Russell Stothard, Liverpool School of Tropical Medicine
Last week I was in very interesting discussions with a panel of around 40 international technical experts, brought together by WHO-Geneva to review and revise the application of new diagnostics for the control of schistosomiasis. The meeting was expertly chaired by my longstanding colleague and friend Narcis Kabatereine, and, from the outset it was clear that discussions would be complex.
We covered many diagnostic nuances that ranged from the biomarkers and mechanics of the tests themselves to how these tests might be deployed and used appropriately to guide treatment decisions in the large-scale use of praziquantel. Some of these issues were covered in our special issue of Parasitology which is useful background reading.
Complexities in diagnosis
To me, it was hardly a surprise that consensus was difficult to reach as we all often want different things. It is the subtle distinction between active infection versus chronic disease that causes so much confusion and blurring in schistosomiasis diagnosis. Without wishing to digress too much, it hangs on the distinction between schistosomiasis versus schistosomosis. The later terminology was adopted in veterinary helminthology as an attempt to resolve the tensions in disconnect between infection and disease, but it was never accepted by the medical community. Perhaps, this was a mistake as an imprecise terminology begets confusion and mixed objectives.
In short; infection (schistosomiasis) is caught by exposure to water infected by larval stages, these larval stages mature to adult male and female worms that pair and mate. The fertilised female sheds numerous eggs each day into the blood stream which are either voided in the urine/faeces or become trapped in internal organs. As the eggs secrete potent toxins, trapped eggs induce a very strong inflammatory reaction and with it the gradual accumulation of lesions, these then conglomerate into fibrotic masses that irreversibly disease the body (schistosomosis).
The worms themselves are relatively benign but their laid eggs, however, are not. Also the numbers of voided eggs in urine/stool versus those accumulating in tissues is not clear, especially when exit sites of the eggs become progressively blocked.
The relationship between the numbers of adult worms, excreted egg tallies in stool or urine, and the trapped eggs accumulating in tissues reacting with the immune system is complex and not straightforward. Typically in advanced disease, adult worms may not be present having died or excreted eggs fall below detection thresholds, however, the long-lasting lesions around trapped eggs remain causing mischief. All this can have the rather perverse consequence that rampant late-stage clinical signs of diseases, like in Female Genital Schistosomiasis, may be misinterpreted by those who place too much importance on diagnostic tests of active infection (i.e. eggs in stool).
This is like inspecting the damage of a crashed car by looking at its current speedometer reading, where you would be mistaken to think it never moved, but you can of course check its milometer. Unfortunately for schistosomiasis no such cross-check is possible and by analogy not all crashed cars have the same mileage, thus like schistosomiasis (or rather schistosomosis), advanced disease may have completely different presentations following from different durations and rates of the accumulation of trapped eggs.
In areas where there is high transmission and reinfection, treatments with praziquantel slows down the milometer and in so doing averts severe disease.
Point of care diagnosis?
The main thrust of the WHO-Geneva discussion was the acceptance of a point-of-care dipstick which detects schistosome circulating cathodic antigen (CCA). Several of us have shown it to be proven useful for detection of Schistosoma mansoni infection. The advantages of this test are that it is quick, low cost (about $1.5), easy to perform, rapid and with high diagnostic sensitivity. Above all it uses urine samples rather than faecal samples which is easier to collect.
Faecal samples are used for the Kato-Katz test which is the backbone diagnostic method for nearly all faecal helminths, and it was delightful to see Naftale Katz, one of the originators of the test, at the meeting. Naftale is still going strong after 50 years of research and control into intestinal schistosomiasis in Brazil.
Switching from Kato-Katz to the CCA test raises a whole raft of related questions: how can it be used in disease mapping and surveillance; can it be produced in sufficient supply to fulfil future demand; how will its use change the treatment algorithms for praziquantel etc.?
The long road to the WHO
Ten years ago I was the first to evaluate the test for its use in control programmes in East and West Africa. Even then I was convinced that it had an important future role to play in guiding control, especially when you had small teams working in remote areas where it was difficult to carry in equipment. I remember very vividly taking boats to distant islands in Lake Victoria and uncovering alarming levels of disease on those island communities simply because we were the very first to travel there with field-based diagnostic tools. Using the CCA in combination with Kato-Katz and ELISA testing in later work, we also mapped the disease on the Sesse Islands, proving it to be much more extensive there than previously thought. However, it has taken several more papers, large-scale funding by Bill & Melinda Gates Foundation via SCORE and several years of advocacy to place the test in front of the eyes of WHO-Geneva for their reconsideration of current diagnostic guidelines.
It was a long journey indeed, and we should not be proud of taking such a prolonged time to put operational research into revised control actions. Had the CCA test been used several years ago in large-scale control programmes we would likely have seen increased use of praziquantel because the Kato-Katz test tends to underestimate the ‘true’ prevalence of schistosomiasis. I ask myself in this elapsed time period how many thousands of children and adults who could have been treated that weren’t? It disappoints me that international advocacy does not quantify these deficits. If we did it might prompt swifter decisions.
One of the major tasks ahead in COUNTDOWN is to turn best evidence into best practice as quickly as possible. This is our driving rationale if we are to be successful in the scale-up of praziquantel treatment and in acceleration towards NTD control targets…so watch this space.
Photo courtesy of the United States Mission Geneva