Don't Neglect the Neglected Tropical Diseases

Will Hamilton, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK

Every night and every morn
Some to misery are born,
Every morn and every night
Some are born to sweet delight.
Some are born to sweet delight,
Some are born to endless night.

William Blake, Auguries of Innocence

Introduction

Neglected Tropical Diseases (NTDs) are a group of infectious diseases, mainly caused by parasitic eukaryotes, which disproportionately affect the world’s poorest people (1, 2). At least 1.2 billion people are infected with one or more NTD, mainly living in tropical regions of Africa, South Asia and Latin America (2). The impact of NTDs on global health and development is substantial: they reduce agricultural productivity, impede socioeconomic development, promote societal destabilisation, civil unrest and conflict, have serious adverse effects on childhood education and cognition, and aggravate cycles of poverty. Despite this, many NTDs are easily treated. Efficacious drugs, particularly for helminth infections, are already available that could eliminate much of the global NTD burden at relatively low cost. Large-scale NTD eradication programmes would improve the quality and quantity of life for over a billion people, contributing to socio-political stability and socioeconomic growth. Such efforts must be a major focus for international development and diplomatic relations at the start of the twenty-first century, and will rely on international collaborations between the public and private sectors. This review examines four key areas of global NTD medicine: causal organisms, epidemiology, public health impact and intervention strategies.

1. Causal organisms: What are the Neglected Tropical Diseases?

Neglected Tropical Diseases (NTDs) are a group of infectious diseases that disproportionately affect the world’s poorest people and contribute to cycles of poverty. They typically exclude “the big three”: HIV/AIDS, tuberculosis (TB) and malaria, which also cause devastating morbidity and mortality in the developing world but generally receive more funding and international attention (3). The major NTDs are shown in Figure 1.

* The seven most severe NTDs, responsible for 90% of global NTD DALY burden.
** Only 1,797 new cases of dracunculiasis were reported in 2010, compared with 3.5 million in 1989 (5). This is due to a sustained and highly successful eradication effort by the WHO, Carter Center and other international organisations

Figure 1: Neglected Tropical Diseases (adapted from (2), Table 1, p. 1572)

In total, the top 13 NTDs result in roughly 57 million disability-adjusted life years lost globally per year, which is greater than that for either malaria or tuberculosis (4). 90% of this disease burden results from seven infections: the soil-transmitted helminths (hookworm, ascariasis and trichuriasis), lymphatic filariasis (which causes elephantiasis), schistosomiasis (both genitourinary and hepatic), trachoma and onchocerciasis (which both cause blindness) (2).
NTDs cause chronic illness, disability and disfigurement; even if their mortality is not on the same scale as falciparum malaria or HIV/AIDS, they reduce the quality of life and general prosperity of afflicted populations in innumerable ways. Moreover, NTDs synergise with one-another and with the big three, owing to their co-prevalence in the same populations. Indeed, there is strong evidence that treating NTDs can help limit the spread and severity of HIV/AIDS, malaria and tuberculosis (3), as will be discussed.

2. NTD epidemiology: A global problem

NTDs are, by definition, infections of poverty. Of the 58 countries in which the poorest billion people on Earth live, 56 are endemic for two or more NTDs (2). Together, the seven most severe NTDs affect approximately 1.2 billion people (ibid).
Peter Hotez (co-founder of the journal PLoS Neglected Tropical Diseases), from the Sabin Vaccine Institute and George Washington University, has documented the vast extent of the NTD global problem (6, 7, 8, 9, 10, 12, 13, 14). Sub-Saharan Africa (SSA) is the worst affected region on Earth, with the majority (over 90%) of the disease burden for schistosomiasis, onchocerciasis, sleeping sickness (Human African Trypanosomiasis, HAT), yellow fever, loiasis and dracunculiasis occurring here. The prevalence in SSA of the seven major NTDs is shown in Figure 2.

Figure 2: Prevalence of the top seven NTDs in Sub-Saharan Africa. Adapted from (6), Table 2

South Asia and Latin America also bear major NTD burdens, particularly for the soil-transmitted helminths (Figure 3). Half of all the cases of lymphatic filariasis in the world, and 41% of all the leprosy, occur in South Asia, where they cause disability and disfigurement (7).

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Figure 3: Prevalence of three major helminths in Sub-Saharan Africa, Latin America and South Asia. Adapted from (6), (7) and (8)

In addition, two NTDs found in Latin America are almost unique to that region: Chagas disease (caused by Trypanosoma cruzi, transmitted by reduviid insects) and mucocutaneous leishmaniasis (caused by Leishmania braziliensis, transmitted via sandflies). Chagas disease currently infects 8-9 million people (8) and can result in multi-organ pathology, including dilated cardiomyopathy and toxic megacolon, which both carry high mortalities. Mucocutaneous leishmaniasis causes progressive destruction of the facial mucosa, resulting in disfigurement and social stigmatization. In Mexico, neurocysticercosis (cysts in the brain) caused by the pig tapeworm, Taenia solium, is the most common aetiology for adult-onset epilepsy. Blinding trachoma, lymphatic filariasis, onchocerciasis, leprosy, yellow fever and dengue are also all reported in Latin America (ibid).
Northern Africa and the Middle East account for significant fractions of the global NTD burden too. The 57 nations that comprise the Organisation of the Islamic Conference (OIC), mainly found in those regions, account for 40% of the global burden of intestinal helminth infections, 20% of the world’s leprosy and 21% of blinding trachoma (9). Over 300 million people in the OIC – 22% of the population – live with Ascaris infection (ibid).
NTDs are limited neither to the tropics nor to developing countries; they are also prevalent in Central Asia (10, 11), Europe (12), the United States of America (13) and even the Arctic Circle (14). In a study of 1,262 school children aged 6-15 living in Osh Oblast, Kyrgyzstan, eight species of intestinal helminth were identified by stool inspection, and 41% of children harboured one or more species (11). The most prevalent worms, Ascaris lumbricoides and Enterobius vermicularis, were found in 23.1% and 19.3% of children respectively (ibid).

Ascaris lumbricoides (image from Wikimedia Commons)

Four million people in the United States of America are infected with A. lumbricoides, with the Appalachia and American South being particularly at risk (13). Many ‘tropical’ conditions, such as Chagas disease, leishmaniasis, cysticercosis, amoebiasis, brucellosis, leprosy and dengue fever occur at the US-Mexican border. Inner cities in the US can be home to pockets of poverty and poor living conditions, where toxocariasis, congenital toxoplasmosis and congenital syphilis occur. Hotez refers to such conditions as ‘neglected infections of poverty’ (ibid).

In Eastern Europe, soil-transmitted helminths (especially ascariasis, trichuriasis and toxocariasis), giardiasis and toxoplasmosis all remain endemic (12). In Western Europe, strongyloidiasis occurs in France, and the prevalence in Spain has been reported as up to 12% (ibid). 700 cases of leishmaniasis are reported annually in Portugal, and the sandfly transmitted disease is also found in France, Italy, Greece, Cyprus and Croatia (ibid).

Even in the polar Arctic, neglected ‘tropical’ diseases exert their debilitating effects. Indigenous Arctic populations, such as the Canadian Inuits and aboriginal Siberian Russians, are often highly isolated and live in settings of socioeconomic deprivation and environmental degradation: ideal for the spread of infectious disease (14).The incidence of trichinellosis in the northern-most region of Canada is 11 cases per 100,000 per year, compared with 0.06 for all of Canada. Arctic trichinellosis is caused by a unique species of nematode, Trichinella nativa, which, unlike the more well-known tropical variant, T. spiralis, can withstand freezing temperatures and thus persist in the carcasses of dead polar bears and walruses, which are eaten by the Inuits. T. nativa causes a unique pattern of disease, commonly involving prolonged diarrhoea, which can be problematic for young children (ibid). Arctic populations also suffer from cystic and alveolar echinococcosis (the latter of which has a mortality of 100% if left untreated), Diphyllobothrium latum (fish tapeworm), toxoplasmosis, giardiasis and cryptosporidiosis (ibid).

Thus, the greatest NTD burden is focused in a tropical band running from Latin America, through Sub-Saharan Africa into South Asia, where over a billion people are affected. But NTDs (or perhaps more broadly, ‘neglected infections of poverty’), also pose serious health challenges for peoples across the entire planet, from ‘developed’ countries such as the United States of America and states in Western Europe, to non-tropical regions such as Central Asia and the Arctic Circle.

3. The devastating impact of NTDs

Not only do NTDs cause chronic, debilitating and disfiguring illness in hundreds of millions of people, resulting in reduced quality of life and social stigmatization, but they also contribute to maintaining cycles of poverty, inequality and geopolitical instability.

Soil-transmitted helminths and schistosomiasis impair childhood growth, development, physical fitness, cognition and learning (2, 15). Combined with the direct effect of school days lost due to illness, NTDs seriously impact on a child’s educational achievements and hence future career prospects, making it more likely that the child will stay trapped in low-income jobs during adulthood. Chronic hookworm infection during childhood has been shown to reduce future wage earning by as much as 43% (16). Moreover, NTDs cause maternal ill-health, resulting in low birth weight babies and increased child and maternal mortality (2).

Because many NTDs affect poor, rural communities reliant on subsistence agriculture, they also contribute significantly to the world’s food crisis (2, 15). Agricultural productivity is reduced directly due to physical disability in the farming workforce. Elephantiasis caused by lymphatic filariasis, for example, causes limbs to become grossly and irreversibly oedematous resulting in loss of function. Agricultural losses also occur indirectly, as when farmers are forced to flee arable land due to the high rates of endemic disease, for example during the mosquito breeding season (ibid). Eradicating NTDs is thus a relatively cheap way to promote socioeconomic growth in endemic regions. Ahearn and De Rooy showed by satellite imaging that agricultural productivity during harvest time was significantly increased simply by treating the local population for dracunculiasis (17).

NTDs are also the most common clinical conditions in areas of human conflict and instability (2, 14). By reducing economic prosperity, forcing marginalised populations onto poor land, aggravating food crises, reducing individual wage earning, exacerbating low education standards leading to ignorance and intolerance, and diminishing quality of life particularly for children and mothers, NTDs serve to generally destabilise communities and aggravate conflict (2, 15, 18). In this way, NTDs are both causes and effects of conflict and poverty, giving rise to self-reinforcing cycles of squalor and disease. Civil unrest in the Democratic Republic of the Congo, Colombia and Myanmar exemplify these issues.

Ekwanzala et al. found that civil war in the Democratic Republic of the Congo coincided with a rise in sleeping sickness from 1,000 cases per year in 1959, to 34,400 cases in 1994 (19). Earlier in the 20th Century, King Leopold II of Belgium used Congolese slaves to extract natural latex from rubber trees for export. The combination of demographic upheaval and mass malnourishment led to epidemics of smallpox and sleeping sickness (20). It has been estimated that approximately ten million people – 50% of the Congolese population at the time – lost their lives during this period (21). Similarly, decades of civil war in Colombia has coincided with increased prevalence of Chagas disease, leishmaniasis and yellow fever (18).

Cutaneous leishmaniasis (image from Wikimedia Commons)

Burma (recently renamed Myanmar) bares a significant burden of malaria, multidrug-resistant TB, HIV/AIDS and various NTDs, including 2 million cases of lymphatic filariasis reported to the World Health Organisation (WHO) each year (18). Forty years of underinvestment in health by the Burmese military leadership, which spent less than 3% of the national budget on healthcare compared with 40% on its military (ibid), has contributed greatly to these public health problems. In contrast, and despite similar climatic and geographic conditions, neighbouring Thailand has almost completely eradicated lymphatic filariasis, and malaria is absent from the capital city of Bangkok along with most of the centre of the country. Refugee camps and hospitals along the Thai-Burmese border, organised by the Thai government and various charities, provide essential support for fleeing Burmese refugees, who commonly acquire malaria and dengue fever while crossing the dense forests that border the two countries. Hotez and others have thus argued that treating NTDs in conflict regions, such as Afghanistan, Sudan and Iraq, could help to reinforce and augment diplomatic and peace-keeping efforts (15).

Lastly, NTDs synergise with “the big three” diseases in developing countries: HIV/AIDS, TB and malaria (3). Female genital ulcers caused by Schistosoma haematobium significantly increase the risk of sexual transmission of HIV (22). A 2009 Cochrane review concluded that de-worming reduces plasma HIV viral load and enhances CD4+ T-cell counts in HIV+ patients, and decreases mother-to-foetus viral transmission (23). Patients newly diagnosed with TB present with more severe pulmonary disease and have impaired responses to anti-tuberculosis therapy if already co-infected with one or more helminths (3). In Sub-Saharan Africa, hookworm and malaria significantly overlap in geographic range and are both highly prevalent, making co-infection very common (24). The combination of hookworm-induced iron-deficiency anaemia and malaria-induced haemolysis, splenic sequestration and dyserythropoiesis can cause profound anaemia (ibid). Indeed, among preschool-aged children, anaemia is responsible for almost half of all malaria-associated deaths (3).

Thus, NTDs impose a substantial disease burden in the developing world, particularly among children and mothers, and this has a profoundly damaging effect on socioeconomic development and political stability.

4. NTD control: current and future strategies

Many NTDs, despite their damaging global impact, are surprisingly easy to treat. Anthelmintic agents are highly efficacious, well-tolerated and relatively inexpensive. Just three drugs – albendazole, ivermectin and praziquantel – eliminate nearly all species of helminth that infect humans (Figure 4). A single dose of oral azithromycin greatly reduces Chlamydia trachomatis disease, the leading infectious cause of blindness in the world (25). All four of these drugs are suitable for mass drug administration (25, 26), and could be given to 500 million people at a cost of $200 million per year for five years, or $0.40 per person per year (26). As discussed above, this would not only bring direct benefit to millions of people, but also contribute to promoting socioeconomic development and socio-political stability.
In the international arena, $200 million is a very modest amount. Hotez and colleagues have calculated that states with nuclear weapons programmes – USA, Russia, UK, France, China, India, Pakistan, and probably Israel and North Korea – have spent approximately US$10 trillion building and maintaining their nuclear arsenals. Even though these countries account for significant fractions of the global NTD burden (particularly China, India and Pakistan), they have together spent only US$1 billion on NTD eradication and R&D, roughly 1/10,000th of their investment in generating nuclear weapons (27).

Figure 4: Common anthelmintic agents and their helminth range (adapted from (28))

Among governments, the US Agency for International Development (USAID) and the British Department for International Development (DFID) are currently the main financial supporters of NTD control (29), and additional funding from other Western European nations should be encouraged. In what has been termed the “post-American world” (30), large economies such as Thailand and the ‘BRIC’ countries (Brazil, Russia, India and China) will soon possess comparable financial resources to the ‘developed word’, and hence can take on increasing responsibility for national and international public health initiatives (29). The World Health Organisation – the public health arm of the United Nations – is central in co-ordinating and organising global public healthcare.

Non-governmental organisations (NGOs) also play a significant role in combating NTDs. Guinea Worm Disease (caused by the nematode Dracunculus medinensis) has been almost entirely eradicated, with incidence dropping by >99% from 1989 to 2011 (5). This is due in large part to efforts made by the Carter Center, founded by former US President Jimmy Carter, working alongside the WHO and UNICEF (5).
The Bill & Melinda Gates Foundation has invested over US$13 billion in global health since 1994, focusing on diarrheal disease, HIV/AIDS, malaria, pneumonia, TB and NTDs (31). Their approach has been dubbed “philanthrocapitalism”, as it is modelled on venture capitalism with a strong emphasis on innovation, building infrastructure and maximising “social returns” on investment (32).

The pharmaceutical industry is another key player in the war on NTDs. In 1987, Merck & Co. launched the Mectizan Donation Program (MDP), a partnership between public and private enterprises that includes Merck, the WHO, the World Bank and national ministries of health (33). In 2008, a report published in the Annals of Tropical Medicine and Parasitology, written by an Executive Director at Merck, reported that over 1,800 million tablets of Mectizan® (trade-name for ivermectin) had been donated by the company, allowing 530 million treatments for onchocerciasis, since 1987 (34). From 2000 to 2010, GlaxoSmithKline (GSK) donated 2.6 billion albendazole treatments to the WHO (35). In combination with Merck’s ivermectin, significant progress has been made in de-worming school children from endemic countries.

In 1998, the International Trachoma Initiative (ITI) was co-founded by Pfizer, another major US pharmaceutical company, in response to calls from the WHO to eliminate blinding trachoma by 2020 (36). Since then Pfizer has donated 225 million Zithromax® (trade-name for azithromycin) treatments, distributed across 19 countries (ibid). This is planned to be expanded to over 40 countries by 2015.

The future of NTD eradication lies in building partnerships between these different organisations, with collaborations between the public and private sectors. There is cause for optimism. In January 2012, a united commitment to tackling the ten most severe NTDs was pledged by USAID, DFID, WHO, the World Bank, the Bill & Melinda Gates Foundation, Pfizer, GSK and 11 other pharmaceutical companies (36, 37). Over US$785 million was jointly guaranteed to fund NTD drug discovery, development, distribution and implementation programmes until 2020 (37). Several major pharmaceutical companies – including GSK and Pfizer – also agreed to participate in the Drugs for Neglected Diseases initiative (DNDi). The DNDi promotes collaboration between pharmaceutical companies by encouraging them to make their compound libraries public. These libraries contain details on all of the molecules being tested as potentially therapeutic (36), and are usually kept a closely guarded secret. It is hoped that increased transparency and cross-talk will improve NTD drug R&D efficiency. Novel drug discovery is particularly needed for the protozoal parasitic diseases, such as leishmaniasis and trypanosomiasis, for which treatments are currently highly toxic. With international public-private partnerships such as this, making headlines in both the UK (39) and USA (40), it is tempting to conclude that neglected tropical diseases may not remain neglected for much longer.

However, the system is far from perfect and there are on-going setbacks, as recent protests over the Obama administration’s proposed Intellectual Property (IP) laws demonstrate (40). The ‘Trans-Pacific Partnership (TPP), a regional trade agreement currently being drafted by the Obama administration and leaked in July 2012, has been accused of enhancing the patent and data protection powers of the pharmaceutical industry, making it more difficult to manufacture cheap generic drugs (41). For example, it is alleged that the TPP agreement would allow pharmaceutical companies to patent minor and therapeutically trivial modifications to drugs after the original 20-year patent expires, potentially delaying the production of affordable generic drugs indefinitely (41). Médecins Sans Frontières (MSF) produced a 22-page document entitled ‘Trading Away Health’, which concluded that the proposed agreement will, “severely restrict access to affordable, life-saving medicines for millions of people” (ibid).

Pharmaceutical companies, NGOs and governments must be incentivised to maintain their commitments to NTD eradication and affordable healthcare for the world’s poorest people, by a combination of economic, political and social pressures. Raising public awareness of issues relating to NTDs and global public health policy is essential, so that decision making can be influenced by public demand acting on governments through the democratic process, and private companies through consumer choice.

5.Conclusions

NTDs pose a substantial threat to the global health, prosperity and stability of the human species. They affect over 1.2 billion people living primarily, but not exclusively, in the tropics, and are the cause of mass morbidity, poverty and social destabilisation. Many NTDs, particularly those caused by helminths, are easily treated at low cost; relatively cheap healthcare interventions would improve the quality of life of millions of people. NTD eradication programmes should thus be a top priority for the world health organisation and international development agencies in the twenty-first century. Collaborations between public and private sectors, including NGOs, the WHO and the pharmaceutical industry, will be essential in combating neglected tropical diseases through novel therapy discovery and mass delivery schemes. Hopefully, in the twenty-first century, the ‘N’ can be dropped from ‘NTD’.

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