Learning Objectives
- List the neglected tropical diseases (NTDs) of the developing world and the factors contributing to their being “neglected”
- Discuss the many links between NTDs and poverty and how the Millennium Development Goals might break these links
- Review the symptoms, diagnosis, treatment, and control measures for 13 chronic NTDs and one acute NTD (dengue)
- Discuss the application of various disease control strategies (vector control, mass drug administration, vaccination, reservoir elimination, etc.) to NTDs
Introduction
The neglected tropical diseases (NTDs) are chronic infections affecting the poorest people of the world, living in sub-Saharan Africa, Asia, and Latin America (Table 11-1). Because most health care workers in developed countries are unfamiliar with NTD diagnosis and treatment, these are summarized in Tables 11-2 and 11-3. The term neglected tropical diseases was first introduced in the 1980s as the “great neglected diseases of mankind” by the late Dr. Ken Warren. These chronic, disabling but rarely fatal diseases not only afflict the poor, but they also keep them in poverty. Many NTD victims are stigmatized by their illness and unable to find employment. These are the diseases with the horrific photos in the tropical medicine texts, and in many cultures the stigma is intensified by the condition being attributed to witchcraft or a curse. Although none are as deadly as the three most important tropical diseases, malaria, tuberculosis (TB), and acquired immune deficiency syndrome (AIDS), if taken together the total disability of just 13 of these “lesser” diseases approaches that of HIV/AIDS and exceeds that of malaria and TB.1 NTDs are “neglected” only because the suffering from these ancient scourges is largely confined to the so-called third world, effectively veiling their existence from wealthier nations. Many Americans are amazed to learn that they still exist. In the words of the World Health Organization (WHO), they are “not adequately addressed either nationally or internationally.” There is also little financial incentive for pharmaceutical firms to develop or distribute new drugs or vaccines in the absence of a ready market for them, especially because most NTDs occur in the 2.7 billion people making less than $2 US per day.2 Before philanthropic interests made them priorities, NTDs were literally “out of sight and out of mind.”
Disease | Prevalence (in millions) | Areas of prevalence |
|---|---|---|
Roundworm (Ascariasis) | 807 | Developing world (moist climates) |
Whipworm (Trichuriasis) | 604 | Developing world (moist climates) |
Hookworm (Necator, Ancylostoma) | 576 | Developing world (moist climates) |
Schistosomiasis | 207 | Sub-Saharan Africa, Latin America |
Lymphatic filariasis | 120 | India, Southeast Asia, Sub-Saharan Africa, East Asia-Pacific |
Trachoma | 84 | North and Sub-Saharan Africa, Middle East, South Asia, East Asia-Pacific (dry climates) |
Onchocerciasis | 37 | Sub-Saharan Africa, limited areas of Latin America |
Leishmaniasis | 12 | India and South Asia (visceral), Latin America (cutaneous), Sub-Saharan Africa |
Chagas disease | 8–9 | Latin America |
Leprosy | 0.4 | India, Sub-Saharan Africa, Brazil |
Human African trypanosomiasis | 0.3 | Sub-Saharan Africa |
Buruli ulcer | 0.05 | Sub-Saharan (West) Africa |
Dracunculiasis | 0.01 | Sub-Saharan Africa |
Dengue | Acute illness and epidemics Incidence: 50–100 million cases annually | Southeast Asia, Caribbean, Latin America, Africa |
Disease | Diagnostic tests |
|---|---|
Roundworm (Ascaris) | Stool O&P (eggs) |
Whipworm (Trichuris) | Stool O&P (eggs) |
Hookworm (Necator, Ancylostoma) | Stool O&P (characteristic eggs and sometimes larvae), CBC (iron deficiency anemia) |
Schistosomiasis | Stool O&P (S. mansoni) or spun urine O&P (S. haematobium), Schistosoma antigen testing (available CDC), + eosinophilia; liver biopsy + exudative granulomata |
Lymphatic filariasis | Blood parasite smear drawn at appropriate time, +LF antigen test, ultrasound (filarial dance) |
Trachoma | Clinical appearance (WHO trachoma grading system) |
Onchocerciasis | Six skin snips from iliac crests, biopsy of nodule, slit lamp examination of eye, CDC serologic testing (Onchocerca antigen tests)—serology unable to distinguish past from present infection,+ eosinophilia |
Leishmaniasis | Microscopy of lesion biopsy or tissue smear, immunochromatographic test strip for leishmanial anti-K39 antibody, PCR, Montenegro (leishmanin) skin test (unable to distinguish current from past infection) |
Chagas disease | Serologies for chronic infection: ELISA testing (e.g., Chagatest ELISA Recombinante) or Ortho T. cruzi ELISA Test System), then Chagas Radioimmune Precipitation Assay (Chagas RIPA) as confirmatory test Thin and thick blood smears (+ acute infection only); xenodiagnosis (development in triatomid bug) used historically |
Leprosy | Confirmed by skin biopsy or microscopic exam of earlobe fluid (+ acid-fast bacteria typical only in multibacillary disease), still often a clinical diagnosis; + lepromin skin test only in tuberculoid leprosy (no culture possible) |
Human African trypanosomiasis | Blood smear (East African form) or microscopy of lymph node aspirate (West African form); latter usually not seen in blood smear; serology used in research |
Buruli ulcer | Clinical appearance, PCR standard for confirming diagnosis |
Guinea worm (Dracunculiasis) | Clinical: ulcerated extremity with visible worm (rarely mimicked by onchocerciasis) |
Dengue fever | RT-PCR for viremia (first 5 days of infection); DENV Detect IgM Capture ELISA for IgM antibodies after 5 days; four fold antibody increase in acute and convalescent serum samples; tourniquet test for dengue hemorrhagic fever |
Disease | Treatment |
|---|---|
Roundworm (Ascaris) | Albendazole 400 mg or mebendazole 500-mg single dose |
Whipworm (Trichuris) | Mebendazole 500 mg once or albendazole 400 mg qd × 3 d |
Hookworm (Ancylostoma, Necator) | Albendazole 400 mg or mebendazole 500-mg single dose |
Schistosoma haematobium/mansoni | Praziquantel 40 mg/kg/d in 2 divided doses × 1 d |
Schistosoma japonicum | Praziquantel 60 mg/kg/din3 divided doses × 1 d |
Lymphatic filariasis (LF) | Diethylcarbamazine 6 mg/kg/d in 3 doses × 12 d |
Trachoma | Azithromycin 20 mg/kg single dose up to 1 g maximum |
Onchocerciasis | Ivermectin 150 μg/kg once, repeated every 6–12 months until asymptomatic Doxycycline 100 mg qd × 6 wk may be added several days after the ivermectin dose19 |
Leishmaniasis | |
Cutaneous | Sodium stibogluconate 20 mg Sb/kg/dIV or IM × 10–28 d or observation Liposomal amphotericin B superior to sodium stibogluconate |
Mucocutaneous | Liposomal amphotericin B 3 mg/kg/d IV d1–5, 13, 21 or |
Visceral | Sodium stibogluconate 20 mg Sb/kg/d IV or IM × 28 d or Miltefosine 2.5 mg/kg/d PO(max 150 mg/d) × 28 d (India) |
Chagas disease | Nifurtimox 8–10 mg/kg/d in 3–4 doses × 90–120 d or Benznidazole 5–7 mg/g/d in 2 doses with food × 30–90 d |
Leprosy paucibacillary or tuberculoid form, <5 skin lesions | Dapsone 100 mg qd and monthly rifampin 600 mg × 6 mo (finish 6 packs in 6–12 mo) |
Multibacillary or lepromatous form, 6+ lesions, + smear | Dapsone 100 mg qd and clofazimine 50 mgqd, with monthly rifampin 600 mg and clofazimine 300 mg, × 12+ mo (finish 12 packs in 12–18 mo) Reference: A New Atlas of Leprosy30 |
| Human African trypanosomiasis | |
West African | Early West African: Pentamidine 4 mg/kg/d IM × 7 d or suramin 100–200 mg IV (test dose) then 1g IV on days 1,3,7,14,21 Late West African: Eflornithine 400 mg/kg/d IV in 4 doses × 14 d or melarsoprol 2.2 mg/kg/d IV× 10 d |
East African | Early East African: Suramin (doses as above) Late East African: Melarsoprol 2–3.6 mg/kg/d IV × 3 d, after 7 d: 3.6 mg/kg/d × 3 d; repeat again after 7 d |
Buruli ulcer | Rifampin 10 mg/kg and streptomycin 15 mg/kg administered daily × 8 wk (some experimental regimens substitute clarithromycin for streptomycin)—a paradoxical reaction (temporary exacerbation) sometimes noted Reference: Converse et al32 |
Guinea worm (Dracunculiasis) | Manual extraction using stick; no medical treatment |
Dengue fever | Hydration and supportive care (no pharmacologic treatment) |
Although only the 13 “classic” chronic NTDs proposed by Peter Hotez and one acute viral disease, dengue fever, are covered in this chapter, this by no means suggests that many other diseases are not equally neglected.2 In addition to dengue, the WHO adds cysticercosis, echinococcosis, fascioliasis, rabies, and yaws to Hotez’s list. The WHO considers the soil transmitted helminths as one NTD instead of three (Hotez) for a total of 17 conditions. There are also WHO “neglected conditions” such as snakebite and podoconiosis (nonfilarial elephantiasis).3 Indeed it has been suggested that all tropical diseases other than the “big three” of HIV, malaria, and TB are neglected. Many diseases of the tropics have limited therapeutic options and remain in great need of further research.
The common factor with all the NTDs is poverty. How people live determines how they get sick and even how they die. These diseases thrive in crowded, dirty environments where there is little sanitation, a scarcity of potable water, and extensive exposure to the elements. Most people with NTDs depend on agriculture or herding to survive and spend much of their life outdoors. They live in crowded substandard housing (contributing to Chagas disease), are in contact with fecally contaminated soil (hookworm), bathe in snail-infested rivers (schistosomiasis), and are bitten by numerous insect vectors.
It makes sense that the elimination of poverty is therefore the best single approach to ending these diseases. Introducing privies or flush toilets is the surest way to eliminate soil-borne helminthic infections. Hygiene eradicates trachoma. Safe drinking water stops guinea worm. Bed nets and window screens dramatically reduce insect-borne diseases.
Affluence enables travelers from wealthy countries to “cocoon” themselves from most of these environmental threats. Travelers to these regions can be shielded by expensive insect repellents, air-conditioned hotels, bottled water, sturdy footwear, vaccinations, and antibiotics, but few if any of these resources are available to the impoverished local population. Although most of the diseases discussed in this chapter have specific control measures, a temporary lapse in implementation (due to regional conflict or loss of funding) has often resulted in their resurgence. The only permanent solution is the eradication of poverty.
The United Nations Millennium Declaration (2000) lists eight specific Millennium Development Goals (MDGs) to eliminate extreme poverty, hunger, and disease by 2015.4 These include eliminating extreme poverty and hunger, achieving universal primary education, promoting gender equality and empowering women, reducing childhood mortality, improving maternal health, combating HIV/AIDS, malaria, and other diseases, ensuring a sustainable environment, and developing global partnerships for development. Lifting people out of poverty is the most effective way of ending the grip of NTDs on their lives. Although criticized as overly idealistic, these goals have spotlighted such issues, and many MDGs have received extensive funding from governmental (e.g., Presidents Emergency Plan for AIDS Relief, or PEPFAR) and philanthropic (e.g., Bill and Melinda Gates Foundation) organizations.
The Neglected Tropical Diseases
The first three NTDs are soil-transmitted helminthic infections, affecting perhaps a billion people.5 Many children are coinfected by all three of these worms (polyparasitism). Intestinal worms stunt the growth of impoverished children in Africa, Asia, and Latin America. They are especially prevalent in the humid tropics where adequate rainfall and poor hygiene create ideal environments for these parasites. Together they are suspected of being a leading cause of child growth retardation.6
Ascaris, or roundworm, infections are especially common in areas of poor sanitation, where human feces contaminate the soil. These abundant roundworms are acquired by ingesting embryonated eggs, after which the larvae pass through the lungs to develop in the small intestine. Children are especially prone to heavy infections, which retard appetite, growth, and school performance, occasionally causing intestinal obstruction. Migration of these worms into the bile ducts or pancreas may cause acute cholecystitis or pancreatitis.
Trichuris, or whipworm, infections commonly coinfect children with Ascaris and are acquired in a similar fashion, although these worms develop in the large intestine without passing through the lungs. They are associated with colitis and rectal prolapse.
The most important of the three helminth infections is hookworm. These parasites rob their victims of blood, producing profound iron deficiency anemia and fatigue. Both hookworm species, Necator americanus and the less abundant Ancylostoma duodenale, are acquired from contact with fecally contaminated soil. Larvae penetrate the skin, often causing a pruritic “ground-itch” rash. They then migrate to the lungs, are coughed up and swallowed, and attain maturity in the small intestine where they survive for decades. Hookworm anemia results in a sallow complexion, and many cultures refer to it as “yellow disease.”
Transmission of all of these soil-transmitted helminthes is most effectively stopped by modern sanitation, which prevents fecal contamination of soil. Latrine use is a first step that is much more feasible than indoor plumbing for impoverished communities. Because any skin exposure to infected soil can result in hookworm infection, proper footwear is at best only a partial solution. Regular deworming of all schoolchildren with benzimidazoles (BZAs) is a practical interim solution, especially in high- incidence areas where infection rates exceed 50%.7 In 2001, the WHO adopted resolution 54.19, urging regular deworming of at least 75% of at-risk schoolchildren by 2010.8 Single-dose albendazole 400 mg or mebendazole 500 mg every 6 to 12 months is safe and effective, although these programs fail to reach preschoolers and children not attending school. BZA resistance is well known in veterinary use and emerging in human infection, necessitating an urgent need to develop new drugs. Unfortunately, there are few antiparasitic drugs in development. The newest alternative drug for human use is tribendimidine, which was approved in China in 2004.9
Vaccination against hookworm infection would be a major milestone on the road to eradication because it would prevent reinfection in areas of poor hygiene. The Human Hookworm Vaccine Initiative was established in 2000 with the goal of developing both effective hookworm and Schistosoma vaccines.
Schistosomes are blood flukes that afflict over 200 million people, most (97%) of whom live in Africa.10 Endemic areas of less importance include Brazil, Yemen, Southeast Asia, and the Philippines. Substantial eradication has already occurred in China and Egypt. Three principal species exist: Schistosoma haematobium, residing in bladder vessels and causing urinary schistosomiasis in Africa (63% of cases); S. mansoni, residing in the greater mesenteric vessels (intestinal schistosomiasis, 35%); and S. japonicum, residing in the lesser mesenteric vessels (Asian intestinal schistosomiasis, now less than 1%).11 Other species, such as S. mekongi and S. intercalatum, are far less significant.
These flukes depend on freshwater snails, an intermediate host, to complete their life cycle, hence the alternative term snail fever. Another name, bilharzia, is derived from Theodor Bilharz, who first described urinary schistosomiasis in the 19th century. The infection is acquired from entering snail-infested water. Free-living cercariae (larval flukes) are released from snails and swim until they come in contact with and penetrate human skin. Some victims develop a pruritic rash or cercarial dermatitis (“swimmer’s itch”) at the sites of penetration, but this is variable. After entry, the cercariae lose their tails and migrate through the lungs and liver, eventually making their way to the bladder or mesenteric vessels, where they develop into blood-feeding permanently paired adults. An intense immune response to schistosome egg production may provoke an acute febrile illness termed Katayama fever in previously nonexposed travelers, but more commonly the infection is insidious. Although the flukes themselves remain largely invisible to the immune system (they mask their presence by shrouding themselves with their host’s antigens), their spined eggs provoke significant inflammation as they penetrate through the bladder and intestinal walls. In the case of S. haematobium, this results in hematuria (sometimes termed male menstruation), bladder granulomas (which may cause hydronephrosis and renal failure), squamous cell cancer of the bladder, and female genital lesions (which increase the risk of HIV transmission). In the case of S. mansoni and S. japonicum, granulomas of the intestinal wall and liver develop leading to colitis, hepatosplenomegaly, and hepatic fibrosis. Hepatocellular carcinoma is a later, fatal complication.12
Eggs are excreted in the urine (S. haematobium) or stool (S. mansoni, S. japonicum), and the species can be easily identified by the spine’s location on the egg (terminal in haematobium, lateral in mansoni, absent in japonicum). When human waste enters fresh water, the eggs hatch into miracidia that seek out snails to parasitize.
Vaccines against schistosomiasis would help prevent the continual threat of reinfection after treatment. Only one schistosomal prototype vaccine (Bilhvax for S. haematobium) has undergone successful human trials.13 Although the vaccine was safe and effective, there are as yet no schistosome vaccines in clinical use.
The turning point in the war on schistosomiasis came with the discovery of praziquantel (Biltricide) by Bayer Pharmaceuticals in the mid-1970s. Praziquantel is effective for most flatworms (flukes and tapeworms), although resistance is starting to emerge.14 Mass treatment programs with donated praziquantel 40 mg/kg/day, sometimes combining this therapy with albendazole for roundworm infection, have been effective and well tolerated.14 The Schistosomiasis Control Initiative (SCI), funded by the Gates Foundation, has led these mass drug administration efforts. Single-dose praziquantel is often sufficient to eradicate infection. Molluscicides to kill snails in ponds, rivers, and streams have been used in conjunction with praziquantel in many areas. This integrated approach is termed preventive chemotherapy and transmission control, and similar strategies are used for controlling many NTDs.
