Building links with polio surveillance in Ghana

By Lucas Cunningham

The COUNTDOWN team in Ghana completed a successful qPCR workshop and I stayed on in Accra and with Dr Mike Osei-Atweneboana to help consolidate research links with The Noguchi Memorial Institute for Medical Research (NMIMR).  During the week I started to implement the practical skills learnt and develop laboratory protocols for our qPCR diagnostic assays acquired during our workshop.

The NMIMR was founded in 1979 as a memorial to the Japanese scientist Hideyo Noguchi who died in Accra from yellow fever in 1928. The NMIMR is part of the University of Ghana and is a world leading biomedical research facility in West Africa. The NMIMR includes the Ghanaian national polio laboratory, which is part of the global polio laboratory network (GPLN). The Ghanaian polio laboratory receives over 1000 faecal samples from across the country of suspected polio cases. Typically the samples have come from individuals presenting with acute flaccid paralysis, a classic sign of acute polio.

COUNTDOWN will carry out a preliminary screening of the faecal collections to test the possibility of tapping into the vast resources of the global polio surveillance programme to co-screen for worm infections. Along with schistosomiasis, these diseases are collectively grouped within the soil-transmitted helminth and make up a considerable public health burden in Ghana and across the developing world, ranking that of other, more infamous diseases such as malaria and TB.

Using the TaqMan® qPCR assay, the team at NMIMR will screen for the six major helminth parasites associated with poor sanitation and hygiene, Ascaris lumbricoides, Trichuris trichuria, Strongyloides stercoralis plus the two hookworm species Necator americanus and Ancylostoma duodenale. In addition, faecal samples will be screened for Schistosoma spp.. Several of Mike’s staff from Council for Scientific and Industrial Research (CSIR) were part of the visit to NMIMR which provided another opportunity for crosstalk between two of the research centres focal to COUNTDOWN in Ghana.

In total seven collaborators from both institutes took part, including two members of NMIMR’s parasitological department. Dealing with a smaller group allowed for a more informal approach to the optimisation and testing of the compatibility of the reagents with the specific equipment in the polio lab. Our adapted assays were carried out efficiently, resulting in an effective triplex assay, where three species of parasite can be detected simultaneously in each tube. Armed with this new tool we were then able to screen 15 faecal DNA extracts obtained from a recent pilot survey undertaken at a Lake Weij. The test results were surprising. Although all 15 samples were negative for the five soil transmitted helminths (STH) they all tested highly positive for Schistosoma s.l., indicating a heavy egg load in the faecal samples.

Having carried out the work at NMIMR we were able to reinforce the methods developed in the workshop and also leave behind enough laboratory materials for our colleagues at both the CSIR and NMIMR to practice and perfect their qPCR assays and hone their TaqMan® skills. We have also shown the importance of the COUNTDOWN consortium in bringing together different silos within Neglected Tropical Disease work and helping with the capacity building and thereby control of some the most neglected of NTDs.

Our experiences and successes in Ghana were recently broadcast to a wider audience at the British Society for Parasitology’s Spring Meeting (@BSPparasitology, #BSP2016). There I provided an overview and account of our recent activities in Accra during a well-attended session dedicated to research on NTDs and I hoped to show how our interdisciplinary research links have been strengthened. In short I outlined how the second year of COUNTDOWN research is shaping up, so watch this space!

Photo credit: Our teams from CSIR and NMIMR by the Noguchi memorial plaque, from left to right: Buhari Hamid, Linda Boatemaa, Edward Tettevi, Deborah Pratt, Millicent Opoku, Nana Pels and Nana Asante-Ntim

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“Replacing the lid on this can of worms” is not an option we should want or hope to achieve

By Mark Taylor, Liverpool School of Tropical Medicine

Having spent some time trying to absorb the vast quantity (and diverse quality) of material generated on #wormwars has led to me to see the debate as a wonderful opportunity for COUNTDOWN. Although I have read much, but by no means all of the material I have focused on two key sources, which I found to be most helpful in forming a view within a short timeframe, The Cochrane Review and the article Worms, Wisdom and Wealth from 2013 by Don Bundy and colleagues in Trends in Parasitology (from the last #wormwar battle in 2012). I encourage you all to read both articles, which for the most part are quite readable and provide a measured and informed summary of the key arguments from both sides of the debate.

In a nutshell

We have the key gold standard for evidence (as considered by many, but not all health professionals – a Cochrane Review) concluding that mass de-worming of ‘soil transmitted helminths’ (STH) from school children has little or no measurable health benefit. The response from the entire STH Neglected Tropical Disease (NTD) stakeholder community aggressively defended the policy, denouncing the review and rapidly releasing endorsing statements of “No change in policy”.

The consensus (which is thin on the ground to say the least) now appears to be that more evidence is needed and is unlikely to come only from more randomised controlled trials (RCT) and should include social science and economic evidence. RCTs and other research should be on contemporary populations and be sufficiently powered and designed to detect the relevant outcomes.

Some historical context

My initial reaction to #wormwars was shaped by a long history of skirmishes and battles from 2000 onwards on this debate (one comment from key stakeholder in the current debate – ‘here we go again’). Previously there was lively debate and argument in the literature. The outcome was no change in policy by the World Health Organization. So, I assumed that this time around it would be more of the same. A flurry of arguments over the details of statistical analysis together with polarised views of the ‘quality’ and sources of evidence used to support policy, i.e. the ‘gold standard’ evidence (Cochrane Review of RCTs) said no benefit, whilst other evidence including social and economic evidence, historical success of similar programmes in US and other evidence was therefore used to support and expand WHO policy. Result: no change in policy, even an expansion.

I have no particular strong criticism of the Cochrane review per se. But, it is difficult to avoid the conclusion that no matter how compelling or robust the evidence might be, including new re-analysis and de-bunking of an influential trial, this change in evidence will never be adopted by policy makers as they use different evidence to promote and guide their policies. No sign of a retreat from either pole of the argument – perhaps even more polarised than before.

What kind of evidence do we need to make policy decisions?

One problem with the Cochrane Review is that it includes some RCTs conducted 15 years ago with drug regimes and strategies that have already been advanced and changed. So this does not reflect the evidence of current strategies, which can use different regimes and are targeting different populations (for example, communities treated for lymphatic filariasis will have added benefits on the impact on their STH as combinations of worm drugs are used). So the data is not contemporary from the perspective of strategies or target populations. This is a generic problem caused by the length of time it takes to conduct and analyse trials and create the critical mass of trials sufficient to perform meta-analysis.

Another problem with much of the #wormwars broader debate is in the detail. Both sides and journalistic précis have moved the debate out of the context of what the review actually concluded, which has only served to confuse the issue. The broad use of the term “worms” and “de-worming” has led some to extend the reviews outcomes to all worm Neglected Tropical Diseases other than just the STH that were the subject of the review. These include three distinct types of worm. Roundworms, hookworms and whipworms.

The outcomes of the review therefore do not apply to the other NTD worms, schistosomiasis, lymphatic filariasis and onchocerciasis, for which there is robust evidence of health and economic benefit using mass de-worming.

So why no benefit of mass de-worming for STH? This might relate to the more benign and chronic morbidity that these worms cause. The three types of STH worm all have different pathologies (mostly benign in the majority of cases) and population frequencies and uneven geographical distribution, which may confound some of the RCT outputs. Although the worms are mostly only few in number in most cases, some “wormy” people get high worm burdens, which can cause clinically relevant symptoms. ‘Hookworms’ (the vampires of the wormy world) attach to the gut wall as adults (after migrating though the skin, heart and lungs as larvae) with their hooks and feed on our blood and cause anaemia. ‘Roundworms’ (Ascaris) can block the intestine and cause tissue damage as they migrate from the gut to the liver and lungs to be coughed up back into the gut. Whipworms (Trichuris) burrow into the bowel wall and can cause bloody diarrhoea and rectal prolapse. These symptoms might be rare, but how can removing these risks from children in extreme poverty be bad or of no benefit?

The key is probably related to mass treatment and community level analysis (i.e. the majority of the target population have few or no worms, which will mask the rare and subtle benefit to health, which may develop over long periods of infection and re-infection and so not captured by existing historic RCT design endpoints) combined with rapid re-infection rates (limited worm free periods in treated populations). We also know that the drugs are not given at doses or frequencies, which are the best for removing worms, but at doses that are considered to be safe and easy to give to communities. Most of the trials only used one drug, which is known to be only effective against one of the STH trinity (Ascaris).  So lack of existing RCT evidence maybe due to poor trial design, sub-optimal drug efficacy, frequency or coverage and endpoint analysis coupled with minor or subtle improvements in health, which are challenging to measure. Hence we need different approaches to measure and gather evidence.

Even if the evidence for mass de-worming of communities is based on flawed conclusions from the original RCT data in relation to some of the educational/health benefits (as assessed by RCTs), it is counter-intuitive to many that such a relatively cheap and easily delivered intervention is not of any benefit to these communities.

A natural human reaction to having worms is – get rid of them! Even the Cochrane review states: “It is good medical practice that children known to be infected with worms should receive treatment. This is obvious and not the subject of this Cochrane Review.” Hence the presence of strong beliefs and even faith – that it must have some benefit.

What next?

We need to continue to support Cochrane reviews as one of the primary ways of assessing the evidence from RCTs, but to acknowledge that other forms of evidence (albeit with their own advantages/disadvantages) are used by NTD policy makers from a variety of sources to inform policy decisions. The evidence from social science and health economics studies on STH programmes is underway within COUNTDOWN in four endemic countries and will meet the clarion call for more and better data on contemporary populations to provide robust evidence to support scale-up of existing strategies or promote alternative strategies.

This evidence will, for the first time, focus heavily on sector wide endemic country views from individuals, communities, national programme managers, Ministry of Health staff and international policy makers. Understanding how best to translate new evidence into policy in the context of this complex process is something that COUNTDOWN is addressing through multi-trans-disciplinary approaches and sector wide engagement to produce research uptake to deliver informed choices for policy makers.

We welcome informed debate on whether the Cochrane review has been appropriately conducted under the published criteria for such reviews, but we do not support suppression of meta-analysis in this area. Instead we have designed different approaches through social science and health economics to address the deficiency in existing evidence to either promote scale-up of current strategies or adoption of alternative strategies.

Photo credit: Sabin Institute (to reflect what de-worming programmes look like rather than an endorsement of the content of this site)