Dr John Fincham Amoebiasis Research Unit, Medical Research Council
About 25% of all the people on earth are infested by various kinds of worms (helminths). Nearly all these people live in less-developed countries. The probable link with AIDS and tuberculosis (TB) is that chronic helminthic infection downregulates the cellular immune response that is needed to prevent infection by the human immunodeficiency virus (HIV) and Mycobacterium tuberculosis.
In South Africa, the MRC has estimated that HIV/AIDS accounted for 40% of deaths in adults aged 15-49 in 2000, and will probably kill between 5 and 7 million people by 2010,. The prevalence of TB is exceptionally high. The risk of paediatric HIV and TB might increase when mothers have worms because their immune profile reaches the fetus and persists in young children. Poverty is also a co-factor in the epidemiology of helminthiasis, HIV/AIDS and TB. In the context of these facts, researchers from Ecuador, Germany, Kenya, South Africa, Uganda and the UK exchanged information during a workshop on the implications of interaction between the three diseases. Results from Ethiopia were also considered.
The workshop was organised and chaired by Prof. Miles Markus, Director of the Parasitology Research Programme at the University of the Witwatersrand, and was part of the 30th Annual Conference of the Parasitological Society of Southern Africa (A Parasite Odyssey). The support of the MRC, the National Research Foundation, the World Health Organisation and other sponsors, made it possible to bring together researchers in disciplines that ranged from human and veterinary helminthology to molecular and cellular immunology, thereby setting a precedent for transdisciplinary communication.
In brief, the workshop demonstrated that:
- There is accumulating evidence that prevention of helminthiasis could be part of the solution to the pandemics of HIV/AIDS and TB, and to epidemics of enteric disease.
- Prevention of helminthiasis needs to incorporate poverty alleviation, effective sanitation, supply of clean water, appropriate education and deworming programmes.
- Research needs to be based on transdisciplinary interaction, in order to maximise the benefit to health.
- Deworming programmes are an entry point to successful community-based health initiatives because they start to address perceived needs. Through them, local people will get involved in health delivery and accept responsibility.
Prof. Frank Brombacher, Director of the MRC Unit for Immunology of Infectious Diseases, explained how co-infection by pathogens that elicit opposing immune responses, particularly helminths versus HIV and TB, could influence the infection dynamics, progression, and immunoprophylaxis of the diseases they cause. Disease models in mice have been manipulated at molecular and cellular levels, in order to demonstrate priming of immune responses by contact with viral, bacterial and parasitic organisms. The respective antigenic exposures influence differentiation of T-helper 1 (Th1) or Th2 cells, as well as the associated cytokine profiles and Th1/Th2 crossregulation.
It was the rapid heterosexual spread of HIV/AIDS in sub-Saharan Africa that captured the attention of clinical immunologists and epidemiologists. The first large-scale human research model was provided by the migration of 33 000 Ethiopians to Israel, between 1978 and 1991. Worm infestation ranged from 86-98% amongst different batches of the immigrants, and there were cases of HIV/AIDS in men and women. Analysis of markers such as cytokines, immunoglobulins and lymphocyte counts and ratios, showed that when the people from Africa first arrived, their immune status was characterised by chronic activation. The profile was generally dominated by Th2 lymphocytes and their cytokines, which is characteristic of chronic helminthic infections. For optimal resistance to HIV and TB, and for efficacious vaccines, a predominantly Th1 response is necessary. Pre-existing immune bias to Th2 could potentially have a profound effect on the pathogenesis of HIV/AIDS because the cytokine milieu in vivo is critical to modulation of HIV expression. After the immigrants were treated with anthelmintic, and exposure to reinfection by worms was minimised through the availability of effective sanitation and clean water, their immune profile changed and stabilised. In this respect they were no longer different from long-term residents in Israel. It was concluded that:
"Treatment of helminthic infections is possible, relatively inexpensive and simple, and has already become a priority for public health in developing countries" (but not South Africa!).
"Furthermore, without eradication of helminths, HIV and tuberculosis vaccines will fail to confer protection in helminth-endemic areas".
In the densely populated informal settlements in South Africa, co-infection by HIV and Ascaris worms is particularly important because this worm is common. Adult Ascaris worms reside in the small intestine, but larvae migrate through tissues. Dr Philip Cooper of the Division of Infectious Diseases, St. George's Hospital Medical School, London, has research projects in Ecuador. He presented results that are relevant to sexual transmission of HIV, progression to AIDS and cholera vaccine efficacy. They show that ascariasis polarises the immune response in young adults to Th2, which should increase the risk of sexual transmission of HIV. Ascariasis also suppresses interleukin-2, a Th1 cytokine that can be used as a treatment for HIV/AIDS because it improves counts of CD4+ T cells and restores immune function substantially.Finally, the efficacy of a cholera vaccine improved after children with ascariasis were dewormed. Research on ascariasis in Ethiopia by a group headed by Dr Dawit Wolday was also considered. Their results indicate that the cellular immune responses needed to protect against TB and HIV, are impaired by ascariasis and other helminthic infections.
Effective deworming was associated with a reduction in viraemia, which may result in slower progression to AIDS. Severe helminthic infection, expressing either as more eggs/g in faeces or infestation simultaneously by several helminths, correlated positively with the load of HIV particles in plasma. With regard to TB, impaired efficacy of bacille Calmette-Guérin (BCG) vaccine during helminthic infection was confirmed. The Ethiopians recommend that "deworming is a low-cost and feasible treatment in the setting of developing countries, where helminthic infections are widespread, and TB and HIV are rampant". They have also emphasised the public health implications of helminthiasis, such as the epidemiological link to cholera and other enteric diseases.
Filarial worms that reside in blood vessels or lymphatics are constantly exposed to the immune system of the host. Research showed that in vitro it was easier for HIV to infect monocytes from peripheral blood of West Africans who were infected by these worms. Deworming reversed this susceptibility. At the workshop, Dr Elizabeth Sentongo from Makerere University in Uganda, where people are also infected by filarial worms, described how she has confirmed and extended the West African results. She concluded that regular deworming resulting in parasite clearance may prevent the dominance of Th2 immune responses, as well as reduce immune activation and alleviate cell anergy, all of which favour infection by HIV and M. tuberculosis, and could impair the HIV vaccine trials that are starting in Uganda and other countries.
In South Africa, filarial worms only occur in migrants from other countries, but in five provinces many people have another kind of worm that resides in small blood vessels. These are called schistosomes and they cause a disease known as bilharzia (schistosomiasis). This disease cycles via contamination of water by human urine or faeces containing schistosome eggs. Pauline Mwinzi presented results on the consequences of co-infection by HIV and schistosomiasis. She works for the Kenya Medical Research Institute and is based at Kisumu on the shore of Lake Victoria. In Kisumu there are men who earn a living by washing cars at the lakeshore. This inevitably exposes them to infection by schistosome cercaria in the water and as a result they all have bilharzia. Co-infection with HIV is present in 35% of these men. Experiments in vitro have shown that blood cells from car washers with bilharzia, were more susceptible to infection by HIV. Pauline has also detected, by means of liver scans, that in car washers who have HIV, liver fibrosis due to damage by bilharzia, was more rapid.
South African research
Joanita Adams from University of Stellenbosch is working in a suburb of Cape Town where the TB notification rate is 1000/100 000 per year, which is very high by international standards. In an attempt to test the Th1/Th2 hypothesis, relationships between helminthic infection, TB vaccination scars (BCG), and Mantoux TB skin test reactions, were determined in 2616 children. Children with BCG scars had significantly fewer worms, but positive Mantoux reactions were associated with more worms. These results seem to be conflicting and more research is necessary.
Clive Gray of the National Institute of Virology (NIV) explained that the potential for immunological interaction is recognised at NIV and that research on this aspect is at a preliminary stage. Hospital patients who are co-infected by HIV, TB and worms are being studied, and there is a trend for infection by any intestinal parasite to be associated with higher HIV loads.
Dr John Fincham described how mass deworming programmes at two schools significantly reduced mean eosinophil counts in blood. Before deworming, the mean counts at both schools exceeded the upper limit of the normal paediatric count. Since eosinophils are effector cells of the Th2-driven allergic response to helminths and other antigens, the reductions imply a lowering of Th2 activity. They may also indicate that mass deworming has potential to influence other endemic diseases, apart from worms.
Dr Manouchehr Yazhari, originally from Iran, described progress with international efforts to develop partnership programmes for mass deworming. The successful reconstruction of public and community health in Japan and Korea after devastation by war, provides fascinating insight into what can be achieved. A book called 'It all started with worms' describes how the Japanese addressed the problem. The destruction of the health services and general infrastructure, manifested as high prevalence of worms and other enteric diseases. In many communities, all the people had worms because of environmental pollution by faeces. Deworming programmes were a catalyst or entry point to reconstruction of public health. They provided models that generated confidence in successful delivery. A key ingredient was partnership between communities and academic institutions. Worm infestation has been virtually eliminated and health services and standards of hygiene are now excellent. Experience showed that it was better to deliberately exclude political agendas. Health needs to transcend politics and perhaps the recent collapse of the provincial deworming programme in KwaZulu-Natal was mainly due to political differences and the disinclination of teachers to get involved.
Intervention research in an informal settlement in Cape Town, shows that a successful school-based deworming programme convinces parents and teachers that personal involvement can make health delivery work. The catalyst is that children pass worms after treatment and clearly benefit as a result. All those involved, including the children, also soon appreciate that health education focused on local problems, is beneficial. In the workshop, the exchange of information made it clear that synchronised, mass deworming programmes, especially in densely populated informal settlements, probably have the potential to contribute to overall health for reasons that are not generally understood. In particular, they may be a practical and affordable way to reduce the incidence of infection by HIV and M. tuberculosis, slow down the progression of the diseases they cause, and to improve the efficacy of vaccines against HIV/AIDS and TB.