Neglected diseases

Md. Murad Hossain, Maria Elena Sarmiento, Armando Acosta, Mohd Nor Norazmi

Introduction

Neglected diseases often termed as neglected tropical diseases (NTDs) are endemic in 149

countries, affect over one billion of the world’s poorest people, claim an estimated 534000 deaths

each year and cause a disease burden of 57 million disability-adjusted life–years (DALYs) (1-3).

Although billions of peoples are still getting affected with NTDs, much progress has been made in

the efforts of controlling and eliminating the diseases. According to the third World Health

Organization (WHO) report on NTDs published in 2015, over 74 countries worldwide are ready to

implement national NTD master plans, six countries have the elimination of lymphatic filariasis,

incidence of human African trypanosomiasis has been reduced by 90% in African countries, 27

countries achieved the WHO target of 75% treatment coverage of school-age children to prevent

soil-transmitted helminthiases at the end of 2014 (1).

In 2011, WHO Strategic and Technical Advisory Group (STAG) for NTDs adopted a roadmap named

“Accelerating work to overcome the global impact of neglected tropical diseases” for control,

elimination and eradication of NTDs. In this roadmap, WHO has recommended five strategies for

prevention and control of NTDs: preventive chemotherapy intensified case management, control

of disease vectors, provision of clean water and sanitation and veterinary public health measures

(4). Preventive chemotherapy with community based mass drug administration plays central role

in the prevention and control of NTDs in the endemic areas. For many NTDs, low-cost, safe and

effective treatments are available; however, their accessibility often remains limited to the people

living the endemic areas with high risk of getting infected. For some other NTDs, it needs complex

diagnosis and expensive treatment. Therefore, adopting preventive measures such as combined

preventive chemotherapy, increased access to clean water, improved sanitation, reduction of

disease transmission and execution of integrated control measures might play crucial part in the

confinement of the diseases.

The WHO roadmap 2011 has set up numerous targets and milestones for eradication, elimination

and control of NTDs by 2015 and 2020 (4). In 2013, the 66th World Health Assembly adopted

resolution WHA66.12 which calls for intensified, integrated measures and planned investments to

improve the health and social well-being of people affected with NTDs. WHO is working with

Member States to ensure implementation of roadmap of 2011 and resolution of WHA66.12. In

April 2015, the eighth meeting of the STAG for NTDs took place where the meeting agenda

focused on the progress in achieving WHO’s roadmap-2011 targets and increased domestic

investments targets for the control, elimination and eradication of NTDs.

Neglected diseases

Neglected diseases are a group of infectious, chronic, debilitating diseases which are endemic in

the populations of low-income settings of tropical and subtropical countries. These diseases are

caused by bacterial, protozoal, helminth, ectoparasitic, fungal and viral diseases; mostly prevalent

in tropics and subtropics and remain truly neglected, and therefore they are often termed as

NTDs.

NTDs are closely associated with poverty and exert negative effects on the social-ecological

systems. They have emerged as a severe health burdens on the world’s poorest economic regions

of Africa and Asia, which typically affect the poorest people particularly living in areas with poor

sanitation, unsafe drinking water, substandard housing and little or no access to health care. These

diseases cause an estimated death of 0.5 to 1 million per annum which apparently ranked them a

higher global disease burden than that of HIV/AIDS. Moreover, the co-incidence of NTDs with

HIV/AIDS and tuberculosis can cause HIV/AIDS and tuberculosis more lethal. At present, some

NTDs have effective therapeutic drugs which have easy access to the people of the developed

world but, ironically, these drugs are not universally available to the poor people of the developing

or poorer areas, the people who suffer from the NTDs most.

List of neglected diseases and the causative pathogen

There was an argue among theWHO, centers for disease control and prevention (USA),

and infectious disease experts over which diseases would be classified as NTDs. Feasey et al. listed

13 NTDs namely ascariasis, buruli ulcer, Chagas disease, dracunculiasis, hookworm infection,

human African trypanosomiasis, Leishmaniasis, leprosy, lymphatic filariasis, onchocerciasis,

schistosomiasis, trachoma, and trichuriasis (5). Another NTD expert, Fenwick, included 12 of the

above diseases except the hookworm infection in his list of NTDs (6). The WHO recognized 17

diseases as NTDs: African trypanosomiasis, Buruli ulcer, Chagas disease, Cysticercosis and

taeniasis, Dengue fever, Dracunculiasis, Echinococcosis, Leishmaniasis, Leprosy, Lymphatic

filariasis, Onchocerciasis, Rabies, Snakebite, Schistosomiasis, Soil-transmitted helminthiasis,

Trachoma, Yaws (7).

However, with the course of time, the list of NTDs has been largely expanded and currently

comprises over 40 diseases (8). These NTDs result mainly from four different causative pathogens

such as Bacteria, Protoza, Helminths and Viruses. Beside these, a few NTDs are also caused by

Fungal and Ectoparasitic infections. Table 1 presents the causative agent(s) and the endemic areas

of these potential NTDs (3).

. Table 1. List of NTDs, their causative agent(s) and the potential endemic areas of these NTDs

Bacterial infections

NTDs Causative agent(s) Endemic areas

Buruli ulcer Mycobacterium ulcerans Australia, Guyana, Malaysia, Mexico, Peru, Sri Lanka, Papua New Guinea, West and Central Africa

Bartonellosis Bartonella henselae, other Bartonella spp.

Globally distributed

Bovine tuberculosis

Mycobacterium bovis Globally distributed (highest rates in developing countries)

Cholera Vibrio cholerae Southern and Central Africa, Dominican republic, Haiti, Cambodia, Papua New Guinea, Thailand, Malaysia, Indian subcontinent

ETEC infection Enterotoxigenic Escherichia coli (ETEC)

Globally distributed (highest rates in developing countries)

Salmonellosis Salmonella enteric serovars, S. enteridis, S. typhimurium, S. typhi, S. paratyphi

Globally distributed (highest rates in developing countries)

Shigellosis Shigella dysenteriae, S. boydii, S. flexneri, S. sonnei

Globally distributed (highest rates in developing countries)

Leprosy Mycobacterium leprae Brazil, China, Mozambique, Myanmar, Madagaskar, Indonesia, India, Nepal, Philippines, Vietnam, Sudan and other tropical and subtropical regions

Leptospirosis Leptospira interrogans Globally distributed (highest rates in developing countries)

Trachoma Chlamydia trachomatis Africa, Middle East, part of Asia, Australia, Mexico, South America

Treponematoses Treponema pallidum Globally distributed (highest rates in tropical regions)

Relapsing fever Borrelia recurrentis, B. duttoni, other Borrelia spp.

Africa (highest rates), parts of Americas, Asia, Europe

Viral infections

NTDs Causative agent(s) Endemic areas

Dengue Dengue fever virus (genus: Flavivirus) Indian subcontinent, South-East Asia, Pacific Islands, Central and South America, Parts of Africa and Northern Australia

Rabies Rabies virus (genus: Lyssavirus) Globally distributed

Yellow fever Yellow fever virus (genus: Flavivirus) South America, West and Central Africa, occasionally in East Africa and central America

Japanese encephalitis

Japanese encephalitis virus (genus: Flavivirus) Indian subcontinent, South-East Asia, intermittently in Northern Australia, and the Western Pacific

Rift Valley fever Rift Valley fever virus (genus: Phlebovirus) Africa and Arabian Peninsula

Viral haemorrhagic fevers

Arenaviridae: Lassa virus, Chapare virus, Guanarito virus, Junin virus, Machupo virus, Sabia virus Bunyaviridae: Crimean-Congo haemorrhagic fever virus (HFV), Hanta viruses, Puumala virus, Filoviridae: Ebola virus, Marburg virus Falviviridae: Omsk HFV, Kyasanur forest disease virus

Certain viruses are endemic in certain areas. Lassa virus: Guinea, Liberia, Nigeria, Sierra Leone Crimean-Congo HFV: Africa, Arabian Peninsula, Bulgaria, Central Asia, Turkey, South-West Russia Hanta virus: Globally distributed; Filoviridae: Angola, Congo, Gabon, Kenya, Sudan, Uganda Omsk HFV: West Siberia Kyasanur forest disease virus: India

Helminth infections

NTDs Causative agent(s) Endemic areas

Dracunculiasis Dracunculus medinensis Mali, South Sudan, Ethiopia

Cysticercosis/taeniasis

Taenia solium, T. saginata, Diphyllobothrium latum

Globally distributed

Enterobiasis Enterobius vermicularis Globally distributed (highest rates in developing countries)

Echinococcosis Echinococcus granulosus, E. multilocularis

Globally distributed

Intestinal fluke infection

Echinosoma spp. Fasciolopsis buski, Metagonimus spp.

Bangladesh, India, Malaysia, Indonesia, Taiwan, China, Philippines, Vietnam, Thailand, Cambodia

Fascioliasis Fasciola gigantic, F. hepatica Bolivia, Cuba, Chile, Ecuador, Egypt, Iran, France, Portugal, Peru, Spain

Clonorchiasis Clonorchis sinensis China, South Korea, Taiwan

Paragonimiasis Paragonimus spp. India, Pakistan, Nepal, Sri Lanka, Malaysia, Thailand, Vietnam, Laos, Philippines, Taiwan, China, South Korea, Japan, Cameroon, Nigeria, Liberia, Costa Rica, Ecuador, Guinea, Guatemala, Gabon, Peru, Panama, Mexico

Opisthorchiasis Opisthorchis felineus, O. viverrini Thailand, Vietnam, Laos, Ukraine, Siberia, Kazakhstan, Russia

Lymphatic filariasis

Wuchereria bancrofti, Brugia malayi, B. timori

Africa, Asia, Central and Southern America

Loiasis Loa loa Central and West Africa

Mansonellosis Masonella perstans, M. streptocerca, M. ozzardi

Caribbean, Central and South America, Sub-Saharan Africa

Onchocerciasis Onchocerca volvulus Africa, a small part of Central and Southern America

Schistosomiasis Schistosoma haematobium, S. guineensis, S. intercalatum, S. japonicum, S. mansoni, S. mekongi

Sub-Saharan Africa, Parts of Central and West Africa, some Caribbean islands, China, Indonesia, Philippines, Cambodia, Laos

Ascariasis Ascaris lumbricoides Globally distributed

Hookworm infection

Ancylostoma duodenale, Necator americanus

Globally distributed

Strongyloidiasis Strongyloides stercoralis Globally distributed

Trichuriasis Trichuris trichiura Globally distributed

Toxocariasis Toxocara canis, T. cati Globally distributed

Trichinellosis Trichinella spiralis, other Trichinella spp.

Globally distributed

Fungal infections

NTDs Causative agent(s) Endemic areas

Mycetoma (Madura foot)

Various fungi (eumycetoma) and bacteria (actinomycetoma, pseudomycetoma)

Africa, India, Central and South America

Paracoccidiomycosis

Paracoccidioides brasiliensis Argentina, highest rates in Brazil (80%), Colombia, Ecuador, Mexico, parts of central America, Venezuela

Ectoparasitic infections

Myiasis Parasitic fly larvae (Calliphoridae Oestridae, Sarcophagidae and others)

Globally distributed (highest rates in tropical and subtropical regions)

Scabies Sarcoptes scabiei Globally distributed (highest rates in tropical and subtropical regions)

Protozoal infection

NTDs Causative agent(s) Endemic areas

Chagas disease Trypanosoma cruzi Latin America

Human African trypanosomiasis

Trypanosoma brucei gambiense, T. brucei rhodesiense

Africa

Amoebiasis Entamoeba histolytica Globally distributed (highest rates in developing countries)

Balantidiasis Balantidium coli South America, Middle East, Phillipines, Papua New Guinea

Giardiasis Giardia intestinalis Globally distributed (highest rates in developing countries)

Leishmaniasis Visceral leishmaniasis: Leishmania donovani, L. chagasi, L. infantum Muco-cutaneous leishmaniasis: L. major, L. tropica, L. mexicana, L. braziliensis

Indian subcontinent, Asia, Africa, South Africa, Mediterranean basin

Why neglected diseases are called neglected?

Neglected diseases are said to be neglected because they were often overlooked by country’s

public health programs, drug developers, or by government officials involved in drug access and by

the news media. Now why did neglected diseases remain neglected? Reasons for these diseases to

remain neglected are many-fold. Lack in visible danger because they usually do not cause dramatic

outbreaks, and they are not able to kill a large numbers of people at a short course of time.

Instead, they usually toll their due over a longer period of time, leading to crippling deformities,

severe disabilities and/or relatively slow deaths (9). Neglected diseases did not receive high

priorities for their treatment or prevention because they typically affect the poorest of the poor

people in the tropical areas and do not affect people who live in the developed nations. Private

pharmaceutical companies usually focus on their profit and mainly interested to do invest for the

development of treatment tools of the diseases that persist in developed countries from where

they can make profit. In contrary, pharmaceutical companies cannot recover the cost of

developing and producing drugs/treatments for the neglected diseases where the consumers are

mainly the poorest people of the world. Most important reason may be over focusing on the ‘big

three’ diseases ‘Malaria, tuberculosis and HIV/AIDS’ due to their overwhelming role of in major

global health burden, mortality and morbidity rate which are responsible for several million deaths

every year. These ‘big three’ diseases account for millions of disability-adjusted life years (DALYs)

which collectively put a massive negative impact on the social and economic development of the

most severely affected countries, which, in turn, exacerbates poverty (10, 11). For their

devastating role, most of the funding has been allocated for the research and development of new

tools to control, prevent and eventually to eliminate the “big three” diseases.

The other reasons could be the scarcity of data regarding local and global burden estimates,

inadequate political willingness, weak leadership and lack of lobbies for the people who are most

severely affected by these diseases, and insufficient financial support mechanisms for their control

and prevention [12, 13].

Global burden of neglected tropical diseases

The Global Burden of Disease Study 2010 (GBD 2010) and its related articles attempted

comprehensively to quantify the burden of almost 300 diseases, including NTDs (14). The GBD

2010 introduces a metric called “disability-adjusted life year (DALY), in order to assess and

compare the relative impact of a number of diseases locally and globally (15). The DALY values are

the summation of two components: years of life lost due to premature mortality (YLLs) and years

lived with disability (YLDs) (14). So the DALY estimates could represent the metric of estimating

the burden of the chronic effects of NTDs infections. Table 2 presents estimated DALYs caused by

the major NTDs. Recent studies suggest that most of the NTDs are disablers rather than killers.

Therefore the DALYs for many of the NTDs (such as hookworm disease and the food-borne

trematodiases, schistosomiasis, intestinal nematode infections, trachoma, cysticercosis, and

onchocerciasis) result from YLDs (i.e., disability, not deaths).

Table 2. Estimated global burden (in DALYs, YLDs and YLLs) of the NTDs from the Global Burden of Disease Study 2010.

Disease DALYs in millions YLDs in millions

YLLs in millions No. of deaths

Intestinal nematode infections

Hookworm disease 3.23 3.23 0 -

Ascariasis 1.32 1.11 0.20 2700

Trichuriasis 0.64 0.64 0 -

Leishmaniasis 3.32 0.12 3.19 51600

Schistosomiasis 3.31 2.99 0.32 11700

Lymphatic filariasis 2.78 2.77 0 -

Food-borne trematodiases 1.88 1.87 0 -

Rabies 1.46 <0.01 1.46 26400

Dengue 0.83 0.01 0.81 14700

African trypanosomiasis 0.56 0.08 0.55 9100

Chagas disease 0.55 0.30 0.24 10300

Cysticercosis 0.50 0.46 0.05 1200

Onchocerciasis 0.49 0.49 0 -

Trachoma 0.33 0.33 0 -

Echinococcosis 0.14 0.11 0.03 1200

Yellow fever <0.001 <0.01 <0.01 -

Other NTDs 4.72 3.69 1.03 23700

Intestinal nematode infections were the most severe among the NTDs considering the DALY

estimates in the GBD 2010. Among intestinal nematodes, hookworm disease was estimated to

have the largest YLDs which accounts for 62% of the DALYs. The huge contribution of hookworm

disease to the YLDs of nematodes is due to moderate and severe anemia across several different

populations, including children and pregnant women (16, 17).

Schistosomiasis is another important NTD that results in chronic pain, inflammation, exercise

intolerance, and malnutrition, among other morbid sequelae. Schistosomiasis, under certain

scenarios, generated higher DALYs compared to that of malaria or other better-known conditions

(18). Recent study showed the link of female urogenital schistosomiasis in the risk of acquiring

HIV/AIDS (19). Trachoma and onchocerciasis are the major NTDs that are linked to blindness.

Trachoma is also evident to affect more than 40 million people in over 50 countries and over 8

million people are at immediate risk of irreversible blindness (4). The food-borne trematodiases,

cysticercosis, and echinococcosis, might be considered as important pathogens of global disability.

Two other key food-borne trematodiases, clonorchiasis or opisthorchiasis, were shown associated

with cholangiocarcinoma in Southeast Asia (20, 21). Cysticercosis is involved in causing epilepsy,

severe chronic headaches and hydrocephalus, depressive disorders, stroke, gliomas, and other

neurological sequelae (22).

NTDs like dengue, rabies, and African trypanosomiasis are considered as killer NTDs and practically

no disability was associated with nonlethal effects from these diseases. However, according to the

roadmap 2011, dengue fever affects millions of people worldwide. In 2010, dengue fever was

reported in all six WHO regions and indigenous outbreaks were reported for the first time in

Europe. Dog-mediated rabies causes the death of nearly 55000 people every year in Africa and

Asia. More than 14 million people worldwide receive post-exposure prophylaxis following bites

from suspected rabid animals (4).

It is argued that the collective global burden of NTDs is higher than that of malaria and

tuberculosis and is close to that of HIV/AIDS. On the basis of technical reports of WHO and the

annex table 3 of the world health report 2004, it was shown that the collective global burden of

the initial set of WHO recognized 13 most important NTDs (56.6 million DALYs) is higher than that

of tuberculosis (34.7 million DALYs) and malaria (46.5 million DALYs) which strongly urges for

adopting measures for the integrated control of NTDs (23). According to GBD 2010, the collective

global burden for NTDs was estimated up to almost 48 million DALYs which is comparable to

tuberculosis (49 million) and is almost half of the global burden of malaria (83 million DALYs) and

HIV/AIDS (82 million DALYs) (24). However, it is worth mentioning that there are substantial

uncertainties and limitations regarding the estimation of global burden, and it particularly proved

challenging for estimating the global burden of NTDs.

Although the global burden of diseases has been measured in terms of DALY, however, DALY itself

has some shortcomings and accounts only the effects on direct health loss by NTDs but do not

consider the economic impact of the NTDs that results from detrimental effects on school

attendance and child development, agriculture (especially from zoonotic NTDs), and overall

economic productivity (12, 25). Even it doesn’t consider the direct costs of treatment, surveillance,

and prevention measures. Besides these, many NTDs also cause a matter of social stigma and the

spillover effects to family and community members (26, 27), loss of tourism (28), and health

system overload (e.g., during dengue outbreaks). Ultimately NTD control and elimination efforts

could produce social and economic benefits not necessarily reflected in the DALY metrics,

especially among the most affected poor communities.

Interventions to prevent NTDs

In the ‘Roadmap 2011’ to overcome the global impact of NTDs approved by strategic and technical

advisory group for NTDs, WHO adopted five strategies for the prevention, control, elimination and

eradication of NTDs (4).

Preventive chemotherapy

Preventive chemotherapy intends to optimize the large-scale use of safe, single-dose medicines

that can effectively reduce the extensive morbidity associated with four helminthiases (lymphatic

filariasis, onchocerciasis, schistosomiasis and soiltransmitted helminthiases). Moreover, the large-

scale administration of azithromycin, a key component of the SAFE (Surgery, Antibiotics, Facial

cleanliness and Environmental improvement) strategy against trachoma, is amenable to close

coordination (and, in future, possibly co-administration) with interventions targeted at

helminthiases. WHO is promoting preventive chemotherapy as a potential intervention to reduce

significantly the morbidity caused by five widely distributed NTDs (lymphatic filariasis,

onchocerciasis, schistosomiasis, soil-transmitted helminthiases and trachoma) since 2001. By the

end of 2009, 705 million people suffering from these five NTDs reached under coverage of the

preventive chemotherapy.

Implementation of preventive chemotherapy with high coverage will reduce morbidity and halt

the recurrence of the above five targeted NTDs which will ensure to reach to WHO’s goals of

elimination of these five NTDs by 2020. Some intermediate milestones for their elimination can be

achieved by 2015. Critical assumptions to reach these objectives are: (1) that solutions be found to

make praziquantel widely available along with the other donated medicines in the preventive

chemotherapy package; and (2) that funding for implementation accompanies the scaling up of

interventions, through sustained commitment of international donors and enhanced in-country

support by the health and education sectors.

Intensified case-detection and case management

Intensified case-detection and management intervention targets the prevention and controlling of

NTDs those have no appropriate medicines available for preventive chemotherapy. This

intervention urges caring for infected people and for those who are at risk of infection. The key

processes are (i) making the diagnosis as early as possible, (ii) providing treatment to reduce

infection and morbidity, and (iii) managing complications. Under the intensified case management

strategy, WHO focuses on the prevention and control of Chagas disease, Buruli ulcer,

leishmaniasis, human African trypanosomiasis, leprosy and yaws. The new focus on better access

to specialized care through improved case-detection and decentralized clinical management aims

to prevent mortality, reduce morbidity and interrupt transmission.

Vector and intermediate host control

Vectors and their intermediate hosts control is an important cross-cuting intervention that aims to

enhance the impact of preventive chemotherapy and intensified disease management. Almost all

NTDs involve transmission by vectors (insects) or intermediate hosts (such as aquatic snails).

Therefore, vector and intermediate host control is crucial to prevent the transmission of NTDs.

Vector control is particularly important for controlling of dengue and Chagas disease, and in

preventing some forms of leishmaniasis. Vector control intervention can play a major role for the

elimination phase of diseases like lymphatic filariasis and schistosomiasis.

WHO is implementing vector control through its integrated vector management (IVM) approach

which is a combination of different intersectoral interventions aimed at improving the efficiency,

ecological soundness and sustainability of disease control measures against vector-borne

neglected tropical diseases, including the sound management of public-health pesticides.

Veterinary public health at the human–animal interface

Veterinary public-health at the human–animal interface implements those actions that are

essential to prevent, control and eliminate suffering and economic loss caused by neglected

zoonotic diseases (NZDs) in both humans and animals. Veterinary public health deals with the

health of peoples as well as animals. An integrated human and animal health program will be

effective in the prevention, control and elimination of a number of NZDs (such as human dog-

mediated rabies, cystic and alveolar echinococcosis, fasciolasis and foodborne trematodiases) and

NTDs with a zoonotic component (including zoonotic trypanosomiasis, and visceral and cutaneous

forms of zoonotic leishmaniasis).

Provision of safe water, sanitation and hygiene

According to the estimation of United Nations, globally 900 million people are in lack of access to

safe drinking-water, and 2500 million live without appropriate sanitation. Without having the

health benefits that can obviously be obtained from safe water, improved sanitation and hygienic

life styles, the targets of Millennium Development Goal 7 would not be achievable, especially in

WHO’s African and South-East Asia regions.

If the current situation of “access to safe water, improved sanitation and hygienic life styles”

doesn’t improve, many of the NTDs and other communicable diseases will not be eliminated, and

certainly not be eradicated.

Eradication, elimination and control of NTDs: Target 2015 and 2020

In the roadmap approved in 2011 for “Accelerating work to overcome the global impact of

neglected tropical diseases”, WHO set up important targets and milestones for the eradication,

elimination and control of NTDs.

Eradication

Among the 17 NTDs, WHO currently aims to global eradication of two NTDs, Dracunculiasis

(guinea-worm disease) by 2015 and Endemic treponematoses (yaws) by 2020.

Dracunculiasis (guinea-worm disease)

Dracunculiasis eradication campaign was started in the early 1980s. Since then, there has been a

significant decline (more than 99%) in the annual incidence of the disease, from 892 055 cases in

1989 to 1058 in 2011. Several initiatives such as active searches of the dracunculiasis infection in

the endemic villages, rapid case-containment, enhanced surveillance and access to improved

drinking-water have helped to drastically reduce the prevalence of dracunculiasis infection.

Dracunculiasis is now on the verge of eradication.

WHO in its roadmap for overcoming the impact of NTDs announced in 2011 has set up a target of

global eradication of dracunculiasis infection by 2015. To achieve WHO’s goal - interruption of

transmission by 2015, a heightened surveillance should be enforced and the momentum should be

maintained - even when a country or a particular area of an endemic region has interrupted the

transmission completely - until global eradication is achieved.

Endemic treponematoses (yaws)

Endemic treponematoses (yaws) infection is the only other NTD that is targeted for global

eradication by 2020. Yaws mainly affects children. According to the estimation by WHO, globally

460000 infectious cases were reported in 1995, and these infections were mostly occurred in west

and central Africa (400000 cases), South-East Asia (50000) and the remainder in other tropical

regions. In 2007, WHO launched a global program for the elimination of yaws and other endemic

treponematoses. Since then, yaws has been eliminated from many endemic countries. In India, no

new case of infection has been reported since 2004. In South-East Asian Region, two endemic

countries - Indonesia and Timor-Leste - who set the goal for Yaws elimination by 2012. Currently

three countries (Papua New Guinea, the Solomon Islands and Vanuatu) in the Western Pacific

Region remain endemic.

WHO’s goal is to eliminate the yaws from the Western Pacific and South-East Asia regions by 2015

and from Africa by 2020, which will lead to eradicate the disease globally.

Elimination

Some of the NTDs are aimed to eliminate their transmission or to reduce their burden regionally or

globally by 2015, while some others are targeted for global elimination by 2020.

Dengue

Millions of people worldwide are being affected by dengue fever. Dengue is mostly prevalent in

poor populations of crowded urban and periurban areas, however, it also affects affluent

neighbourhoods of tropical and sub-tropical countries. In 2010, the incidence of dengue fever has

been recorded in all six WHO regions and indigenous outbreaks were reported for the first time in

Europe. The principal vectors, Aedes aegypti and Aedes albopictus, are gradually spreading their

range of distribution in the European and African continent. Intensive efforts to control the spread

of the vectors and to apply sustainable control measures are required to stop the tide by 2015.

Now the aim is to reduce the rate of morbidity by at least 25% and mortality by 50% through

implementing an integrated vector management approach by 2020.

Human dog-mediated rabies

Domestic dogs are the major sources of human rabies cases. Children are the main victim where

between 30% and 50% of human dog mediated rabies cases (and therefore human rabies deaths)

occur in children aged below 15 years. About 55000 people die from dog-mediated rabies every

year in Africa and Asia. More than 14 million people worldwide receive post-exposure prophylaxis

following bites from suspected rabid animals. Therefore, controlling the disease in dogs is

important for the elimination. WHO is coordinating pilot studies in the Philippines, South Africa

and the United Republic of Tanzania for the immunization of dog in order to prevent dog mediated

rabies in humans.

A mass dog vaccination programme in Latin American countries initiated in 1983 has stopped the

progress of dog-to-dog transmission in most countries. Elimination of human dog-mediated rabies

and dog-to-dog transmission is achievable by 2015 in all endemic areas in Latin America; and in all

affected countries in WHO’s South-East Asia and Western Pacific regions by 2020. Intensified

control and enhanced surveillance should lead to a 50% reduction of the number of human rabies

deaths in these two regions by 2015.

Buruli ulcer

A combined antibiotic treatment with rifampicin and streptomycin, recommended by WHO in

2004, has radically changed the prospects for Buruli ulcer treatment. Almost 36000 people during

2004–2010 became benefited from this combined treatment, 50% of whom were children aged

under 15 years. Combined antibiotic treatment has reduced almost 50% of the need for surgery.

WHO aims to develop oral antibiotic therapy for full incorporation into control and treatment by

2015. WHO also aims to cure 70% of all cases with antibiotics in all endemic countries by 2020.

Cysticercosis

Cysticercosis is a disease which is caused by the development of Taenia solium cysticerci in human

tissues. Cysticercosis may also develop in central nervous system which is called

neurocysticercosis. The infection is prevalent in all six WHO regions. Currently China is the only

country who is running a national surveillance and control programme for cysticercosis.

Elimination of cysticercosis requires improved sanitation, chemotherapy for humans, pig

husbandry and marketing practices, and pig treatment combined with improved vaccination. WHO

aims to launch a sustainable strategy for the control and elimination of T. solium taeniasis/

cysticercosis by 2015 and to scale up the interventions in selected countries in Africa, Asia and

Latin America by 2020.

Chagas Disease

WHO is leading a global awareness campaign to interrupt global transmission of the chagas

disease through blood transfusion and organ transplantation. Sustained vector control over the

years has become successful and significantly reduced the transmission in Latin America. WHO has

set up the target for the elimination of the disease in Latin America through interruption of vector

transmission via intra-domiciliary infestation by 2015 and via peri-domiciliary infestation by 2020.

Interruption of transmission via blood transfusion has also been targeted in Latin America, Europe

and the Western Pacific by 2015. Besides vector control strategy, WHO also largely provided the

first-line treatment with benznidazole and second-line treatment with nifurtimox in the endemic

areas during 2007 - 2010 in order to achieve the goal of global elimination.

Echinococcosis

Echinococcosis is a globally prevalent zoonotic disease which is caused by the larval stages of the

dog tapeworm Echinococcus granulosus. Approximately 200000 new cases of cystic echinococcosis

are diagnosed annually. Elimination of echinococcosis transmission has been achieved in

developed countries by adopting the interventions such as treating dogs regularly, carrying out

strict controls during the slaughter of livestock, destroying infected offal and public education.

However, these interventions may not work in low or middle-income countries and may require

alternative strategy in addition to traditional interventions.

WHO is now willing to validate the efficacy of echinococcosis/hydatidosis control strategies in

selected countries by 2015 to scale up the interventions in selected countries in North Africa,

Central Asia and Latin America for control and elimination of the disease as a public-health

problem by 2020.

Foodborne trematode infections

More than 56 million people worldwide suffer from one or more foodborne trematode infections

(e.g. clonorchiasis, fascioliasis, opisthorchiasis, paragonimiasis and others). WHO is working to

expand preventive chemotherapy to include foodborne trematode infections which can be treated

with praziquantel or triclabendazole.

WHO aims to control morbidity associated with foodborne trematodiases in selected countries by

2015 and in all endemic countries by 2020.

Human African trypanosomiasis in selected countries

Human African trypanosomiasis or sleeping sickness is caused by Trypanosoma brucei gambiense

which is endemic in 24 countries of west and central Africa, and by T. brucei rhodesiense which is

endemic in 13 countries of eastern and southern Africa. Sleeping sickness is highly prevalent in

WHO’s African Region (90% of reported cases) and the remaining 10% in the Eastern

Mediterranean Region. The incidence of new cases has been reduced by 75% during the period of

1999 and 2010.

WHO has been implemented a new strategy for sustaining case detection at the peripheral level in

countries with low endemicity and foci. WHO’s current initiatives aim to enhance wider patient

accessibility in order to eliminate the disease in 80% of foci by 2015 and to achieve 100%

elimination of the foci globally by 2020.

Soil-transmitted helminthiases (intestinal worms)

More than 1 billion people are infected with nematodes that cause soil transmitted helminthiases.

A significant progress has been made in controlling these infections over the past 10 years. In

2010, 31% of all preschool and school-aged children in the world at risk of soil-transmitted

helminthiases were dewormed. However, the target of bringing 75% of school-aged children under

coverage by 2010 was not achieved. WHO now aims to achieve 75% coverage in all endemic

countries by 2020.

Onchocerciasis

Onchocerciasis elimination programme is actively working to interrupt the transmission in the

region of Latin Americas. Elimination of the transmission by 2015 seems feasible in Latin America

(13 foci in 6 endemic countries - Venezuela, Brazil, Colombia, Ecuador, Guatemala and Mexico)

where approximately 0.5 million people are at risk of onchocerciasis infection.

Yemen adopted national plan to eliminate onchocerciasis transmission in the country by 2015

through mass distribution of ivermectin and vector control. Onchocerciasis control in Africa is

being monitored through the African Programme for Onchocerciasis Control (APOC) and the

former Onchocerciasis Control Programme in West Africa (OCP). In African continent, 23 countries

(12 APOC countries and 11 ex-OCP countries) out of a total of 31 endemic countries are expected

to achieve elimination through surveillance activities and mass drug administration with

ivermectin by 2020.

Schistosomiasis

With the current scheme and interventions, elimination of S. haematobium is reasonable in the

countries of Eastern Mediterranean Region such as Egypt, Libya, Saudi Arabia and the Syrian Arab

Republic by 2015. Continuous surveillance is needed to confirm that the transmission of S.

haematobium has stopped in Iran, Jordan and Morocco. By 2015, WHO also aims to eliminate S.

haematobium infections in the Bolivarian Republic of Venezuela, Saint Lucia and Suriname, S.

japonicum infections in Indonesia, S. mansoni infections in the Carribean and S. mekongi infections

in the Mekong River basin. By 2020, S. mansoni infections and S. japonicum infections have been

projected to be eliminated in Brazil and Western Pacific Region respectively. S. mekongi infections

have been targeted to eliminate from parts of Western Pacific region such as two endemic

provinces from each of Cambodia and Lao People’s Democratic Republic by 2020.

However, in sub-Saharan Africa, it is not yet been scheduled for elimination of Schistosomiasis

particularly S. mansoni even by 2020, primarily due to lack of sufficient amounts of medicines.

Necessary steps should be taken immediately for the elimination of the infection in Africa. A large-

scale preventive chemotherapy programme has been enduring for at least 5 years in some

countries in Africa including Uganda, Burkina Faso and Niger. If the necessary medicines (especially

parziquantel treatment) can be made available, then the elimination of schistosomiasis as a public

health problem could be achieved in many countries in Africa by 2020, and globally by 2025 under

the guidance of WHO.

Blinding trachoma

More than 40 million people in over 50 countries are affected by trachoma, and over 8 million are

at immediate risk of irreversible blindness. The prevalence of trachoma has reduced significantly

since 1998 as a result of the implementation of SAFE strategy. Blinding trachoma has been aimed

to be eliminated globally by 2020. Some countries like Ghana, Gambia, Iran, Morocco and Oman

may achieve the target of elimination by 2020, while remaining countries must be needed enough

support from WHO to achieve the targets within the deadline set by resolution WHA51.11. In the

prerequisite of achieving the global elimination goal by 2020, it was expected to attain the

ultimate intervention goal (UIG) in 10% of endemic countries by 2013. By 2016, 40% of endemic

countries are expected to achieve the UIG and to enter the post-endemic surveillance. By 2020,

WHO aims to achieve the UIG in all endemic countries and to be free from blinding trachoma as a

public-health problem.

Leprosy

Leprosy was endemic in 122 countries. Interestingly, the infection has been successfully eliminated

as a public-health problem in 119 out of these 122 countries (elimination is defined as achieving a

prevalence of less than 1 case/10000 population). The incidence of transmission has been reduced

by more than 90% since 1985, primarily because of timely case-finding and multidrug therapy. The

transmission is prevalent in few countries or areas that were previously highly endemic. By 2020,

WHO aims to eliminate the transmission globally through the intervention of prompt case-finding

and treatment.

Visceral leishmaniasis in the Indian subcontinent

Regional leishmaniasis control programmes and the elimination of visceral leishmaniasis in the

Indian subcontinent (mainly in Bangladesh, India and Nepal) over the past five years have

strengthened capacity, improved access to medicines and enhanced surveillance. Leishmaniasis

affects people in more than 90 countries which can be eliminated implanting the intervention of

early case-finding and prompt treatment. WHO has set up the target of detecting at least 70% of

all cutaneous leishmaniasis cases and treating minimum of 90% of all detected cases in the Eastern

Mediterran Region by 2015. With sustained efforts in the Indian subcontinent, 100% case-

detection and treatment of visceral leishmaniasis is feasible by 2020, implying that less than 1 case

per 10 000 population at district and subdistrict levels can be achieved.

Lymphatic filariasis

The Global Programme to Eliminate Lymphatic Filariasis is the key towards the efforts to control

lymphatic filariasis and to interrupt transmission through integrated interventions of regular

treatment with preventive chemotherapy, vector control and morbidity management. Despite

significant successes, achieving the goal of elimination as a public-health problem by interrupting

transmission remains challenging in the many places where clinical cases persist.

If current levels of interventions are maintained, elimination of transmission can be achieved in all

Pacific Islands, excluding Papua New Guinea, by 2015. By 2017, 70% of all 81 endemic countries

will have met the criteria to stop interventions and entered the post-intervention surveillance

phase. By 2020, 100% of all endemic countries will have been verified as free of transmission or

will have entered post-intervention surveillance.

Treatment

Among the five strategies recommended by WHO for the prevention and control of NTDs,

preventive chemotherapy (the intervention of using drugs) is the best affordable measure for the

treatment of those diseases. A large-scale community-based drug intervention has become the

key strategy for the poor settings of the developing world where peoples are mostly affected.

However, as these are neglected diseases and the affected peoples are mostly the poorest of the

poor world, the research and development of drugs for these diseases was limited due to a lack of

market incentives (29). Recently, the public-private partnerships for drug development has been

formed which has accelerated funding for research and drug development (30). Affordable and

effective drugs for many NTDs infections have been developed, however, the access to these

drugs often remain limited for the victims living in NTDs endemic areas (30).

For some NTDs, treatments are easy to administer, do not require health professionals and a non-

medical personnel (e.g., school teachers) can deliver these drugs to large populations (e.g., all

children in a school) as a public health measure (31). The development of albendazole,

mebendazole, ivermectin and praziquantel, which are highly effective against most of the NTDs

including soil-transmitted helminthiases, has become a great blessing for the treatment of NTDs.

Albendazole and mebendazole are suggested for preventive chemotherapy against hookworm

infection, ascariasis, trichuriasis, strongyloidiasis, toxocariasis and mansonellosis (M. perstans).

Ivermectin is useful against strongyloidiasis, lymphatic filariasis, mansonellosis (M. perstans, M.

streptocerca) and onchocerciasis. Praziquantel is effective killer for schistosomiasis,

paragonimiasis, clonorchiasis, opisthorchiasis and intestinal fluke infections. For human African

trypanosomiasis, pantamidine is commonly used, while nifurtimox or benznidazole is used for the

treatment of Chagas disease (3). The co-administrations of these drugs are often recommended.

For example, ivermectin and albendazole are used in Africa while diethylcarbamazine (DEC) and

albendazole are used in areas outside Africa for the treatment and elimination of lymphatic

filariasis (3, 32). However, the recommended dosages for the treatment of NTDs may vary in the

typical endemic and non-endemic settings.

Recently, a combination of five drugs known as ‘rapid impact package’has shown a lot promise in

the treatment and prevention of five NTDs (e.g. soil-transmitted helminthiasis, schistosomiasis,

lymphatic filariasis, onchocerciasis, trachoma) at once (33). These rapid impact packages are

exceptionally cost-effective which need to be taken only once a year and treatment throughout

one's school years can offer life-long protection. The major advantages of these drugs are the fact

that they do not require refrigeration and are safe to take even if one is not infected which provide

a means of mass prevention of these NTDs. Hence, preventive chemotherapy has been endorsed

by WHO as the key strategy for the control of morbidity and socio-economic damages.

Prevention and control of NTDs

"The global effort to control and eliminate neglected tropical diseases must be led by the countries

themselves,” said by Kesetebirhan Admasu, Minister of Health, Ethiopia in the meeting of “The

Addis Ababa NTD Commitment, 2014”. In the Addis Ababa declaration, Ministers of Health from

the participating countries pledged to take ownership, responsibilities and to increase local

funding in the research and control efforts of national NTD programmes. A good sign in the

elimination and control of NTDs is that recently endemic countries are increasingly taking

ownership and responsibilities of their national NTD programmes, have started providing new

funding and are pursuing innovative approaches to combat these devastating diseases. In doing

so, they are significantly contributing in increasing the overall global coverage rates under the

national NTDs programmes and thereby making a great stride toward elimination of these

diseases. WHO director of the Department of control of NTDs said “sustained political

commitment, innovative domestic financing and greater coordination can bring about game-

changing treatments and care to millions of people and improve the prospects of achieving WHO’s

goal of universal health coverage against NTDs.”

The invention of effective and cheap drugs that are safe and can be administer by non-

professional health personnel spurred the way for preventive chemotherapy (31). And therefore

mass drug administration in the endemic settings has become the best strategy for the prevention

and control of NTDs. However, this strategy has quite a few limitations. As for example, some

interventions are needed to repeat once or twice a year for an unknown period of time. Here,

compliance becomes an issue where quite a good number of people may feel healthy after initial

treatment and, hence, might not appreciate to undergo for the repeated treatments. Preventive

chemotherapy is not available for some diseases in the endemic countries and therefore they need

enhanced patient management. The usage of drugs must be needed to monitor carefully as the

excessive use of may evolve in resistance. Moreover, recurrence of the infection may occur as

preventive chemotherapy does not address the root of behavioral, ecological and socio-economic

causes. Therefore emphasis should be given to adopt preventive measures, such as increased

access to clean drinking water, improved sanitation and hygiene (34-36). It is also important to

step up for the implementation of integrated control measures, with the combination of two or

more interventions together that are suitable to an endemic setting and adapted over time, in

order to prevent and control the infection of NTDs. A profound knowledge regarding the

demographic, health and socio-ecological status could help in tailoring suitable integrated control

measures for a particular area or country (34).

Conclusions

“UK Coalition against NTDs: Annual Report 2014-2015” has been launched on 24th February, 2015

in which a key message was that although a substantial progress has been made on the way to

combat against NTDs, more efforts are needed to reach to WHO’s 2020 targets. Although WHO

recognized 17 NTDs, however, currently the number of NTDs has reached over 40 who are caused

by various bacterial, fungal, helminth, protozoal, viral and ectoparasitic infections. Many of these

infections can effectively be treated with short oral drug regimen (e.g., soil-transmitted

helminthiasis, including strongyloidiasis) while some other NTDs may require extensive and more

costly diagnosis (e.g., leishmaniasis, leprosy). Preventive chemotherapy would play vital role in the

elimination and control of NTDs. In the endemic settings where there is very limited or no access

to preventive chemotherapy, preventive measures including access to safe drinking water,

improved sanitation and hygiene and awareness programmes should be conducted.

In order to achieve WHO’s 2020 goals, individual countries should come up with increased

responsibilities and funding for innovative research that will eventually lead to the development of

new improved tools and strategies that can be applied in the prevention and control of NTDs. In

the meantime, a number of endemic countries including Bangladesh, the Philippines and Honduras

have already taken on primary responsibility for financing their NTD control programmes which

will significantly contribute in achieving elimination goals for individual diseases. In fact, global

coverage (at least with one drug) rates improved to 43% in 2015 compared to around 35% in 2008

(37).

Therefore, increased participation from endemic countries, WHO and other global partners,

biotechnology and pharmaceutical companies in funding for innovative research and support for

the control of NTDs is essentially expected for elimination and gradual eradication of these

devastating diseases for good.

References

1. Investing to overcome the global impact of neglected tropical diseases: Third WHO report

on neglected tropical diseases. WHO 2015.

2. UK Coalition against NTDs: Annual Report 2014-2015, 2015.

3. Utzinger J, Becker SL,Knopp S, Blum J, Neumayr AL, Keiser J, Hatz CF. Neglected tropical

diseases: diagnosis, clinical management, treatment and control. Swiss Med

Wkly.2012;142: w13727.

4. Accelerating work to overcome the global impact of neglected tropical diseases: A

roadmap for implementation-2011. WHO 2011.

5. Feasey N, Wansbrough-Jones M, Mabey DC, Solomon AW (2010). Neglected tropical

diseases".Br. Med. Bull. 93 (1): 179–200.

6. Fenwick A (March 2012). "The global burden of neglected tropical diseases". Public

Health126(3): 233–6.

7. Reddy and Gill, Table 1. Key Features of 13 Neglected Tropical Diseases Listed by

Prevalence. 2007.

8. Hotez PJ, Yamey G. The evolving scope of PLoS Neglected Tropical Diseases. PLoS Negl Trop

Dis. 2009;3:e379.

9. http://www.genome.gov/27531964 (Retrieved: 06.09.2015)

10. Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJL. Global and regional burden of

disease and risk factors, 2001: systematic analysis of population health data. Lancet.

2006;367:1747–57.

11. Murray CJL, Rosenfeld LC, Lim SS, Andrews KG, Foreman KJ, Haring D, et al. Global malaria

mortality between 1980 and 2010: a systematic analysis. Lancet. 2012;379:413–31.

12. Hotez PJ, Fenwick A, Savioli L, Molyneux DH. Rescuing the bottom billion through control of

neglected tropical diseases. Lancet. 2009;373:1570–5.

13. Allotey P, Reidpath DD, Pokhrel S. Social sciences research in neglected tropical diseases 1:

the ongoing neglect in the neglected tropical diseases. Health Res Policy Syst. 2010;8:32.

14. Murray CJL, Vos T, Lozano R, Naghavi M, Flaxman AD, et al. (2012) Disability-adjusted life

years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis

for the Global Burden of Disease Study 2010. Lancet 380: 2197–2223.

15. Mathers CD, Ezzati M, Lopez AD (2007) Measuring the burden of neglected tropical

diseases: the global burden of disease framework. PLoS Negl Trop Dis 1: e114.

16. Brooker S, Hotez PJ, Bundy DAP (2008) Hookworm-related anaemia among pregnant

women: a systematic review. PLoS Negl Trop Dis 2: e291.

17. Smith JL, Brooker S (2010) Impact of hookworm infection and deworming on anaemia in

nonpregnant populations: a systematic review. Trop Med Int Health 15: 776–795.

18. King CH (2010) Parasites and poverty: the case of schistosomiasis. Acta Trop 113: 95–104.

19. Mbabazi PS, Andan O, Fitzgerald DW, Chitsulo L, Engels D, et al. (2011) Examining the

relationship between urogenital schistosomiasis and HIV infection. PLoS Negl Trop Dis 5:

e1396.

20. Sripa B, Brindley PJ, Mulvenna J, Laha T, Smout MJ, et al. (2012) The tumorigenic liver fluke

Opisthorchis viverrini–multiple pathways to cancer. Trends Parasitol 28: 395–407.

21. World Health Organization (1994). Infection with liver flukes (Opisthorchis viverrini,

Opisthorchis felineus and Clonorchis sinensis). IARC Monogr Eval Carcinog Risks Hum 61:

121–175.

22. Carabin H, Ndimubanzi PC, Budke CM, Nguyen H, Qian Y, et al. (2011) Clinical

manifestations associated with neurocysticercosis: a systematic review. PLoS Negl Trop Dis

5: e1152.

23. Hotez PJ, Molyneux DH, Fenwick A, Ottesen E, Ehrlich Sachs S, Sachs JD. Incorporating a

rapid-impact package for neglected tropical diseases with programs for HIV/AIDS,

tuberculosis, and malaria. PLoS Med. 2006;3:e102.

24. Hotez PJ, Alvarado M, Basanez MG, Bollinger I, Bourne R, Boussinesq M, et. al. The global

burden of disease study 2010: interpretation and implications for the neglected tropical

diseases. PLoS Negl Trop Dis. 2014, 8(7): e2865.

25. Miguel E, Kremer M (2004) Worms: Identifying Impacts on Education and Health in the

Presence of Treatment Externalities. Econometrica 72: 159-217.

26. Perera M, Whitehead M, Molyneux D, Weerasooriya M, Gunatilleke G (2007) Neglected

patients with a neglected disease? A qualitative study of lymphatic filariasis. PLoS Negl Trop

Dis 1: e128.

27. Weiss MG (2008) Stigma and the social burden of neglected tropical diseases. PLoS Negl

Trop Dis 2: e237.

28. Mavalankar D, Tapasvi P, Murtola TM, Vasan S (2009) Quantifying the Impact of

Chikungunya and Dengue on Tourism Revenues. In: IIMA Working Papers, WP2009-02-03.

India: Indian Institute of Management Ahmedabad, India Research and Publication

Department.

29. Trouiller P, Olliaro P, Torreele E, Orbinski J, Laing R, Ford N. Drug development for

neglected diseases: a deficient market and a public-health policy failure. Lancet

2002;359:2188–94.

30. Cohen J, Dibner MS, Wilson A. Development of and access to products for neglected

diseases. PLoS One 2010;5:e10610.

31. Preventive chemotherapy in human helminthiasis: coordinated use of anthelminthic drugs

in control interventions: a manual for health professionals and programme managers.

Geneva: World Health Organization 2006.

32. Hopkins A. Treating neglected tropical diseases. Community Eye Health. 2013;26(82):26-27.

33. https://www.givingwhatwecan.org/research/charities-area/neglected-tropical-diseases-

ntds (Retrieved: 04.09.2015)

34. Utzinger J, Raso G, Brooker S, de Savigny D, Tanner M, Ørnbjerg N, et al. Schistosomiasis

and neglected tropical diseases: towards integrated and sustainable control and a word of

caution. Parasitology. 2009;136:1859–74.

35. Bartram J, Cairncross S. Hygiene, sanitation, and water: forgotten foundations of health.

PLoS Med. 2010;7:e1000367.

36. Ziegelbauer K, Speich B, Mäusezahl D, Bos R, Keiser J, Utzinger J. Effect of sanitation on soil-

transmitted helminth infection: systematic review and meta-analysis. PLoS Med.

2012;9:e1001162.

37. http://ntd-coalition.blogspot.my/ (Retrieved: 05.09.2015)