Microbes and Infection 16 (2014) 601e606 www.elsevier.com/locate/micinf

Brazil's neglected tropical diseases: an overview and a report card Peter J. Hotez a,b,c,*, Ricardo T. Fujiwara d,** a

Sabin Vaccine Institute and Texas Children's Hospital Center for Vaccine Development, Departments of Pediatrics and Molecular Virology and Microbiology, National School of Tropical Medicine, Baylor College of Medicine, Houston, TX, United States b Department of Biology, Baylor University, Waco, TX, United States c James A. Baker III Institute for Public Policy, Rice University, Houston, TX, United States d Department of Parasitology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Brazil Received 22 July 2014; accepted 23 July 2014 Available online 1 August 2014

Abstract Today, the nation of Brazil leads the Western Hemisphere in terms of the number of its citizens living with neglected tropical diseases (NTDs). These diseases continue to trap Brazil's “bottom 20 million” in extreme poverty. © 2014 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Keywords: Neglected tropical diseases; NTDs; Brazil; Helminth infections

1. Introduction When it comes to extreme disparities between its wealthy and its poor, there is no other nation quite like Brazil. While the World Bank categorizes Brazil as an “upper middle income country” [1], the reality is that it is a nation of economic extremes (Fig. 1). In 2013 Brazil's population surpassed 200 million people such that it now accounts for approximately 34% of the population of the Latin American and Caribbean (LAC) region and 20% of the roughly one billion people living in the Western Hemisphere (Box 1) [2e4]. Brazil also represents the largest economy in the LAC region with a gross domestic product that now exceeds $2.5 trillion; it is also the second largest economy in the Western Hemisphere behind the United States, and the seventh largest globally [4,5]. Brazil is one of * Corresponding author. National School of Tropical Medicine, 1 Baylor Plaza, Houston, TX 77030, USA. Tel.: þ1 713 798 1199. ** Corresponding author. Department of Parasitology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil. Tel.: þ55 (31) 3409 2827. E-mail addresses: [email protected] (P.J. Hotez), [email protected] (R.T. Fujiwara).

the world's fastest growing economies in recent years, with its gross domestic product growing by 7.5 percent in 2010, down to 2.7 percent in 2011, and recovering to 2.3 percent growth in 2013 after just one percent growth in 2012 [5,6]. Unfortunately such explosive economic growth has left behind approximately 10 percent of Brazil's population that still lives on less than $2 per day [7] e approximately 20 million people, which includes around 12 million people living below the World Bank poverty line of $1.25 per day [8]. Thus Brazil comprises approximately 20% of the 100 million people who live in extreme poverty in the LAC region and the Western Hemisphere [9]. Such extremes reflect the finding that at 54.7 Brazil has one of the world's highest GINI indices e a measurement used by economists to assess disparities between wealthy and poor [10]. Brazil's GINI coefficient is exceeded only by the nations of Colombia, Honduras, South Africa and Zambia [10]. As shown in Fig. 1, poverty is not evenly distributed in Brazil, but instead it is concentrated in the northeastern part of the country, including the states of Alagoas, Bahia, Ceara, Maranhao, Paraiba, Pernambuco, Piaui, Rio Grande do Norte, Sergipe, and the northern area of Minas Gerais state, and in northwest in Amazonas state [11].

http://dx.doi.org/10.1016/j.micinf.2014.07.006 1286-4579/© 2014 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

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Brazilians in extreme poverty [14]. Here we update some of the latest information on Brazil's NTDs published since 2010 using World Health Organization (WHO, Preventive Chemotherapy and Transmission Control [PCT] http://www.who.int/ neglected_diseases/preventive_chemotherapy/databank/en/) and Pan American Health Organization (PAHO) databases, as well as key published papers, including a 2009 review by Lindoso and Lindoso [15]. We find that with a few exceptions all of Brazil NTDs continue to remain widespread among the poor. 2. Neglected parasitic infections Brazil's neglected parasitic infections include the major vector-borne protozoan and helminth infections, and the intestinal nematode infections and schistosomiasis. 2.1. Vector-borne protozoan infections Fig. 1. Percentage of population living in extreme poverty, less than US$70 per month. Original figure produced from data in Municipal social indicators: analysis from the Demographic Census of 2010 by the Brazilian Institute of Geography and Statistics, available here: http://www.ibge.gov.br/home/ estatistica/populacao/censo2010/indicadores_sociais_municipais/tabelas_pdf/ tab24.pdf.

Also concentrated in these impoverished areas where most of Brazil's affected people live on less than $2 per day are high rates of neglected tropical diseases (NTDs). NTDs and poverty are closely linked in part because these chronic and debilitating parasitic and related infections can be demonstrated to cause poverty through their adverse impact on adult worker health and productivity and child growth and intellectual development [9]. NTDs also disproportionately affect girls and women [12], as well as indigenous populations [13]. In 2008, it was previously pointed out that NTDs disproportionately affect Brazil relative to other LAC nations and that these diseases represented one of the most potent forces that trap

Box. 1. Population and poverty of Brazil. Brazil's Population (2013 estimate) Percentage of Latin American & Caribbean Population living in Brazil Percentage of Western Hemisphere Population living in Brazil Number of Brazilians living on less than $1.25 per day (World Bank estimate in 2009) Number of Brazilians living on less than $2 per day (World Bank estimate in 2009) Brazil's GINI indexa a

200.4 million people 34% 20% 12 million (6.1%) 22 million (10.8%) 54.7

GINI index measures the extent to which the distribution of income or consumption expenditure among individuals or households within an economy deviates from a perfectly equal distribution. For more information, please see http://data.worldbank.org/indicator/SI.POV.GINI.

Brazil still leads the LAC region and Western Hemisphere in terms of the number of cases of Chagas disease, both cutaneous and visceral forms of leishmaniasis, and vivax malaria. Although many of the new cases of Chagas disease (American trypanosomiasis caused by Trypanosoma cruzi) resulting from Triatoma infestans vector-borne transmission have been eliminated in Brazil [15], there remain an estimated 1.9 million people living with the disease, accounting for approximately one-quarter of the world's cases [16]. However, an alternative estimate based on a systematic review indicates that as many as 4.6 million people may be infected with T. cruzi, with clear evidence of high prevalence in endemic areas, especially in urbanized regions and the elderly [17]. Outside of transmission from T. infestans there are concerns for continued emergence of this infection in Brazil through either sylvatic or oral transmission, especially in Amazonas where large numbers of impoverished Brazilians live [15,17]. More than 90% of the LAC region's several thousand cases of visceral leishmaniasis (Leishmania chagasi infection) occur in Brazil [18], with the highest concentration in the impoverished northeastern region [15]. Almost 40% of the LAC's region's cutaneous and mucocutaneous leishmaniasis is also found in Brazil equivalent to approximately 100,000 new cases annually [18]. Urbanization and deforestation are key social determinants that contribute to new cases [15]. According to PAHO, Brazil has the highest number of malaria cases in the LAC region, with approximately 87% caused by Plasmodium vivax [19,20]. More than one-third of the entire LAC region's 100 million people at risk for malaria are found in Brazil e mostly in the Amazon region [15] - despite important reductions of this disease in collaboration with WHO's Roll Back Malaria program and the Global Fund to Fight AIDS, Tuberculosis, and Malaria [19,20]. 2.2. Vector-borne helminth infections Both lymphatic filariasis (LF, caused by Wuchereria bancrofti) and onchocerciasis (Onchocerca volvulus) represent

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two NTDs for which Brazil does not lead the LAC region in terms of the number of cases. With respect to LF, Brazil together with the Dominican Republic, Guyana, and Haiti comprise four of the last remaining endemic countries in the LAC region [21e25]. Beginning in the 1950s, Brazil made tremendous strides towards LF elimination [25]. Today all of the estimated 1.7 million Brazilians at risk, accounting for just more than 10% of the people at risk for LF in the Americas [21,22], live in cities in the metropolitan region of Recife in the State of Pernambuco [23e25]. The WHO estimates that just over one-half of the individuals who require mass drug administration (also known as ‘preventive chemotherapy’) for LF receive access to essential medicines [21]. All of Brazil's onchocerciasis cases occur among the Yanomami indigenous populations in Amazonas State in an area that is contiguous with Venezuela [26]. Approximately 13,000 people are at risk for onchocerciasis, although through quarterly mass drug administration treatments the disease may be eliminated in the coming years [26]. 2.3. Intestinal helminth infections and schistosomiasis The three major intestinal helminthiases, i.e., ascariasis, trichuriasis, and hookworm infection, together with intestinal schistosomiasis (Schistosoma mansoni infection) rank among the most common NTDs in Brazil, especially among children. Today, almost 12 million Brazilian children (both preschoolaged and school-aged children) require preventive chemotherapy (“deworming”) with either albendazole or mebendazole [27], accounting for approximately one-quarter of the children in the LAC region with intestinal helminths [28,29]. However, according to the WHO only about 15% of children at risk in Brazil actually receive regular deworming [27]. With respect to intestinal schistosomiasis almost all (96%) of the LAC region's cases occur in Brazil [30,31]. Intestinal schistosomiasis is widespread in Brazil, occurring in 19 states according to Lindoso and Lindoso [15]. Although a national schistosomiasis control program, which includes mass drug administration has been in place since 1975 [15], the WHO estimates that fewer than 3% of the almost 1.5 million Brazilians infected with S. mansoni are actually receiving treatment with praziquantel or oxamniquine [30,31]. 3. Neglected viral, bacterial, and fungal infections 3.1. Dengue Dengue fever is the major arbovirus infection now affecting Brazil, with recent estimates suggesting that approximately 22 million cases occur annually or 40% of the cases in the LAC region [32]. The disease re-emerged in Brazil in 1986 after a nearly 20-year absence [33]. Subsequently, dengue type-3 (DENV-3) was introduced in Brazil in 1990 leading to large epidemics that included hemorrhagic fever and shock syndrome [15]. Dengue incidence exceeded 400 per 100,000 in 2010, when DENV-4 was introduced and DENV-1 re-emerged [34]. According to one author, dengue is now Brazil's greatest

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health threat [34], and it is considered to be hyperepidemic [33]. 3.2. Neglected mycobacterial infections Both neglected mycobacterial infections e leprosy and Buruli ulcer e occur in Brazil. According to the WHO there are almost 30,000 registered cases of leprosy in Brazil, accounting for almost all of the registered cases in the LAC region [35]. The Amazon region is disproportionately affected with the state of Mato Grosso in 2007 reporting the highest case detection rate [36]. The first autochthonous case of Buruli ulcer was reported in Brazil in 2010 [37]. 3.3. Trachoma and other NTDs Brazil is one of three trachoma-endemic countries in the LAC region (the other two are Guatemala and Mexico, with Colombia undergoing confirmatory investigation) and the only country where this disease is considered a public health problem [38e40]. Most of the estimated 7000 trachoma cases in Latin America occur in Brazil [41], and are concentrated in the northern states and among indigenous populations [38e40]. A national trachoma program is in place to detect active cases [41]. Brazil was previously believed to be endemic for yaws but the current status of this disease is unknown [42]. Another very important NTD in Brazil is leptospirosis but there are no accurate figures regarding the number of cases. Recently it was reported that more than 90 percent of the reported deaths from leptospirosis occur in Brazil [43]. Paracoccidiomycosis is an important systemic neglected fungal disease for which very little disease burden information is available. Government programs are in place in the south and southeastern part of the country [44]. 4. Future directions and concluding statements In 2008 Brazil was identified as “ground zero” for NTDs in the LAC region, ranking the highest in terms of cases of the LAC region's NTDs, and with a disease burden that even exceeded what might be expected for its large population [14,45]. As shown in Table 2, this situation has not changed significantly over the last seven years. Thus despite accounting for 35% of the population of the LAC region, Brazil has greater than this percentage of the region's number of cases of schistosomiasis, leprosy, trachoma, leptospirosis, dengue, malaria, both forms of leishmaniasis, and possibly Chagas disease. Indeed almost all of the LAC's number of cases of schistosomiasis, visceral leishmaniasis, and leprosy still occur in Brazil. Given the link between NTDs and poverty, it is likely that Brazil's entire bottom 20 million living in poverty are affected by at least one of the diseases listed in Tables 1 and 2. Because NTDs have been shown to cause poverty for reasons highlighted earlier, the disproportionate number of Brazilians affected by NTDs represents a major reason why its poor cannot escape poverty and a basis for why Brazil's high GINI coefficient and index will not likely improve anytime

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Table 1 Neglected tropical diseases in Brazil. Disease

Cases in Brazil or number Rank of people at risk or requiring in the treatment Americas

Cases in the Americas

Approximate % Cases in the Americas found in Brazil

Comments

Ref

1.9e4.6 million

1

7e8 million

25%

Two published estimates vary considerably

[16,17]

72,800e119,600 (incidence)

1

39%

[18]

4200e6300 (incidence)

1

187,200e307,800 (incidence) 4500e6800 (incidence)

93%

[18]

38 million at risk in 2011; 267,045 cases confirmed

1

106 million at risk

36%

[19,20]

1.7 million requiring PC in (Pernambuco State only)

2

13.3 million

13%

Onchocerciasis

12,988 at risk in 22 endemic areas (Amazonas)

5

560,911 at risk

2%

Intestinal helminth infections

3.045 million preschool children requiring treatment

1

13.9 million preschool 24% children requiring treatment in 2011 35.1 school-aged children requiring treatment 49 million children total requiring treatment in 2011 1,551,140 people 96% requiring preventive chemotherapy in 2012

Protozoan infections Chagas disease

Cutaneous leishmaniasis Visceral leishmaniasis Malaria Helminth infections Lymphatic filariasis

8.892 million School-aged children requiring treatment 11.9 million children total require treatment Schistosomiasis

1,485,112 people requiring preventive chemotherapy

Viral infections Dengue

5.4 million apparent 16.4 million inapparent 21.8 million cases Bacterial and fungal infections Leprosy 29,311 registered cases in 2012 Buruli ulcer Case reported Trachoma Endemic country number of cases not determined

Yaws

Previously endemic status unknown Leptospirosis 349 reported deaths Paracoccidiomycosis Not determined

1

1

13.3 million apparent 40.5 million inapparent 53.8 million cases

1

All cases in [21e25] Pernambuco State 57% Program coverage 10% National coverage Other countries: Dominican Republic, Guyana, Haiti [26] All cases in Amazonas with 85% coverage during 2001e2012 Other countries: Colombia, Ecuador, Guatemala, Venezuela 15% Programme [27e29] Coverage

Only 2.7% received access to treatment

[30,31]

40%

[32e34]

33,926 registered cases in 2012 Not determined Not determined 1 Most of the estimated 7000 cases in Latin America 341,385 living in endemic areas in 2012 Not determined Not determined

86%

[35,36]

Not determined Not determined but most of the cases found in Latin America occur in Brazil

[37] [38e41]

Not determined

[42]

1 380 reported deaths Not determined Not determined

92% Not determined

[43] [44]

P.J. Hotez, R.T. Fujiwara / Microbes and Infection 16 (2014) 601e606 Table 2 Brazil's burden of NTDs in the Latin American and Caribbean (LAC) Region. Disease

Percentage of LAC Disease burden Reference disease burden rank in the LAC

Schistosomiasis 96% Visceral leishmaniasis 93% Leptospirosis 92% Leprosy 86% Dengue 40% Cutaneous leishmaniasis 39% Malaria 36% Chagas disease 25% Intestinal helminth 24% infections Lymphatic filariasis 13% Onchocerciasis 2%

1 1 1 1 1 1 1 1 1

[30,31] [18] [43] [35] [32] [18] [19,20] [16,17] [27,28]

2 5

[21] [26]

soon. Among populations at particular risk for NTDs are those living in impoverished regions of the northeast, the Amazon region, and indigenous populations [13e15,17,24,25,41]. In response to this overwhelming situation of NTDs and poverty, in 2012 the Brazilian Ministry of Health established an integrated and coordinated plan to eliminate some of the major NTDs highlighted here including schistosomiasis, LF, and onchocerciasis, together with proposed reductions in the number of children affected by intestinal helminth infections [23,24,41]. A key element is mass drug administration for these infections in areas where the known prevalence exceeds a selected threshold [24,41]. Together with leprosy screening school-based deworming is now a component of Brazil's Without Extreme Poverty Plan (Plano Brazil Sem Miseria) [24,46]. Brazil's first national deworming plan began in 2013 [24]. Prior to this time mass drug administration was decentralized as many disease control responsibilities were delegated to state or municipal governments [23,24]. Today both LF and onchocerciasis stand out for their potential for being eliminated in the coming years [23e26]. Regarding Chagas disease, it has been noted that despite important gains in national control and elimination efforts, the prevalence remains high in some endemic areas especially the Amazon region [17]. According to Martins-Melo et al., new control strategies aimed at controlling oral transmission in the Amazon region together vector control for so-called “secondary species” in the northeastern part of Brazil need to be implemented [17]. Moreover, because the national notification strategy relies on diagnosing acute Chagas disease, which is often asymptomatic, the disease is greatly underreported [17]. Still another key issue is the low percentage of T. cruzi chronically-infected people who have access to essential antitrypanosomal thereapy and receive treatment for Chagas disease. In addition to monitoring progress on the plan launched in 2012, it will be equally critical to implement a parallel research and development (R&D) strategy for new control tools and technologies e i.e., drugs, diagnostics, and vaccines e that may be required to eliminate most of Brazil's NTDs. Indeed, Brazil's R&D investments e especially from its

605

Ministry of Science, Technology, and Innovation e appear to be substantial, although it is not entirely clear from publiclyavailable information exactly what percentage of those investments are for NTDs. Such activities need to be prioritized by Brazil's academic and research institutions, and coordinated in ways to convert scientific discoveries into new products by a growing translational and product development enterprise. Conflict of interest The authors declare no conflict of interest. References [1] World Bank. Data. http://data.worldbank.org/country/brazil, [accessed 11.03.14]. [2] Brazilian Institute of Geography and Statistics. ftp://ftp.ibge.gov.br/ Estimativas_de_Populacao/Estimativas_2013/populacoes_estimativas_ BR_UF_TCU_31_10_2013.pdf, accessed through http://www.ibge.gov. br/home/estatistica/populacao/estimativa2013/estimativa_tcu.shtm, [accessed 12.04.14]. [3] World Bank. http://data.worldbank.org/region/latin-america-andcaribbean, [accessed 11.07.14]. [4] World Bank. http://data.worldbank.org/country/brazil, [accessed 19.07.14]. [5] Central Intelligence Agency. https://www.cia.gov/library/publications/ the-world-factbook/geos/br.html, [accessed 12.04.14]. [6] SBS News. http://www.sbs.com.au/news/article/2014/02/28/brazil-posts23-gdp-growth-2013, [accessed 01.03.14]. [7] World Bank. Data. http://data.worldbank.org/indicator/SI.POV.2DAY, [accessed 18.01.14]. [8] World Bank. Data. http://data.worldbank.org/indicator/SI.POV.DDAY, [accessed 11.01.14]. [9] Hotez PJ, Dumonteil E, Heffernan MJ, Bottazzi ME. Innovation for the ‘bottom 100 million’: eliminating neglected tropical diseases in the Americas. Adv Exp Med Biol 2012;764:1e12. [10] World Bank. Data. http://data.worldbank.org/indicator/SI.POV.GINI, [accessed 18.02.14]. [11] World Bank. Poverty in Latin America and the Caribbean. http://web. worldbank.org/WBSITE/EXTERNAL/COUNTRIES/LACEXT/EXTLA CREGTOPPOVANA/0,contentMDK:22416581~pagePK:34004173~pi PK:34003707~theSitePK:841175,00.html, [accessed 18.03.14]. [12] Hotez P, Whitham M. Helminth infections: a new global women’s health agenda. Obstet Gynecol 2014;123:155e60. [13] Hotez PJ. Aboriginal populations and their neglected tropical diseases. PLOS Negl Trop Dis 2014;8:e2286. [14] Hotez PJ. The giant anteater in the room: Brazil’s neglected tropical disease problem. PLOS Negl Trop Dis 2008;2:e177. [15] Lindoso JAL, Lindoso AABP. Neglected tropical diseases in Brazil. Rev Inst Med Trop S Paulo 2009;51:247e53. [16] Bern C, Kjos S, Yabsley MJ. Montgomery SP Trypanosoma cruzi and Chagas disease in the United States. Clin Microbiol Rev 2011;24:655e81. [17] Martins-Melo FR, Ramos Jr AN, Alencar CH, Heukelbach J. Prevalence of Chagas disease in Brazil: a systematic review and meta-analysis. Acta Trop 2014;130:167e74. [18] Alvar J, Velez ID, Bern C, Herrero M, Desjeux P, Cano J, et al. Leishmaniasis worldwide and global estimates of its incidence. PLOS One 2012;7:e35671. [19] Pan American Health Organization. Report on the situation of malaria in the Americas; 2011. Brazil, http://www.paho.org/hq/index.php? option¼com_content&view¼article&id¼2459&Itemid¼2000&lang¼en [accessed 18.07.14]. [20] Pan American Health Organization. Report on the situation of malaria in the Americas; 2011. Regional Section, http://www.paho.org/hq/index.php?

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