling to take the
medication in the future, reducing compliance and increasing transmission(18). Therefore, providing some food to
take the medication alongside, although at an additional cost, may increase
effectiveness and compliance.

PZQ dose
should be calculated according to weight. Due to the limited access to actuate weighing
scales the ‘dose pole’ was developed. This allows CMD to administer the drug
according to height, which is easier and possibly more time efficient (7). Although practical and portable,
the dose pole may prescribed an incorrect dose. In around 75% of cases the
patient received a dose in the same range that they would have done if they had
been accurately weighed (7). A 2014 study suggested that there
could be 4 different doses per height of child implying many children receive
an incorrect dose (34).

Health education in the population

A study published in 2017 outlines the perceptions about
interventions to control schistosomiasis in lake shore communities in Uganda.
It revealed that most of the community do not consider schistosomiasis to be a
major health problem anymore due recent programmes implementing MDA of PZQ (13). It suggested the majority
had heard about schistosomiasis from CMD or from teachers at school. Some
members of the community were unsure of schistosomiasis transmission suggesting
drinking contaminated water was the main source of infection. This implies they
do not take relevant precautions to prevent schistosomiasis as individuals cannot
be expected to apply knowledge they do not have. It is important that CMD
receive training on the benefits of receiving PC and communicating with their
community which may incur an additional cost to the programme (33).

Local people do not feel they have the knowledge, skills or
resources to implement public health initiatives as they feel they do not get
enough support from the government (13). They feel undermined rather
than empowered and ignored rather than listened to. Local people have the best
understanding of local issues which suggests investing in the skills and
knowledge of local people to deliver public health education could increase MDA
compliance. Communities must be involved in the designing of interventions to
promote ownership of projects and to make investments long lasting and
sustainable.

Water, Sanitation and Hygiene: WASH

Water, sanitation and hygiene are important areas to address
if the WHO is to meet the target to eliminate schistosomiasis from selected
countries in Africa by 2020 (35). Following the millennium
development goals, the 6th sustainable development goal put forward
by the United Nations in 2015 was to provide clean water and sanitation for
everyone by 2030 (36). As Schistosomiasis is caused
by a parasite that lives in the water, clean water supplies and sanitation are
recognised as being needed as a vital to eliminate schistosomiasis and to
reduce the reservoir of the parasite (32).

In the interim period where access to clean water is not
universal, minimising contact with contaminated water will prevent
schistosomiasis. When this intervention has been discussed in local communities
in Uganda, most females believed it would be a successful intervention
providing safe water sources are available (13). Male participants deemed it
unrealistic because, as fishermen it would affect their income. Development
initiatives aiming to provide clean water for all are part of aid programmes
but few are linked to NTDs despite the association (32).

A 2010 study in the International Journal of Epidemiology found
that incidence of diarrhoea could be reduced by up to 48% by washing hands with
soap and water and up to 36% by disposing of human excrement appropriately (37). Presently, only 29% of
Uganda’s population wash their hands with soap after visiting the toilet (8). Most people have a
willingness to use toilets, but only 35% of people have access to a toilet. The
use of toilets would reduce human excrement in water sources and the
concentration of schistosomiasis eggs. People suggest affordability and
permission from land owners as barriers to having a toilet. There are some
traditional beliefs that use of a toilet will prevent one catching fish or
having children (13). These issues could be
addressed through public health teaching in schools, places of worship and
through community groups.

Molluscicide use

Although PC is the mainstay of prevention nowadays, chemotherapy
alone is unlikely to stop transmission of the parasite (38). Additional interventions
must be integrated to reduce reinfection, lower prevalence and move towards
elimination. The focus on PC over the last 20 years has been successful, but
has potentially limited the development of new ideas for snail control and
reduced research into molluscicides. In the 20th century chemicals
were used to try to eliminate snails from water sources with little success.
Despite this, a report published by the WHO in 2017 strongly encourages the further
development and use of malacological substances to be trialled in partnership
with PC to achieve elimination of schistosomiasis as soon as possible (38).

Population migration and urbanisation

Movement of people from politically unstable or con?ict
zones in Africa into Uganda, such as the south Sudanese refugees, has lead to schistosomiasis
prevalence in previously lesser effected areas. Urbanisation for economic
opportunities has introduced the disease into urban areas where people live in
close proximity and transmission is high (12).

Political influences and government policy

The Government of Uganda provides a health care system where
treatment must be paid individually. However, some programmes, including MDA of
PZQ, are subsidised or fully funded. Health is not the highest priority as they
pursue economic gain. It is
thought that the incidence of schistosomiasis increased after  the construction of the Bujagali
Hydroelectric Dam across the River Nile in 2012 as this increased the
stagnation of the water (14). The hydroelectric dam has enabled
Uganda to generate a large amount of electricity which can be sold to
neighboring countries for a profit. Although the effect on the economy has been
positive, it is believed influenced the health of the population negatively.

Betty Bigombe who was the State Minister for Water Resources
from 2011-2014 feels “sanitation has been marginalised” (8). The government releases US$2
million annually for sanitation projects, equivalent to around $13 000 per
district. She feels this is “negligible.”

The WHO estimate the percentage of people in Uganda with
access to a latrine is 35%, but the Government suggests it is 70% (8). Some aid agencies have
implied Uganda is misleading organisations in order to suggest development.
Uganda ranks 151 out of 176 in Transparency International’s Corruption
Perception Index for 2016 suggesting that there is distrust and dishonestly
between the government and its citizens (39).

 

Vaccination: the future?

Despite decades
of MDA of PZQ, schistosomiasis has not been eliminated and continues to effect
new areas.  The development of a protective vaccine is possibly the most
effective measure for control of schistosomiasis, especially if immunity is
provided after one injection. A vaccine could reduce the burden of disease by
decreasing egg production and parasite load. The proposed vaccine would be
given to children aged 3-12 to prevent severe infection and reduce long term
morbidity (40). If a vaccine was developed, it is likely
that it would be widely accepted by most communities as children are routinely
vaccinated against other life-threatening diseases (13). Government and charitable programmes
exist with trained workers to administer these vaccines and the schistosomiasis
vaccine could be integrated alongside. A vaccine would reduce the need for a
logistically difficult and relatively expensive annual MDA programme. A study
in 2011 suggested that more funding and research should be dedicated to this
area in order to reduce the time taken for a vaccine to be developed (40). A 2016 study echoed the call for more
funding, suggesting a vaccine was an essential part of the elimination tool box
(41). Both studies cautioned against taking some
vaccines currently in development to clinical trial, because they believe there
may be adverse effects. Despite this, scientists are optimistic about a starter
vaccine within a decade.

Conclusion

Overall, the
current MDA programme has been largely successful in reducing the morbidity of
schistosomiasis on communities in Uganda within challenging circumstances.
However, the current levels of PC being administered suggest the target of
elimination by 2020 is unachievable. With more research and funding
schistosomiasis could be eliminated from Uganda soon if a multi system approach
is used. All demographics in at risk populations should be treated with MDA to
reduce transmission within communities. More research is required to establish
the most effective and feasible frequency of MDA given current resources. Training
for CMD to deliver higher quality public health education and incentivising
volunteers may be effective in increasing community engagement. Additionally, it is important global
health bodies encourage pharmaceutical companies to donate PZQ but in
partnership with the Ugandan government committing to allocate funding to
address issues surrounding sanitation and improving basic resources in health
centres. Some multifactorial challenges, such as neighboring conflict, are more
difficult to overcome. However, it is essential that research and development of a potential vaccine, a
paediatric formulation of PZQ and an effective molluscicide continues to have a
multi systems approach to elimination.