Personal backgroundDuring my gap year prior to studying medicineat University of Dundee, I lived for 12 months in Uganda, spending the majorityof time at Jinja, the source of the Nile on Lake Victoria, and some timehelping with health care on Lingira Island on Lake Victoria. I was involvedwith the diagnosis and management of patients with Schistosomiasis and have hadexperience of the health care burden inflicted by this disease.
It hastherefore been of great personal interest to me researching this topic for mySSC.PathologySchistosomiasisis one of the World Health Organisation’s (WHO) Neglected Tropical Diseases. Schistosomiasisis a parasitic disease caused by an infection with the blood flukes of thegenus Schistoma (1). There are two types ofschistosomiasis: Urogenital schistosomiasis caused by the species S. haematobium and intestinalschistosomiasis caused by S.
guineensis,S. intercalatum, S. mansoni, S. japonicum or S. mekongi.S.
Haematobium and S. mansoni are the most frequent causes ofdisease in Sub Saharan Africa (1). Schistosomiasis is a water bornedisease in which eggs from an infected individual are passed, in the urine orfaeces, hatch in fresh water and release larvae called miracidia. Miracidia penetratethe tissue of an intermediate host, a specific snail species, where theymultiply and release cercariae back into the water. The cercariae can survivefor up to 3 days in the water (2). During this time, they canpenetrate the skin of humans who come into contact with water.
In the case ofintestinal schistosomiasis, the adult worms mature in the mesenteric veins andtheir eggs pass into the intestines to reach the faeces. With urinary schistosomiasis, the adult wormslive in veins surrounding the urinary tract and the eggs are excreted via theurine (2). The schistosomiasis transmissioncycle requires excrement containing eggs, specific fresh water snails asintermediate hosts and human water contact. Swimming, washing and walking incontaminated fresh water is the most common cause of infection. Schistosomiasisis a disease of poverty, characterized by poor sanitation and a lack of cleanwater access (3). Diagram 1:A diagram to illustrate the schistosomiasis life cycle (4).
EpidemiologyFirstrecognized in 1902, schistosomiasis effects around 200 million people globally (5), with 90% of the disease burdenfound in Sub-Saharan Africa (6). It is estimated that 4.5 milliondisability adjusted life years (DALYs) are lost due to schistome infections worldwide(7). In Uganda, up to 36 million peopleare through to be at-risk and approximately 4 million people are currentlyliving with the disease (8). Intestinal schistosomiasis isendemic in 73 of the 112 districts in Uganda but prevalence varies from 92% to2% in different districts (8,9). A 2013 study in Cameroon suggeststhat the geographical distribution of the disease is dependent on waterdevelopment schemes, control initiatives, the environment and migration (10).
The annualnumber of deaths resulting from schistosomiasis in sub-Saharan Africa is over200,000, but the greatest burden is due to chronic disease (11). The disease has long termconsequences, including infertility. Chronic intestinal schistosomiasisprogresses from abdominal pain and bloody diahorrhoea to hepatosplenomegaly,periportal liver fibrosis and portal hypertension. Urogenital schistosomiasiscan result in haematuria, dysuria, hydronephrosis, calcification of the bladderand is rarely related to bladder cancer (12). Impact oncommunities Watercontact is part of daily activities for those living in rural Uganda.
Men commonlymake a living from fishing for tilapia, commonly found in Lake Victoria (13). This traditionally involvesspearing the fish, therefore fisherman frequently swim in the water. Women usethe lakes for washing and children often bathe in the shallow waters of lessthan 1.5m, where the concentration of snails is greatest (14).
Schistosomiasishas an adverse effect on cognitive development due to anemia (7). This has the largest effect on developingchildren and can lead to poor educational performance. This may prevent youngpeople from reaching their academic potential which is linked to an increase inpoverty (3). Iron deficiency is a seriousthreat to the health of pregnant women and unborn children (7). On the basis of a 2003 study, theWHO now recommends praziquantel (PZQ) is given to pregnant and lactating women (15), the most common schistosomiasiscontrol measure at present.
However, some women are excluded or opt out of MassDrug Administration (MDA) programmes during pregnancy and lactation, meaningthose with schistosomiasis may be untreated for over 12 months. The commonpractice of not treating pregnant and lactating women suggests women are untreatedfor years because in rural communities in Uganda, women are either pregnant orlactating for a substantial portion of their reproductive years. According tothe World Bank, in 2016 83.5% of Uganda’s population lived in rural areas (16) therefore this factor cannot beunderestimated. Schistosomiasis is a risk of increased HIV infection,especially in females (1).
This risk is thought to besignificantly high as a study in 2013 suggested that MDA of PZQ is a highlycost effective way, as effective as any other measure currently in place, toprevent HIV infection (17).Present controlmeasures The mostwidely 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’sbut 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 availableat cost of US$0.10 per 600mg tablet (18).
The Schistosomiasis ControlInitiative (SCI), an international charity from Imperial Collage London, hasbeen treating people in Uganda since 2003 after initial funding from the Billand Melinda Gates Foundation. The SCI has since partnered with the vectorcontrol division in the Ministry of Health in the Ugandan Government and otheraid organisations. They work in 30 affected districts and have successfully reducedthe prevalence to below 10% in 4 formally endemic districts (8). Although effective in lowering theprevalence of schistosomiasis and the burden of infection significantly by reducingthe egg replication rate (2), there remain several areas forimprovement with the overall schistosomiasis control programme in Uganda. Thesemust be considered if schistosomiasis is to be eliminated by 2020 or soonafter, in line with the WHO NTD targets.
According to the WHO, 37% of thepopulation at risk in Uganda received PCT in 2016 leaving over 7 million peopleunprotected (19). These areas will be discussedbelow. Graph 1: A graph to show the distribution of Prophylactic Chemotherapy (PC) in Uganda between 2010 and 2016 (15).
Areas forimprovement in present control measures:Targetage groupThe MDAprogramme has focused on the prophylactic treatment of school aged childrenaged 6-16 years old, as this group has the highest rate of infection (5). Pre-school aged children agedunder 6 have been excluded from the MDA programme as there was previouslylittle documentation on the safety and use of PZQ in this group. However, studieshave shown that children aged 2-4 are at a greater risk than originally thought(5). Schistosomiasis infection inyounger children can be the most devastating, as the development of chronic morbidity in childhood before theyare given PC at school may increase the long-term severity of the disease (9).
A 2017 study published inthe Lancet, suggests that a standard dose of 40mg/kg is safe and effective inall children over 2 years old (20).MDA inschools is generally considered cost effective although, Brooker et al. suggestmore research is needed on a global scale (17). Teachers are trained to administerPZQ as there are very few side effects and it is very safe (2).
However, this is overseen by ahealth clinic. The infrastructure is present therefore, little investment isneeded to implement the programme. If carried out as planned, this issuccessful in reducing the prevalence of schistosomiasis in school aged children(21). However, it should be noted theproportion of children attending schools is often variable, with children frompoorer families and girls underrepresented and overlooked in this key publichealth initiative (22). Asystematic review in 2013 showed that combing a schools based programme with acommunity 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-riskgroups within communities for PC such as, the elderly, pregnant or lactatingwomen.
It isdifficult to give PC to younger children because PZQ is currently available onlyin one tablet strength. The large size and bitter taste of the tablet makes it hardto swallow, with many children gagging or vomiting. Crushing the tablets is apossibility but if more time consuming and can alter the dose or efficacy ofthe drug (23).
The Paediatric Praziquantel Consortiumis a recent initiative to develop and register a PZQ tablet formulation totreat schistosomiasis in preschool aged children. In December 2017, theEuropean and Developing Countries Clinical Trails Partnership and the GlobalHealth Innovative Technology Fund announced they will co-fund the phase 3 clinicaltrial for this formulation (24). The aim is to produce a smallorally dispersable tablet, with an acceptable taste for children (25).
The tablet may be available by2020, but there are no plans for distribution or financial resource to make thetablet available to the populations who require it. This is an initiativewhich, if resourced and implemented effectively within the near future, could reducethe prevalence significantly of schistosomiasis in preschool aged children.Socioeconomic division in communitiesA 2016 study showed that the most frequent non recipients ofMDA were individuals of low socioeconomic status, minority religions, and minoritytribes (26).
It is important to ensurethat MDA is provided to these groups in a location that is accessible andacceptable, that information is provided in a language that they understand andthat PZQ is provided without charge. There are many local languages spoken inUganda which provides additional challenges to effective distribution (27). Frequencyof AdministrationPC using PZQis 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 andtreatment must be repeated on a regular basis to protect populations (5). Currently, PC is given annuallythrough 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 thecercaria have penetrated the human skin, the female adult worms begin toproduce eggs (28). This suggests if treated, 6 weekslater an individual may be re-infected with the parasite. A different study ofpreschool aged children in Uganda in 2014 looked at the benefits of giving asecond dose of praziquantel 2 weeks after the first dose rather than a singledose with the aim of killing any remaining eggs which mature into adult worms (5).
They found that two doses lead toa significant reduction in egg excretion compared to a single dose. However,the cure rates one month post treatment and reinfection rates 8 months posttreatment were equal irrespective of a single or double dose. There is someevidence to suggest that if the intensity of the infection is initially high, adouble dose can lead to increased cure rates (29). There issome research which suggests that after repeated rounds of infections and PZQtreatment, 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-infectionwith the parasite (31).
This implies children aged 1–5 wouldexperience increased re-infection because as they have a lesser cumulative exposureto S. mansoni which is insufficientto produce partial acquired immunity. This research has encouraged thedevelopment of a vaccine.Availabilityand Distribution The SCI wasinitially funded using US$34 million from the Bill and Melinda Gates Foundationin 2002 which was used in 6 sub Saharan countries, including Uganda, to deliver40 million treatments in the initial 5 years (32). More funding was offered followingpublicity from the WHO. In 2007 Merck KGaA pledged 200 million tablets of PZQover 10 years and increased their donation in 2012 to 250 million tabletsannually by 2017 (32).
This was for use in school basedprogrammes.Currentlythe government funded health system in Uganda implemented by the Ministry of Healthis not accessible in every village. This means MDA of PZQ is administered by CommunityMedical Distributors (CMD) who are selected. They are trained annually by a DistrictHealth Officer who is linked to a District Health Centre. CMD are unpaidvolunteers which reduces the cost of the distribution programme (8,26).
They can have a positive effect onuptake by being familiar to communities, setting an example by taking the PCwith the community and visiting before MDA programme. Some of the volunteersare poorly motivated or have poor communication skills, which can lead toreduced distribution in the communities (33). Most are not incentivised andvolunteer work can take them away from paid employment (8). Financial incentives may besuccessful in increasing the community’s engagement (33).AdministrationWhen PZQ isdistributed, it is important the correct dose is given and taken under theright conditions. The efficacy of PZQ is greatest when taken just after food (18,32).
This also helps to minimize theside effects which include: dizziness, headache, nausea, vomiting, stomachpain, joint pain and a general feeling of weakness and lethargy. However, thepoorest 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 themedication in the future, reducing compliance and increasing transmission(18). Therefore, providing some food totake the medication alongside, although at an additional cost, may increaseeffectiveness and compliance.PZQ doseshould be calculated according to weight. Due to the limited access to actuate weighingscales the ‘dose pole’ was developed.
This allows CMD to administer the drugaccording 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 thepatient received a dose in the same range that they would have done if they hadbeen accurately weighed (7). A 2014 study suggested that therecould be 4 different doses per height of child implying many children receivean incorrect dose (34).
Health education in the populationA study published in 2017 outlines the perceptions aboutinterventions to control schistosomiasis in lake shore communities in Uganda.It revealed that most of the community do not consider schistosomiasis to be amajor health problem anymore due recent programmes implementing MDA of PZQ (13). It suggested the majorityhad heard about schistosomiasis from CMD or from teachers at school. Somemembers of the community were unsure of schistosomiasis transmission suggestingdrinking contaminated water was the main source of infection. This implies theydo not take relevant precautions to prevent schistosomiasis as individuals cannotbe expected to apply knowledge they do not have. It is important that CMDreceive training on the benefits of receiving PC and communicating with theircommunity which may incur an additional cost to the programme (33).
Local people do not feel they have the knowledge, skills orresources to implement public health initiatives as they feel they do not getenough support from the government (13). They feel undermined ratherthan empowered and ignored rather than listened to. Local people have the bestunderstanding of local issues which suggests investing in the skills andknowledge of local people to deliver public health education could increase MDAcompliance. Communities must be involved in the designing of interventions topromote ownership of projects and to make investments long lasting andsustainable. Water, Sanitation and Hygiene: WASHWater, sanitation and hygiene are important areas to addressif the WHO is to meet the target to eliminate schistosomiasis from selectedcountries in Africa by 2020 (35). Following the millenniumdevelopment goals, the 6th sustainable development goal put forwardby the United Nations in 2015 was to provide clean water and sanitation foreveryone by 2030 (36).
As Schistosomiasis is causedby a parasite that lives in the water, clean water supplies and sanitation arerecognised as being needed as a vital to eliminate schistosomiasis and toreduce the reservoir of the parasite (32). In the interim period where access to clean water is notuniversal, minimising contact with contaminated water will preventschistosomiasis. When this intervention has been discussed in local communitiesin Uganda, most females believed it would be a successful interventionproviding safe water sources are available (13). Male participants deemed itunrealistic because, as fishermen it would affect their income. Developmentinitiatives aiming to provide clean water for all are part of aid programmesbut few are linked to NTDs despite the association (32).A 2010 study in the International Journal of Epidemiology foundthat incidence of diarrhoea could be reduced by up to 48% by washing hands withsoap and water and up to 36% by disposing of human excrement appropriately (37).
Presently, only 29% ofUganda’s population wash their hands with soap after visiting the toilet (8). Most people have awillingness to use toilets, but only 35% of people have access to a toilet. Theuse of toilets would reduce human excrement in water sources and theconcentration of schistosomiasis eggs. People suggest affordability andpermission from land owners as barriers to having a toilet. There are sometraditional beliefs that use of a toilet will prevent one catching fish orhaving children (13). These issues could beaddressed through public health teaching in schools, places of worship andthrough community groups.
Molluscicide useAlthough PC is the mainstay of prevention nowadays, chemotherapyalone is unlikely to stop transmission of the parasite (38). Additional interventionsmust be integrated to reduce reinfection, lower prevalence and move towardselimination. The focus on PC over the last 20 years has been successful, buthas potentially limited the development of new ideas for snail control andreduced research into molluscicides. In the 20th century chemicalswere 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 furtherdevelopment and use of malacological substances to be trialled in partnershipwith PC to achieve elimination of schistosomiasis as soon as possible (38).Population migration and urbanisationMovement of people from politically unstable or con?ictzones in Africa into Uganda, such as the south Sudanese refugees, has lead to schistosomiasisprevalence in previously lesser effected areas.
Urbanisation for economicopportunities has introduced the disease into urban areas where people live inclose proximity and transmission is high (12). Political influences and government policyThe Government of Uganda provides a health care system wheretreatment must be paid individually. However, some programmes, including MDA ofPZQ, are subsidised or fully funded. Health is not the highest priority as theypursue economic gain. It isthought that the incidence of schistosomiasis increased after the construction of the BujagaliHydroelectric Dam across the River Nile in 2012 as this increased thestagnation of the water (14). The hydroelectric dam has enabledUganda to generate a large amount of electricity which can be sold toneighboring countries for a profit.
Although the effect on the economy has beenpositive, it is believed influenced the health of the population negatively.Betty Bigombe who was the State Minister for Water Resourcesfrom 2011-2014 feels “sanitation has been marginalised” (8). The government releases US$2million annually for sanitation projects, equivalent to around $13 000 perdistrict. She feels this is “negligible.”The WHO estimate the percentage of people in Uganda withaccess to a latrine is 35%, but the Government suggests it is 70% (8).
Some aid agencies haveimplied Uganda is misleading organisations in order to suggest development.Uganda ranks 151 out of 176 in Transparency International’s CorruptionPerception Index for 2016 suggesting that there is distrust and dishonestlybetween the government and its citizens (39). Vaccination: the future?Despite decadesof MDA of PZQ, schistosomiasis has not been eliminated and continues to effectnew areas. The development of a protective vaccine is possibly the mosteffective measure for control of schistosomiasis, especially if immunity isprovided after one injection.
A vaccine could reduce the burden of disease bydecreasing egg production and parasite load. The proposed vaccine would begiven to children aged 3-12 to prevent severe infection and reduce long termmorbidity (40). If a vaccine was developed, it is likelythat it would be widely accepted by most communities as children are routinelyvaccinated against other life-threatening diseases (13). Government and charitable programmesexist with trained workers to administer these vaccines and the schistosomiasisvaccine could be integrated alongside. A vaccine would reduce the need for alogistically difficult and relatively expensive annual MDA programme.
A studyin 2011 suggested that more funding and research should be dedicated to thisarea in order to reduce the time taken for a vaccine to be developed (40). A 2016 study echoed the call for morefunding, suggesting a vaccine was an essential part of the elimination tool box(41). Both studies cautioned against taking somevaccines currently in development to clinical trial, because they believe theremay be adverse effects.
Despite this, scientists are optimistic about a startervaccine within a decade.ConclusionOverall, thecurrent MDA programme has been largely successful in reducing the morbidity ofschistosomiasis on communities in Uganda within challenging circumstances.However, the current levels of PC being administered suggest the target ofelimination by 2020 is unachievable. With more research and fundingschistosomiasis could be eliminated from Uganda soon if a multi system approachis used. All demographics in at risk populations should be treated with MDA toreduce transmission within communities. More research is required to establishthe most effective and feasible frequency of MDA given current resources.
Trainingfor CMD to deliver higher quality public health education and incentivisingvolunteers may be effective in increasing community engagement. Additionally, it is important globalhealth bodies encourage pharmaceutical companies to donate PZQ but inpartnership with the Ugandan government committing to allocate funding toaddress issues surrounding sanitation and improving basic resources in healthcentres. Some multifactorial challenges, such as neighboring conflict, are moredifficult to overcome.
However, it is essential that research and development of a potential vaccine, apaediatric formulation of PZQ and an effective molluscicide continues to have amulti systems approach to elimination.