Pediatr Blood Cancer 2015;62:1131–1136
REVIEW Sickle Cell in Sickle Cell Disease in Latin America and the United States Alexandra Huttle,
1 BS,
Gladys E. Maestre,
2 MD PhD,
Latin Americans are an underappreciated population affected by sickle cell disease (SCD). Sickle trait and SCD exist throughout Latin America and U.S. Latino communities. We describe the epidemiology and genetic heterogeneity of SCD among Latin Americans, and fetal hemoglobin expression. National population-based newborn screening for SCD is limited to Brazil, Costa Rica, and the U.S. Available and
Rafael Lantigua,
3 MD,
and Nancy S. Green,
MD
1
*
extrapolated data suggest that over 6,000 annual births and 100,000– 150,000 Latin Americans are affected by SCD. This comprehensive review highlights the substantial numbers and population distribution of SCD and sickle trait in Latin America, and where national newborn screening programs for SCD exist. Pediatr Blood Cancer 2015;62:1131–1136. # 2015 Wiley Periodicals, Inc.
Key words: hemoglobinopathies; Latin America; sickle cell; sickle trait
INTRODUCTION Sickle cell disease (SCD) is among the most common serious single gene disorders [1]. While three quarters of births affected by SCD occur in sub-Saharan Africa, other sizable populations exist worldwide [2]. Recognizing the distribution of the sickle gene and those affected by SCD within Latin America and Latinos in the United States (U.S.) is critical for provision of appropriate medical services for preventative care and treatment, increasing public awareness, and appropriately aligning the allocation of public health resources. The sickle gene was promulgated in the Latino (Hispanic) populations of the Western hemisphere primarily through the transatlantic slave trade, ending in the 1800s. The largest numbers of Africans forcibly taken to the Americas were distributed to the U.S., Brazil, and the Caribbean [3]. Recent estimates suggest that 2–3 million Americans and 1–2 million Brazilians are sickle trait carriers [1,4]. Continued population migration out of the African continent is predicted to increase these numbers. These trends underscore the human dynamics, rather than pressure from malaria, affecting the distribution of the sickle gene among the Americas [3]. This comprehensive review synthesizes available epidemiologic, genetic, and clinical information about SCD from Latino American countries where data from universal newborn screening, national, or clinical sampling have been reported [2,4–8]. We provide novel data on the newborn prevalence data for SCD and sickle trait for a number of countries and an estimate of total number of Latin Americans living with SCD. The status of SCD in two Latin American countries, Venezuela and the Dominican Republic, is described to illustrate gaps in data stemming from lack of national population-based screening and SCD services.
METHODS All 21 Latin American countries were considered: Argentina, Belize, Bolivia, Brazil, Chile, Colombia, Costa Rica, Cuba, Dominica, Dominican Republic, Ecuador, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, Panama, Paraguay, Peru, Uruguay, and Venezuela [9]. Populations identified as Latino/Hispanic in the U.S. were defined by the National Newborn Screening Information System and by state newborn screening programs in New York and California, based on race/ethnicity from maternal self-report [1,5,10,11]. A comprehensive literature review was performed using PubMed as the information source [12] restricted to the English
C
2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25450 Published online 2 March 2015 in Wiley Online Library (wileyonlinelibrary.com).
language. The key reports in Spanish on newborn screening in Latin America and on SCD in Venezuela were identified and reviewed by a native Spanish speaker co-author, (G.E.M.) [13,14,15,16]. Search terms used in English or Spanish were: “Latino and sickle cell,” “Hispanic and sickle cell,” “Latin America and sickle cell,” “South America and sickle cell,” “Central America and sickle cell,” “U.S. and Latino and sickle cell,” “U.S. and Hispanic and sickle cell,” “Puerto Rico and sickle cell,” and each of the 21 Latin American countries, Spain, or Portugal, in combination with “sickle cell.” Data on Venezuela were obtained through targeted Internet searching for pertinent Spanish language materials. Information regarding population and prevalence estimates, the genetic characterization of the sickle gene, newborn screening, therapeutic opportunities and awareness of SCD were reviewed. Data were also extracted from the Malaria Atlas Project and the United Nations Statistics Division to calculate birth prevalence numbers for Brazil, Mexico, Venezuela, Colombia, Guatemala, the Dominican Republic, Nicaragua, and Panama.[17,18] National and regional prevalence data from NBS are available from the U.S. and Brazil. In contrast, countrywide data among Latin American countries were extrapolated from data derived from varying sampling strategies, described below [19].
RESULTS Data Sources Comprehensive review yielded 26 informative papers identified by the search terms listed above. Collectively, data from these sources were available for many of the countries in Latin America, 1
Division of Pediatric Hematology, Oncology, Stem Cell Transplantation, Department of Pediatrics, Columbia University Medical Center, New York, New York; 2Department of Psychiatry and Neurosciences, Cardiovascular Institute, Institute for Biological Research, University of Zulia, Maracaibo Venezuela, and G.H. Sergievsky Center, Columbia University Medical Center, New York, New York; 3Department of Medicine, Columbia University Medical Center, New York, New York Conflict of interest: Nothing to declare. Correspondence to: Nancy S. Green, Division of Pediatric Hematology, Oncology, Stem Cell Transplantation, Department of Pediatrics, Columbia University Medical Center, 630 West 168 St. - Black Building 2-241, New York, NY 10032. E-mail: [email protected]
Received 17 July 2014; Accepted 8 January 2015
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and two states within the U.S. Data on nearly all countries in the region were gathered by the Malaria Atlas Project, which reported on homozygous sickle disease (HbSS) and sickle trait (HbAS) [17]. Malaria Atlas Project data were adapted to demonstrate the geographical distribution of the sickle hemoglobin allele in the Americas, by country and by coastal distribution (Figure 1, with permission from the publisher) [20]. Those data were derived from Piel et al., where national data were extrapolated from prior sampling in each country, and then projected based on national birth rates [19]. Depth of data analysis for each country generally reflects the size of the population affected, and the extent to which population screening or other medical services were reported. The Malaria Atlas Project reported prevalence data derived from sampling of more than 10,000 people from only three countries in the region: U.S., Brazil, and Venezuela. English language data on
sickle cell prevalence, clinical course, genetic analysis, health status, and treatment outcomes exist primarily for the U.S. and Brazil, with some data available from Venezuela (in Spanish). For many Latin American countries, reported prevalence of the sickle allele was extrapolated from testing 100–10,000 people, and excluded Cuba. Moreover, data collection for many of the Latin American countries spanned from the 1960s through the 1980s, not accounting for evolving population demographics.
Origin of SCD in Latin America and U.S. Latinos Several lines of evidence support an African origin of the sickle gene for Latin Americans. First, the geographic distribution of affected people reflects the history of forced migration and its prevalence along the eastern coast of the Americas where slave trading occurred (Figure 1) [19]. Second, prevalence of SCD was
Fig. 1. Geographical distribution of the sickle hemoglobin allele (HbS) [20]. (Reproduced with approval from the publisher.) Pediatr Blood Cancer DOI 10.1002/pbc
Sickle Cell Among Latinos low in Spain and Portugal during those periods [21,22]. Third, genetic analysis of the sickle beta globin gene in Latino populations demonstrates that most of the gene came from West and Central Africa (described below).
TABLE I. Latino (Hispanic) Sickle Cell Disease (all types) Population and Birth Prevalence Estimates Where National Newborn Screening is Practiced or Available from a Large Nationally Representative Birth Sample: United States, Brazil, Costa Rica, and Venezuela.
Demographics Latino sickle cell in the U.S. National and state-specific prevalence estimates for African American and Hispanic populations (Table I) were based on records from the National Newborn Screening Information System (NNSIS) for 2005–2007 for all 50 states and territories, the New York State newborn screening program for the years 2000–2008, and the Registry and Surveillance System for Hemoglobinopathies (RuSH) for 2004– 2008 [1,10,11]. Table I provides U.S. SCD population and prevalence estimates, highlighting the substantial numbers of affected Hispanic newborns across the U.S. Regional variation for Latino SCD reflects considerable differences in prevalence between Latino communities [1,10,23]. Low rates of SCD and sickle trait in U.S. newborns of Mexican ancestry are consistent with low prevalence rates reported from Mexico [17]. Births in Puerto Rico affected by SCD contribute fewer than 10 per year to the U.S. population [24]. New York State reported the largest number of newborns with SCD: 1,916 from 2000–2008, of whom 12% were Hispanic (defined as having a Hispanic mother) (Table I) [1]. Of these Hispanic newborns, 64.5% had foreign-born mothers, with nearly two thirds from the Dominican Republic, about 30% from Central America and 4% from Puerto Rico [1]. States with sizeable Latino populations with SCD also include California, Florida, and Texas [23].
Sickle Cell in Brazil and Selected Latin American Countries SCD population and prevalence estimates for the U.S., Brazil, Costa Rica, and Venezuela (Table I) were reported from the national newborn hemoglobinopathy screening programs, established in Brazil in 2001 [4], and in Costa Rica [14], and from a large national sampling of newborns in Venezuela [16]. These data underscore the presence of SCD in these countries and Brazil’s comparatively large and affected populace. Geographic distribution of SCD in Brazil is similar to that of the U.S., where the northeast and southeast regions have the highest prevalence of affected newborns (Table I, Fig. 1) [4].
Sickle Cell in Other Latin American countries Figure 2 depicts the estimated annual births and birth prevalence affected by SCD and HbAS for each Latin American country projected as having at least 100 annual births affected by SCD [17], or reported by Costa Rica [14] and Cuba [25]. While annual SCD births reported for Honduras met these criteria, those data were excluded because population data were extrapolated from a single skewed sample [19,26]. Brazil vastly outnumbers the other Latin American countries in the number of newborns annually affected by either SCD or HbAS (Fig. 2A, C). Birth prevalence estimates by country (Fig. 2B, D) were calculated by extracting prevalence data from the Malaria Atlas Project and the U.S. Statistics Division [17,18]. Data were obtained by dividing the annual number of births affected by SCD and HbAS Pediatr Blood Cancer DOI 10.1002/pbc
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SCD population estimatesa United States (total) Hispanics New York (total) Hispanics California (total) Hispanics Brazil Bahia Minas Gerais Rio de Janeiro Rio Grande do Sul Costa Rica Venezuelac
89,079 [23] 8,928 [23] 8,308 [23] 1,338 [23] 5,100 [11] 408 [11] 30,000 [4]
100 annual affected births [17,18].
10%), Honduras, and Costa Rica [27–30]. Per-country estimates varied by sample and methodology. While inexact, the proportion of African heritage by country generally correlated with prevalence of the sickle allele in newborns (Figure 2). Older studies described the origins of the sickle cell gene through specific molecular patterns of b-globin sickle gene markers, or haplotypes [31–33]. The distribution of these haplotypes from Latinos with SCD originating in the U.S., Brazil, Panama, and Venezuela provide molecular data to support the African origin of the sickle gene, and demonstrate similar distributions of African regions/ethnicities of origin between sample populations tested [34–37].
Fetal Hemoglobin Fetal hemoglobin (HbF) level is a highly regulated modifier of SCD disease, with an inverse association with risk of severe complications [38–40]. HbF generally ranges from 2–20% in children with SCD [8,41,42]. Similar HbF levels have been reported Pediatr Blood Cancer DOI 10.1002/pbc
across diverse groups from pediatric cohorts from Brazil, African Americans, and a Hispanic cohort in New York [41–44]. Among the ameliorative effects of hydroxyurea on SCD, a major impact is its induction of HbF [40]. Children in Brazil had HbF levels at baseline and with hydroxyurea induction [8] that were similar to those reported for an African American and Latino SCD clinic population in New York [42]. Only scant data have been reported on HbF and hydroxyurea response from other Latin American countries.
Newborn Screening for SCD The proportion of births covered by national newborn screening and the panel of diseases for which screening is performed vary by country within Latin American [29]. Only Brazil and Costa Rica perform mandatory national newborn hemoglobinopathy screening [29]. Brazil’s experience demonstrates the potential impact of universal newborn hemoglobinopathy screening and linked medical specialty services in Latin America, where child mortality rates of 3.7% resulted from diagnosis with implementation of
Sickle Cell Among Latinos comprehensive programs, compared to 5.6% in children diagnosed through less comprehensive programs [4]. Universal newborn screening and organized medical care for preventative strategies (e.g., penicillin prophylaxis and anti-pneumococcal vaccination) and use of hydroxyurea therapy for affected children have nearly eliminated SCD-related child mortality in the U.S. and Brazil [4–8]. Several other Latin American countries provide regional or national newborn screening for heritable conditions, but not for hemoglobinopathies, including Cuba, Brazil, Venezuela, Mexico, and others [29]. There, existing infrastructure may accommodate future inclusion of SCD in newborn screening programs. For example, in Venezuela a national reference center for advanced diagnosis of hemoglobinopathies complements current capacitybuilding activities to support inclusion of hemoglobinopathies in national newborn screening. However, specialized services or public programs are not directed to manage the special medical needs of SCD patients for acute or chronic sickle cell syndromes (personal communication, Dr. Maestre). Some countries in the region do not support any widespread newborn screening, such as Honduras [29] and the Dominican Republic (personal communication, Luis Rivera Mejia, M.D., Professor of Pediatrics at Universidad Autonoma de Santo Domingo; Chief Department of Perinatology, Hospital Maternidad Nuestra Senora de la Altagracia, Santo Domingo, Republica Dominicana). For the latter country, sickle screening is available only by parental request, national prevalence data are lacking and specialty treatment centers do not exist (personal communication, Dr. Mejia).
DISCUSSION SCD is an important genetic condition within Latin America and in the U.S., with prevalence varying between countries [17,18,20]. Only three countries in the Americas support populationbased screening programs for Latinos: U.S., Brazil, and Costa Rica [4,5,45]. Data were available from these countries on HbSS and HbSC and on regional variation. Elsewhere, only HbSS and sickle trait have been reported and are extrapolated from prevalence data based on regional sampling of modest proportion [19]. The major limitation of this review is, for some countries, insufficient national data from small samples of narrow geographic regions. Despite sizeable numbers of Latinos affected by SCD, availability of public health resources for these patients varies across Latin America. The U.S., Brazil, and Costa Rica have demonstrated that widespread population-based newborn screening for SCD coupled with organized specialty treatment have facilitated markedly reduced disease-related child mortality [4–8]. As has been suggested for Venezuela [16], health outcomes for children with SCD elsewhere in Latin America may benefit from expanded public health resources for SCD support. Even where widespread population-based screening exists, limited awareness about SCD and sickle trait was found among at least one Latino community in New York City compared to African Americans [46]. Reasons suggested for this knowledge gap include lower trait prevalence among Dominicans and the perception of SCD as being limited to “African” communities [46]. SCD in the Americas is dynamic, as trends in migration continue to influence the distribution of the sickle allele [3]. Cultural differences in affected populations, as well as the genetic data described above, stem from distinct waves of immigration to Pediatr Blood Cancer DOI 10.1002/pbc
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the U.S. and to Latin America [1]. Enhanced availability of reproductive genetic services may also influence the distribution of the sickle allele. For example, an adult screening program in Cuba provided at-risk couples with genetic information, and may have reduced the number of births affected by SCD [45]. This synthesis of the available data about SCD among Latin Americans is intended to highlight the substantial numbers and distribution of affected children and families, point out biologic similarities to those with SCD in the U.S., and identify data gaps. Our intent is to stimulate interest in public health, clinical approach and biomedical investigation for this population. The existing data and service gaps identify the need for enhanced focus to expand population surveillance to identify communities at risk and affected infants, increase access to specialty treatment, and promote awareness about the disease. Improved services for and research about SCD in Latin America are predicted to be important steps in improved disease outcomes.
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Lavinha J, Goncalves J, Faustino P, Roma˜o L, Osorio-Almeida L, Peres MJ, Picanc¸o I, Martins MC, Ducrocq R, Labie D. Importation route of the sickle cell trait into Portugal: Contribution of molecular epidemiology. Hum Biol 1992;64:891–901. 23. Brousseau DC, Panepinto JA, Nimmer M, Hoffmann RG. The number of people with sickle-cell disease in the United States: National and state estimates. Am J Hematol 2010;85:77–78. 24. Morales A, Wierenga A, Cuthbert C, Sacharow S, Jayakar P, Velazquez D, Loring J, Barbouth D. Expanded newborn screening in Puerto Rico and the US Virgin Islands: Education and barriers assessment. Genet Med 2009;11:169–175. 25. Aguila JD, Zamora MC, Fernandez OA, Jime´nez LP, Vicente OM, Alvarez IV. Comprehensive care for patients with sickle cell disease in Cuba. Haematologica 2008;93:e20. 26. Firschein IL. Population dynamics of the sickle-cell trait in the Black Caribs of British Honduras, Central America. Am J Hum Genet 1961;13:233–254. 27. Gravel S, Zakharia F, Moreno-Estrada A, Byrnes JK, Muzzio M, Rodriguez-Flores JL, Kenny EE, Gignoux CR, Maples BK, Guiblet W, Dutil J, Via M, Sandoval K, Bedoya G, 1000 Genomes Project, Oleksyk TK, Ruiz-Linares A, Burchard EG, Martinez-Cruzado JC, Bustamante CD. Reconstructing Native American migrations from whole-genome and whole-exome data. PLoS Genet 2013;9:e004023.
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28. Moreno-Estrada A, Gravel S, Zakharia F, McCauley JL, Byrnes JK, Gignoux CR, Ortiz-Tello PA, Martı´nez RJ, Hedges DJ, Morris RW, Eng C, Sandoval K, Acevedo-Acevedo S, Norman PJ, Layrisse Z, Parham P, Martı´nez-Cruzado JC, Burchard EG, Cuccaro ML, Martin ER, Bustamante CD. Reconstructing the population genetic history of the Caribbean. PLoS Genet 2013;9:e1003925. 29. Borrajo GJ. Newborn screening in Latin America at the beginning of the 21st century. J Inherit Metab Dis 2007;30:466–481. 30. Cardena MM, Ribeiro-Dos-Santos A, Santos S, Mansur AJ, Pereira AC, Fridman C. Assessment of the relationship between self-declared ethnicity, mitochondrial haplogroups and genomic ancestry in Brazilian individuals. PloS One 2013;8:e62005. 31. Nagel RL, Labie D. DNA haplotypes and the beta s globin gene. Prog Clin Biol Res 1989;316b:371–393. 32. Nagel RL, Erlingsson S, Fabry ME, Croizat H, Susuka SM, Lachman H, Sutton M, Driscoll C, Bouhassira E, Billett HH. The Senegal DNA haplotype is associated with the amelioration of anemia in AfricanAmerican sickle cell anemia patients. Blood 1991;77:1371–1375. 33. Green NS, Fabry ME, Kaptue-Noche L, Nagel RL. Senegal haplotype is associated with higher HbF than Benin and Cameroon haplotypes in African children with sickle cell anemia. Am J Hematol 1993;44:145–146. 34. Crawford DC, Caggana M, Harris KB, Lorey F, Nash C, Pass KA, Tempelis C, Olney RS. Characterization of beta-globin haplotypes using blood spots from a population-based cohort of newborns with homozygous HbS. Genet Med 2002;4:328–335. 35. Belisario AR, Martins ML, Brito AM, Rodrigues CV, Silva CM, Viana MB. Beta-globin gene cluster haplotypes in a cohort of 221 children with sickle cell anemia or Sbeta(0)-thalassemia and their association with clinical and hematological features. Acta Haematol 2010;124:162–170. 36. Rusanova I, Cossio G, Moreno B, Javier Perea, De Borace F, Perea RG, Escames M, Acu~na-Castroviejo D G. Beta-globin gene cluster haplotypes in sickle cell patients from Panama. Am J Hum Biol 2011;23: 377–380.
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37. Arends A, Alvarez M, Velazquez D, Bravo M, Salazar R, Guevara JM, Castillo O. Determination of betaglobin gene cluster haplotypes and prevalence of alpha-thalassemia in sickle cell anemia patients in Venezuela. Am J Hematol 2000;64:87–90. 38. Powars DR, Weiss JN, Chan LS, Schroeder WA. Is there a threshold level of fetal hemoglobin that ameliorates morbidity in sickle cell anemia? Blood 1984;63:921–926. 39. Platt OS. Hydroxyurea for the treatment of sickle cell anemia. New Engl J Med 2008;358: 1362–1369. 40. Green NS, Barral S. Emerging science of hydroxyurea therapy for pediatric sickle cell disease. Pediatr Res 2014;75:196–204. 41. Ware RE, Eggleston B, Redding-Lallinger R, Wang WC, Smith-Whitley K, Daeschner C, Gee B, Styles LA, Helms RW, Kinney TR, Ohene-Frempong K. Predictors of fetal hemoglobin response in children with sickle cell anemia receiving hydroxyurea therapy. Blood 2002;99:10–14. 42. Ender KL, Lee MT, Sheth S, Licursi M, Crotty J, Barral S, Green NS. Fetal hemoglobin levels in African American and Hispanic children with sickle cell disease at baseline and in response to hydroxyurea. J Pediatr Hematol 2011;33:496–499. 43. Silva DG, Belini Junior, Carrocini E, Torres GC, Lde S, Ricci Ju´nior, Lobo CL, Bonini-Domingos CR, de Almeida EA. Genetic and biochemical markers of hydroxyurea therapeutic response in sickle cell anemia. BMC Med Genet 2013;14:108. 44. Ferster A, Vermylen C, Cornu G, Buyse M, Corazza F, Devalck C, Fondu P, Toppet M, Sariban E. Hydroxyurea for treatment of severe sickle cell anemia: A pediatric clinical trial. Blood 1996;88: 1960– 1964. 45. Granda H, Gispert S, Dorticos A, Martı´n M, Cuadras Y, Calvo M, Martı´nez G, Zayas MA, Oliva JA, Heredero L. Cuban programme for prevention of sickle cell disease. Lancet 1991;337:152–153. 46. Siddiqui S, Schunk K, Batista M, Adames F, Ayala P, Stix B, Rodriguez J, McCord M, Green NS. Awareness of sickle cell among people of reproductive age: Dominicans and African Americans in northern Manhattan. J Urban Health 2012;89:53–58.
REVIEW Sickle Cell in Sickle Cell Disease in Latin America and the United States Alexandra Huttle,
1 BS,
Gladys E. Maestre,
2 MD PhD,
Latin Americans are an underappreciated population affected by sickle cell disease (SCD). Sickle trait and SCD exist throughout Latin America and U.S. Latino communities. We describe the epidemiology and genetic heterogeneity of SCD among Latin Americans, and fetal hemoglobin expression. National population-based newborn screening for SCD is limited to Brazil, Costa Rica, and the U.S. Available and
Rafael Lantigua,
3 MD,
and Nancy S. Green,
MD
1
*
extrapolated data suggest that over 6,000 annual births and 100,000– 150,000 Latin Americans are affected by SCD. This comprehensive review highlights the substantial numbers and population distribution of SCD and sickle trait in Latin America, and where national newborn screening programs for SCD exist. Pediatr Blood Cancer 2015;62:1131–1136. # 2015 Wiley Periodicals, Inc.
Key words: hemoglobinopathies; Latin America; sickle cell; sickle trait
INTRODUCTION Sickle cell disease (SCD) is among the most common serious single gene disorders [1]. While three quarters of births affected by SCD occur in sub-Saharan Africa, other sizable populations exist worldwide [2]. Recognizing the distribution of the sickle gene and those affected by SCD within Latin America and Latinos in the United States (U.S.) is critical for provision of appropriate medical services for preventative care and treatment, increasing public awareness, and appropriately aligning the allocation of public health resources. The sickle gene was promulgated in the Latino (Hispanic) populations of the Western hemisphere primarily through the transatlantic slave trade, ending in the 1800s. The largest numbers of Africans forcibly taken to the Americas were distributed to the U.S., Brazil, and the Caribbean [3]. Recent estimates suggest that 2–3 million Americans and 1–2 million Brazilians are sickle trait carriers [1,4]. Continued population migration out of the African continent is predicted to increase these numbers. These trends underscore the human dynamics, rather than pressure from malaria, affecting the distribution of the sickle gene among the Americas [3]. This comprehensive review synthesizes available epidemiologic, genetic, and clinical information about SCD from Latino American countries where data from universal newborn screening, national, or clinical sampling have been reported [2,4–8]. We provide novel data on the newborn prevalence data for SCD and sickle trait for a number of countries and an estimate of total number of Latin Americans living with SCD. The status of SCD in two Latin American countries, Venezuela and the Dominican Republic, is described to illustrate gaps in data stemming from lack of national population-based screening and SCD services.
METHODS All 21 Latin American countries were considered: Argentina, Belize, Bolivia, Brazil, Chile, Colombia, Costa Rica, Cuba, Dominica, Dominican Republic, Ecuador, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, Panama, Paraguay, Peru, Uruguay, and Venezuela [9]. Populations identified as Latino/Hispanic in the U.S. were defined by the National Newborn Screening Information System and by state newborn screening programs in New York and California, based on race/ethnicity from maternal self-report [1,5,10,11]. A comprehensive literature review was performed using PubMed as the information source [12] restricted to the English
C
2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25450 Published online 2 March 2015 in Wiley Online Library (wileyonlinelibrary.com).
language. The key reports in Spanish on newborn screening in Latin America and on SCD in Venezuela were identified and reviewed by a native Spanish speaker co-author, (G.E.M.) [13,14,15,16]. Search terms used in English or Spanish were: “Latino and sickle cell,” “Hispanic and sickle cell,” “Latin America and sickle cell,” “South America and sickle cell,” “Central America and sickle cell,” “U.S. and Latino and sickle cell,” “U.S. and Hispanic and sickle cell,” “Puerto Rico and sickle cell,” and each of the 21 Latin American countries, Spain, or Portugal, in combination with “sickle cell.” Data on Venezuela were obtained through targeted Internet searching for pertinent Spanish language materials. Information regarding population and prevalence estimates, the genetic characterization of the sickle gene, newborn screening, therapeutic opportunities and awareness of SCD were reviewed. Data were also extracted from the Malaria Atlas Project and the United Nations Statistics Division to calculate birth prevalence numbers for Brazil, Mexico, Venezuela, Colombia, Guatemala, the Dominican Republic, Nicaragua, and Panama.[17,18] National and regional prevalence data from NBS are available from the U.S. and Brazil. In contrast, countrywide data among Latin American countries were extrapolated from data derived from varying sampling strategies, described below [19].
RESULTS Data Sources Comprehensive review yielded 26 informative papers identified by the search terms listed above. Collectively, data from these sources were available for many of the countries in Latin America, 1
Division of Pediatric Hematology, Oncology, Stem Cell Transplantation, Department of Pediatrics, Columbia University Medical Center, New York, New York; 2Department of Psychiatry and Neurosciences, Cardiovascular Institute, Institute for Biological Research, University of Zulia, Maracaibo Venezuela, and G.H. Sergievsky Center, Columbia University Medical Center, New York, New York; 3Department of Medicine, Columbia University Medical Center, New York, New York Conflict of interest: Nothing to declare. Correspondence to: Nancy S. Green, Division of Pediatric Hematology, Oncology, Stem Cell Transplantation, Department of Pediatrics, Columbia University Medical Center, 630 West 168 St. - Black Building 2-241, New York, NY 10032. E-mail: [email protected]
Received 17 July 2014; Accepted 8 January 2015
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and two states within the U.S. Data on nearly all countries in the region were gathered by the Malaria Atlas Project, which reported on homozygous sickle disease (HbSS) and sickle trait (HbAS) [17]. Malaria Atlas Project data were adapted to demonstrate the geographical distribution of the sickle hemoglobin allele in the Americas, by country and by coastal distribution (Figure 1, with permission from the publisher) [20]. Those data were derived from Piel et al., where national data were extrapolated from prior sampling in each country, and then projected based on national birth rates [19]. Depth of data analysis for each country generally reflects the size of the population affected, and the extent to which population screening or other medical services were reported. The Malaria Atlas Project reported prevalence data derived from sampling of more than 10,000 people from only three countries in the region: U.S., Brazil, and Venezuela. English language data on
sickle cell prevalence, clinical course, genetic analysis, health status, and treatment outcomes exist primarily for the U.S. and Brazil, with some data available from Venezuela (in Spanish). For many Latin American countries, reported prevalence of the sickle allele was extrapolated from testing 100–10,000 people, and excluded Cuba. Moreover, data collection for many of the Latin American countries spanned from the 1960s through the 1980s, not accounting for evolving population demographics.
Origin of SCD in Latin America and U.S. Latinos Several lines of evidence support an African origin of the sickle gene for Latin Americans. First, the geographic distribution of affected people reflects the history of forced migration and its prevalence along the eastern coast of the Americas where slave trading occurred (Figure 1) [19]. Second, prevalence of SCD was
Fig. 1. Geographical distribution of the sickle hemoglobin allele (HbS) [20]. (Reproduced with approval from the publisher.) Pediatr Blood Cancer DOI 10.1002/pbc
Sickle Cell Among Latinos low in Spain and Portugal during those periods [21,22]. Third, genetic analysis of the sickle beta globin gene in Latino populations demonstrates that most of the gene came from West and Central Africa (described below).
TABLE I. Latino (Hispanic) Sickle Cell Disease (all types) Population and Birth Prevalence Estimates Where National Newborn Screening is Practiced or Available from a Large Nationally Representative Birth Sample: United States, Brazil, Costa Rica, and Venezuela.
Demographics Latino sickle cell in the U.S. National and state-specific prevalence estimates for African American and Hispanic populations (Table I) were based on records from the National Newborn Screening Information System (NNSIS) for 2005–2007 for all 50 states and territories, the New York State newborn screening program for the years 2000–2008, and the Registry and Surveillance System for Hemoglobinopathies (RuSH) for 2004– 2008 [1,10,11]. Table I provides U.S. SCD population and prevalence estimates, highlighting the substantial numbers of affected Hispanic newborns across the U.S. Regional variation for Latino SCD reflects considerable differences in prevalence between Latino communities [1,10,23]. Low rates of SCD and sickle trait in U.S. newborns of Mexican ancestry are consistent with low prevalence rates reported from Mexico [17]. Births in Puerto Rico affected by SCD contribute fewer than 10 per year to the U.S. population [24]. New York State reported the largest number of newborns with SCD: 1,916 from 2000–2008, of whom 12% were Hispanic (defined as having a Hispanic mother) (Table I) [1]. Of these Hispanic newborns, 64.5% had foreign-born mothers, with nearly two thirds from the Dominican Republic, about 30% from Central America and 4% from Puerto Rico [1]. States with sizeable Latino populations with SCD also include California, Florida, and Texas [23].
Sickle Cell in Brazil and Selected Latin American Countries SCD population and prevalence estimates for the U.S., Brazil, Costa Rica, and Venezuela (Table I) were reported from the national newborn hemoglobinopathy screening programs, established in Brazil in 2001 [4], and in Costa Rica [14], and from a large national sampling of newborns in Venezuela [16]. These data underscore the presence of SCD in these countries and Brazil’s comparatively large and affected populace. Geographic distribution of SCD in Brazil is similar to that of the U.S., where the northeast and southeast regions have the highest prevalence of affected newborns (Table I, Fig. 1) [4].
Sickle Cell in Other Latin American countries Figure 2 depicts the estimated annual births and birth prevalence affected by SCD and HbAS for each Latin American country projected as having at least 100 annual births affected by SCD [17], or reported by Costa Rica [14] and Cuba [25]. While annual SCD births reported for Honduras met these criteria, those data were excluded because population data were extrapolated from a single skewed sample [19,26]. Brazil vastly outnumbers the other Latin American countries in the number of newborns annually affected by either SCD or HbAS (Fig. 2A, C). Birth prevalence estimates by country (Fig. 2B, D) were calculated by extracting prevalence data from the Malaria Atlas Project and the U.S. Statistics Division [17,18]. Data were obtained by dividing the annual number of births affected by SCD and HbAS Pediatr Blood Cancer DOI 10.1002/pbc
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SCD population estimatesa United States (total) Hispanics New York (total) Hispanics California (total) Hispanics Brazil Bahia Minas Gerais Rio de Janeiro Rio Grande do Sul Costa Rica Venezuelac
89,079 [23] 8,928 [23] 8,308 [23] 1,338 [23] 5,100 [11] 408 [11] 30,000 [4]
100 annual affected births [17,18].
10%), Honduras, and Costa Rica [27–30]. Per-country estimates varied by sample and methodology. While inexact, the proportion of African heritage by country generally correlated with prevalence of the sickle allele in newborns (Figure 2). Older studies described the origins of the sickle cell gene through specific molecular patterns of b-globin sickle gene markers, or haplotypes [31–33]. The distribution of these haplotypes from Latinos with SCD originating in the U.S., Brazil, Panama, and Venezuela provide molecular data to support the African origin of the sickle gene, and demonstrate similar distributions of African regions/ethnicities of origin between sample populations tested [34–37].
Fetal Hemoglobin Fetal hemoglobin (HbF) level is a highly regulated modifier of SCD disease, with an inverse association with risk of severe complications [38–40]. HbF generally ranges from 2–20% in children with SCD [8,41,42]. Similar HbF levels have been reported Pediatr Blood Cancer DOI 10.1002/pbc
across diverse groups from pediatric cohorts from Brazil, African Americans, and a Hispanic cohort in New York [41–44]. Among the ameliorative effects of hydroxyurea on SCD, a major impact is its induction of HbF [40]. Children in Brazil had HbF levels at baseline and with hydroxyurea induction [8] that were similar to those reported for an African American and Latino SCD clinic population in New York [42]. Only scant data have been reported on HbF and hydroxyurea response from other Latin American countries.
Newborn Screening for SCD The proportion of births covered by national newborn screening and the panel of diseases for which screening is performed vary by country within Latin American [29]. Only Brazil and Costa Rica perform mandatory national newborn hemoglobinopathy screening [29]. Brazil’s experience demonstrates the potential impact of universal newborn hemoglobinopathy screening and linked medical specialty services in Latin America, where child mortality rates of 3.7% resulted from diagnosis with implementation of
Sickle Cell Among Latinos comprehensive programs, compared to 5.6% in children diagnosed through less comprehensive programs [4]. Universal newborn screening and organized medical care for preventative strategies (e.g., penicillin prophylaxis and anti-pneumococcal vaccination) and use of hydroxyurea therapy for affected children have nearly eliminated SCD-related child mortality in the U.S. and Brazil [4–8]. Several other Latin American countries provide regional or national newborn screening for heritable conditions, but not for hemoglobinopathies, including Cuba, Brazil, Venezuela, Mexico, and others [29]. There, existing infrastructure may accommodate future inclusion of SCD in newborn screening programs. For example, in Venezuela a national reference center for advanced diagnosis of hemoglobinopathies complements current capacitybuilding activities to support inclusion of hemoglobinopathies in national newborn screening. However, specialized services or public programs are not directed to manage the special medical needs of SCD patients for acute or chronic sickle cell syndromes (personal communication, Dr. Maestre). Some countries in the region do not support any widespread newborn screening, such as Honduras [29] and the Dominican Republic (personal communication, Luis Rivera Mejia, M.D., Professor of Pediatrics at Universidad Autonoma de Santo Domingo; Chief Department of Perinatology, Hospital Maternidad Nuestra Senora de la Altagracia, Santo Domingo, Republica Dominicana). For the latter country, sickle screening is available only by parental request, national prevalence data are lacking and specialty treatment centers do not exist (personal communication, Dr. Mejia).
DISCUSSION SCD is an important genetic condition within Latin America and in the U.S., with prevalence varying between countries [17,18,20]. Only three countries in the Americas support populationbased screening programs for Latinos: U.S., Brazil, and Costa Rica [4,5,45]. Data were available from these countries on HbSS and HbSC and on regional variation. Elsewhere, only HbSS and sickle trait have been reported and are extrapolated from prevalence data based on regional sampling of modest proportion [19]. The major limitation of this review is, for some countries, insufficient national data from small samples of narrow geographic regions. Despite sizeable numbers of Latinos affected by SCD, availability of public health resources for these patients varies across Latin America. The U.S., Brazil, and Costa Rica have demonstrated that widespread population-based newborn screening for SCD coupled with organized specialty treatment have facilitated markedly reduced disease-related child mortality [4–8]. As has been suggested for Venezuela [16], health outcomes for children with SCD elsewhere in Latin America may benefit from expanded public health resources for SCD support. Even where widespread population-based screening exists, limited awareness about SCD and sickle trait was found among at least one Latino community in New York City compared to African Americans [46]. Reasons suggested for this knowledge gap include lower trait prevalence among Dominicans and the perception of SCD as being limited to “African” communities [46]. SCD in the Americas is dynamic, as trends in migration continue to influence the distribution of the sickle allele [3]. Cultural differences in affected populations, as well as the genetic data described above, stem from distinct waves of immigration to Pediatr Blood Cancer DOI 10.1002/pbc
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the U.S. and to Latin America [1]. Enhanced availability of reproductive genetic services may also influence the distribution of the sickle allele. For example, an adult screening program in Cuba provided at-risk couples with genetic information, and may have reduced the number of births affected by SCD [45]. This synthesis of the available data about SCD among Latin Americans is intended to highlight the substantial numbers and distribution of affected children and families, point out biologic similarities to those with SCD in the U.S., and identify data gaps. Our intent is to stimulate interest in public health, clinical approach and biomedical investigation for this population. The existing data and service gaps identify the need for enhanced focus to expand population surveillance to identify communities at risk and affected infants, increase access to specialty treatment, and promote awareness about the disease. Improved services for and research about SCD in Latin America are predicted to be important steps in improved disease outcomes.
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