Citation: Hotez PJ, Molyneux DH (2008) Tropical Anemia: One of Africa's Great Killers and a Rationale for Linking Malaria and Neglected Tropical Disease Control to Achieve a Common Goal. PLoS Negl Trop Dis 2(7): e270. doi:10.1371/journal.pntd.0000270
Published: July 30, 2008
Copyright: © 2008 Hotez, Molyneux. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The authors received no specific funding for this study.
Competing interests: PJH is President of the Sabin Vaccine Institute. He is an inventor on two international patents on hookworm vaccines. PJH and DHM are co-founders of the Global Network for Neglected Tropical Disease Control.
“Wiping out malaria would join the eradication of smallpox as one of the greatest accomplishments in human history. It is a goal we can achieve.”
Melinda Gates, co-founder,
Bill & Melinda Gates Foundation
With more than 1 million child deaths annually, malaria remains the single leading killer of young children in sub-Saharan Africa . Millions more young children survive, but still suffer from severe anemia and permanent neurological damage , as well as more subtle neuropsychiatric disturbances including impaired cognition and memory . Malaria in pregnancy is also a major cause of maternal deaths and low birth weight , and together these maternal and child health effects account for huge economic losses that trap families in poverty . As a result, malaria is now considered one of the key forces preventing the development of the African continent . In response to a growing malaria crisis, the Bill & Melinda Gates Foundation recently announced an ambitious program of expanded malaria control, with a long-term goal of malaria eradication . The major elements of expanded malaria control include strengthening of prevention and treatment programs worldwide through the Global Fund to Fight AIDS, Tuberculosis and Malaria, the United States President's Malaria Initiative, the World Bank Malaria Control Booster Program, scale-up of national control programs , coordination through the Roll Back Malaria Partnership based at the World Health Organization (WHO) , and advocacy by Malaria No More and other organizations .
In the early 1970s, an intensified effort to interrupt the transmission of malaria was conducted in a group of villages near the town of Garki in northern Nigeria . Through household spraying, mass drug administration, and other measures, there was a temporary reduction in malaria deaths, but overall the Garki Project showed that interrupting malaria transmission was not possible even when a full armamentarium of control tools was applied . An important difference between then and now is the availability of long-lasting insecticide-treated nets (LLITNs) and artemisinin combination therapy (ACT)-based treatments, in addition to the increased willingness to deploy indoor insecticide spraying . However, it is unclear whether even the deployment of these new control tools will directly lead to total success in malaria control because of the threat of emerging insecticide resistance to pyrethroids and the potential for emergence of artemisinin resistance ,,. Also, parallel efforts will be required to strengthen Africa's weakened health systems ,, which today suffer from widespread malaria misdiagnoses in endemic areas  and a lack of access to essential medicines and LLITNs . Accordingly, WHO and other organizations are embarking on renewed efforts to strengthen health systems in Africa and elsewhere , while product development partnerships have evolved in a concerted push to accelerate the development of additional new malaria drugs and insecticides, and safe and effective anti-malaria vaccines ,,.
There is yet another promising, low-cost and highly cost-effective, and complementary approach for potentially reducing the morbidity of malaria in sub-Saharan Africa, which builds on existing efforts and could be implemented for as little as US$0.50 per person per year or less than 10% add-on to projected malaria control costs –. In sub-Saharan Africa, where more than 90% of malaria deaths occur, children and pregnant women are simultaneously infected with both malaria and a group of other parasitic diseases, known as the neglected tropical diseases (NTDs). The major NTDs in sub-Saharan Africa include hookworm infection (198 million cases) and other soil-transmitted helminth infections such as ascariasis and trichuriasis (173 million and 162 million cases, respectively), schistosomiasis (166 million), trachoma (33 million), lymphatic filariasis (46 million), and onchocerciasis (18–37 million) ,. There is evidence that some of these NTDs exert an adverse influence on the clinical outcome of malaria in childhood and in pregnancy –, and even possibly on malaria transmission . Shown in Figure 1 is a previously published map demonstrating the geographic overlap and co-endemicity of falciparum malaria and hookworm infection (Africa's most common NTD), based on statistical and spatial analyses . This analysis shows high spatial congruence of these two infections, with one quarter of all sub-Saharan African schoolchildren simultaneously at risk for hookworm and malaria. Almost all of the estimated 50 million schoolchildren in sub-Saharan Africa with hookworm infection are also at high risk for malaria, except in a small band of the Sahel where the climate is presumably too dry to support the larval development of hookworms . A similar association has also been noted between malaria and schistosomiasis . Therefore, early evidence points to high rates of malaria and NTD coinfections in sub-Saharan Africa, especially with hookworm infection and schistosomiasis.
Geographic overlap of moderate-high hookworm infection prevalence (greater than 20% prevalence of infection among school-aged children) and transmission of falciparum malaria transmission (based on a map of climactic suitability for Plasmodium falciparum malaria transmission, adjusted for urbanization). Modified from .
In Africa and other tropical developing countries, the great killer and disabler that results from malaria and NTD coinfections is anemia , –. Anemia accounts for up to one half of malaria deaths in young children , and is a leading contributor to the huge numbers of maternal deaths that result during pregnancy, as well as premature births . Chronic anemia in young children is also associated with reductions in physical growth, and impaired cognition and school performance ,. Many of the NTDs, but especially two of the most common ones in sub-Saharan Africa, hookworm infection and schistosomiasis, cause anemia , –, while in Asia (and presumably elsewhere), hookworm infection, schistosomiasis, and trichuriasis result in a synergistic anemia . Malaria also causes severe anemia ,, and in cases of malaria and NTD coinfection, anemia in vulnerable children and women develops through one or more of several mechanisms including blood loss, hemolysis, anemia of inflammation, and splenic sequestration –, –. An important consequence of malaria and NTD coinfections is an enhancement in anemia, or what we have called previously “the perfect storm of anemia” . For instance, in Kenya, hemoglobin concentrations were found to be 4.2 g/l lower among children harboring hookworm and malaria coinfections than in children with single-species infections . Because hookworm and schistosomiasis are widespread in Africa ,,, it is likely that these NTDs represent important contributors to the overall mortality from childhood malaria in this region ,,.
Similarly, most of the 7.5 million pregnant women infected with hookworm likely live in areas of sub-Saharan Africa that place them at risk for malaria ,. At the same time, malaria control and NTD control have each been shown to reduce anemia both in children ,,, and in pregnant women ,,,. Therefore, combining malaria and NTD control practices in a unified anemia framework affords one of the best opportunities to reduce the huge burden of morbidity and mortality that results from anemia in sub-Saharan Africa. In addition to the health improvement that would result from anemia reduction, there is also some evidence that hookworm and schistosomiasis (and possibly other NTDs) may immunomodulate their human host and promote increased susceptibility to malaria, so that NTD control would work in synergy with nets and other measures to reduce malaria incidence .
In sub-Saharan Africa, there are several opportunities to link malaria and NTD control programs . They include programs targeted for infants, preschool children, or school-aged children that employ intermittent preventive treatment (IPT), in which use of either sulfadoxine–pyrimethamine or ACT  would be supplemented with anthelminthic drugs (“deworming”) or with a rapid-impact package of NTD drugs that simultaneously target hookworm and other soil-transmitted helminth infections, lymphatic filariasis, onchocerciasis, and trachoma ,,. A joint program of malaria and NTD control could be incorporated as a new element of Integrated Management of Childhood Illness and other programs for children . There are also opportunities for linking IPT in pregnancy with anthelminthic drugs (or the rapid-impact package) for NTD control, especially given the benefit of deworming in terms of improving birth outcome and reducing maternal morbidity and mortality ,. The anthelminthic drugs mebendazole and albendazole can be used in the second and third trimester of pregnancy and are recommended by WHO in the appropriate settings . Community-based prevention efforts could also be integrated. Both untreated bed-nets and LLITNs are proportionately more effective in preventing lymphatic filariasis compared with malaria , and the use of bed-nets was shown to increase substantially, in some cases 9-fold, when used alongside NTD control efforts .
Together, malaria and the seven most common NTDs listed above cause almost 2 million deaths and are responsible for the loss of almost 100 million disability-adjusted life years (DALYs) annually (almost 20% higher than the disease burden from HIV/AIDS) . Much of this high disease burden operates through the mechanism of anemia. According to J. Crawley, “…an integrated and non-disease specific approach is essential if the intolerable burden of anemia that currently exists in malaria-endemic regions of Africa is going to be reduced” . Although there will be operational challenges to integrating NTD with malaria control, the opportunities for improving health, education, and economic development for the poorest people in sub-Saharan Africa are simply too great for us to ignore. Accordingly, the public–private partnerships of the Global Network for NTDs are working to identify opportunities for integration . In addition, given the ability of hookworm and other NTDs to interfere with vaccine immunogenicity, we also need to consider the importance of NTD research for the malaria research agenda , as well as the opportunity to develop new NTD drugs and vaccines alongside new innovations in malaria treatment and prevention .
It is likely that focusing control efforts on malaria alone will thwart global efforts to sustain malaria control, much less achieve eradication. Ultimately, by reducing anemia in sub-Saharan Africa, linking the NTDs with malaria control would have a major impact on almost all of the Millennium Development Goals . It is some four years since this approach was suggested , but policy makers are only gradually recognizing the benefits of more holistic approaches to tackling the diseases of the poor. An integrated control program for tropical anemia in Africa represents one of our better hopes for a quick win in the fight for sustainable disease control and poverty reduction.
- 1. Greenwood BM, Fidock DA, Kyle DE, Kappe SH, Alonso PL, et al. (2008) Malaria: Progress, perils, and prospects for eradication. J Clin Invest 118: 1266–1276. doi:10.1172/JCI33996.
- 2. Kihara M, Carter JA, Newton CR (2006) The effect of plasmodium falciparum on cognition: A systematic review. Trop Med Int Health 11: 386–397. doi:10.1111/j.1365-3156.2006.01579.x.
- 3. Rogerson SJ, Mwapasa V, Meshnick SR (2007) Malaria in pregnancy: Linking immunity and pathogenesis to prevention. Am J Trop Med Hyg 77: (Suppl 6)14–22.
- 4. Sachs JD (2005) Achieving the millennium development goals—The case of malaria. N Engl J Med 352: 115–117. doi:10.1056/NEJMp048319.
- 5. Bill & Melinda Gates Foundation (2007) Bill and Melinda Gates call for new global commitment to chart a course for malaria eradication. Available: http://www.gatesfoundation.org/GlobalHealth/Pri_Diseases/Malaria/Announcements/Announce-071007.htm. Accessed 2 July 2008.
- 6. Roll Back Malaria Partnership (2008) What is the Roll Back Malaria (RBM) Partnership? Available: http://rbm.who.int/aboutus.html. Accessed 2 July 2008.
- 7. Malaria No More (2008) About Malaria No More. Available: http://www.malarianomore.org/about.php. Accessed 2 July 2008.
- 8. Greenwood B (2004) The Garki project (box 8-1). In: Arrow KJ, Panosian CB, Gelband H, editors. Saving lives, buying time: Economics of malaria drugs in an age of resistance. The National Academies Press. Available: http://www.nap.edu/catalog.php?record_id=11017. Accessed 2 July 2008.
- 9. Casimiro SL, Hemingway J, Sharp BL, Coleman M (2007) Monitoring the operational impact of insecticide usage for malaria control on anopheles funestus from Mozambique. Malar J 6: 142. doi:10.1186/1475-2875-6-142.
- 10. Noedl H (2005) Artemisinin resistance: How can we find it? Trends Parasitol 21: 404–405. doi:10.1016/j.pt.2005.06.012.
- 11. Breman JG, Alilio MS, Mills A (2004) Conquering the intolerable burden of malaria: What's new, what's needed: A summary. Am J Trop Med Hyg 71: (Suppl 2)1–15.
- 12. Webster J, Lines J, Bruce J, Armstrong Schellenberg JR, Hanson K (2005) Which delivery systems reach the poor? A review of equity of coverage of ever-treated nets, never-treated nets, and immunisation to reduce child mortality in Africa. Lancet Infect Dis 5: 709–717. doi:10.1016/S1473-3099(05)70269-3.
- 13. Amexo M, Tolhurst R, Barnish G, Bates I (2004) Malaria misdiagnosis: Effects on the poor and vulnerable. Lancet 364: 1896–1898. doi:10.1016/S0140-6736(04)17446-1.
- 14. Lufesi NN, Andrew M, Aursnes I (2007) Deficient supplies of drugs for life threatening diseases in an African community. BMC Health Serv Res 7: 86. doi:10.1186/1472-6963-7-86.
- 15. World Health Organization (2007) Everybody's business: Strengthening health systems to improve health outcomes. WHO's framework for action. Available: http://www.who.int/healthsystems/strategy/everybodys_business.pdf. Accessed 3 July 2008.
- 16. Hemingway J, Beaty BJ, Rowland M, Scott TW, Sharp BL (2006) The innovative vector control consortium: Improved control of mosquito-borne diseases. Trends Parasitol 22: 308–312. doi:10.1016/j.pt.2006.05.003.
- 17. Molyneux DH, Hotez PJ, Fenwick A (2005) “Rapid-impact interventions”: How a policy of integrated control for Africa's neglected tropical diseases could benefit the poor. PLoS Med 2: e336. doi:10.1371/journal.pmed.0020336.
- 18. Hotez PJ, Molyneux DH, Fenwick A, Kumaresan J, Ehrlich Sachs S, et al. (2007) Control of neglected tropical diseases. New Engl J Med 357: 1018–1027.
- 19. Molyneux DH, Nantulya VM (2004) Linking disease control programmes in rural Africa: A pro-poor strategy to reach Abuja targets and millennium development goals. BMJ 328: 1129–1132. doi:10.1136/bmj.328.7448.1129.
- 20. Sachs JD, Hotez PJ (2006) Fighting tropical diseases. Science 311: 1521. doi:10.1126/science.1126851.
- 21. Sokhna C, Le Hesran JY, Mbaye PA, Akiana J, Camara P, et al. (2004) Increase of malaria attacks among children presenting concomitant infection by Schistosoma mansoni in Senegal. Malar J 3: 43. doi:10.1186/1475-2875-3-43.
- 22. Brooker S, Clements AC, Hotez PJ, Hay SI, Tatem AJ, et al. (2006) The co-distribution of plasmodium falciparum and hookworm among African schoolchildren. Malar J 5: 99. doi:10.1186/1475-2875-5-99.
- 23. Brooker S, Akhwale W, Pullan R, Estambale B, Clarke SE, et al. (2007) Epidemiology of plasmodium-helminth co-infection in Africa: Populations at risk, potential impact on anemia, and prospects for combining control. Am J Trop Med Hyg 77: (Suppl 6)88–98.
- 24. Hotez PJ, Molyneux DH, Fenwick A, Ottesen E, Ehrlich Sachs S, et al. (2006) Incorporating a rapid-impact package for neglected tropical diseases with programs for HIV/AIDS, tuberculosis, and malaria. PLoS Med 3: e102. doi:10.1371/journal.pmed.0030102.
- 25. Druilhe P, Tall A, Sokhna C (2005) Worms can worsen malaria: Towards a new means to roll back malaria? Trends Parasitol 21: 359–362. doi:10.1016/j.pt.2005.06.011.
- 26. Korenromp EL, Armstrong-Schellenberg JR, Williams BG, Nahlen BL, Snow RW (2004) Impact of malaria control on childhood anaemia in Africa—A quantitative review. Trop Med Int Health 9: 1050–1065. doi:10.1111/j.1365-3156.2004.01317.x.
- 27. Guyatt HL, Snow RW (2004) Impact of malaria during pregnancy on low birth weight in sub-Saharan Africa. Clin Microbiol Rev 17: 760–769. doi:10.1128/CMR.17.4.760-769.2004.
- 28. Bates I, McKew S, Sarkinfada F (2007) Anaemia: A useful indicator of neglected disease burden and control. PLoS Med 4: e231. doi:10.1371/journal.pmed.0040231.
- 29. Friedman JF, Kanzaria HK, McGarvey ST (2005) Human schistosomiasis and anemia: The relationship and potential mechanisms. Trends Parasitol 21: 386–392. doi:10.1016/j.pt.2005.06.006.
- 30. Hotez PJ, Brooker S, Bethony JM, Bottazzi ME, Loukas A, et al. (2004) Hookworm infection. N Engl J Med 351: 799–807. doi:10.1056/NEJMra032492.
- 31. Crompton DW (2000) The public health importance of hookworm disease. Parasitology 121: (Suppl)S39–S50.
- 32. Stoltzfus RJ, Dreyfuss ML, Chwaya HM, Albonico M (1997) Hookworm control as a strategy to prevent iron deficiency. Nutr Rev 55: 223–232.
- 33. Ezeamama AE, McGarvey ST, Acosta LP, Zierler S, Manalo DL, et al. (2008) The synergistic effect of concomitant schistosomiasis, hookworm, and trichuris infections on children's anemia burden. PLoS Negl Trop Dis 2: e245. doi:10.1371/journal.pntd.0000245.
- 34. Mebrahtu T, Stoltzfus RJ, Chwaya HM, Jape JK, Savioli L, et al. (2004) Low-dose daily iron supplementation for 12 months does not increase the prevalence of malarial infection or density of parasites in young Zanzibari children. J Nutr 134: 3037–3041.
- 35. ter Kuile FO, Terlouw DJ, Phillips-Howard PA, Hawley WA, Friedman JF, et al. (2003) Impact of permethrin-treated bed nets on malaria and all-cause morbidity in young children in an area of intense perennial malaria transmission in western Kenya: Cross-sectional survey. Am J Trop Med Hyg 68: (Suppl 4)100–107.
- 36. Larocque R, Casapia M, Gotuzzo E, Gyorkos TW (2005) Relationship between intensity of soil-transmitted helminth infections and anemia during pregnancy. Am J Trop Med Hyg 73: 783–789.
- 37. Christian P, Khatry SK, West KP Jr (2004) Antenatal anthelmintic treatment, birthweight, and infant survival in rural Nepal. Lancet 364: 981–983. doi:10.1016/S0140-6736(04)17023-2.
- 38. Greenwood B (2006) Review: Intermittent preventive treatment—A new approach to the prevention of malaria in children in areas with seasonal malaria transmission. Trop Med Int Health 11: 983–991. doi:10.1111/j.1365-3156.2006.01657.x.
- 39. Garg R, Lee LA, Beach MJ, Wamae CN, Ramakrishnan U, et al. (2002) Evaluation of the integrated management of childhood illness guidelines for treatment of intestinal helminth infections among sick children aged 2–4 years in western Kenya. Trans R Soc Trop Med Hyg 96: 543–548.
- 40. Albonico M, Montresor A, Crompton DW, Savioli L (2006) Intervention for the control of soil-transmitted helminthiasis in the community. Adv Parasitol 61: 311–348. doi:10.1016/S0065-308X(05)61008-1.
- 41. Manga L (2002) Vector-control synergies, between ‘roll back malaria’ and the global programme to eliminate lymphatic filariasis, in the African region. Ann Trop Med Parasitol 96: (Suppl 2)S129–S132.
- 42. Blackburn BG, Eigege A, Gotau H, Gerlong G, Miri E, et al. (2006) Successful integration of insecticide-treated bed net distribution with mass drug administration in central Nigeria. Am J Trop Med Hyg 75: 650–655.
- 43. Crawley J (2004) Reducing the burden of anemia in infants and young children in malaria-endemic countries of Africa: From evidence to action. Am J Trop Med Hyg 71: (Suppl 2)25–34.
- 44. Druilhe P, Sauzet JP, Sylla K, Roussilhon C (2006) Worms can alter T cell responses and induce regulatory T cells to experimental malaria vaccines. Vaccine 24: 4902–4904. doi:10.1016/j.vaccine.2006.03.018.
- 45. Hotez PJ, Ferris MT (2006) The antipoverty vaccines. Vaccine 24: 5787–5799.