Framing the research agenda for sickle cell trait: Building on the current understanding of clinical events and their potential implications

Sickle Cell Trait (HbAS), the heterozygous state for the sickle hemoglobin beta globin gene is carried by as many as 100 million individuals including up to 25% of the population in some regions of the world (World Health Organization, Provisional agenda item 4.8, EB117/34 (22December 2005) or World Health Organization, Provisional agenda item 11.4 (24 April 2006)). Persons with HbAS have some resistance to falciparum malaria infection in early childhood (Piel FB, Patil AP, Howes RE, et al., Nat Commun 2010;1104:1–7 and Aidoo M, Terlouw DJ, Kolczak M, et al., Lancet 2002;359:1311–1312) and as a result individuals with HbAS living in malarial endemic regions of Africa have a survival advantage over individuals with HbAA. Reports from the US emphasize possible health risks for individuals with HbAS including increased incidence of renal failure and malignancy, thromboembolic disorders, splenic infarction as a high altitude complication, and exercise-related sudden death. The National Heart, Lung, and Blood Institute, National Institutes of Health convened a workshop in Bethesda, Maryland on June 3–4, 2010, Framing the Research Agenda for Sickle Cell Trait, to review the clinical manifestations of HbAS, discuss the exercise-related sudden death reports in HbAS, and examine the public health, societal, and ethical implications of policies regarding HbAS. The goal of the workshop was to identify potential research questions to address knowledge gaps. Studies in the 1950's revealed that the presence of sickle hemoglobin in erythrocytes appeared to protect against malaria, currently responsible for more than 1 million childhood deaths per year in sub-Saharan Africa. In 1,022 children from a birth cohort in Kenya, the highest mortality in children aged 2 to 16 months occurred in those with HbSS (sickle cell anemia), followed by HbAA (normal hemoglobin) and HbAS (sickle cell trait). The study demonstrated a survival advantage for children with HbAS over those with HbAA, with a 55% reduction in all-cause mortality [3]. More recently, investigators followed 800 children and adults in Kenya for clinical events. While HbAS had no impact on the prevalence of asymptomatic parasitemia, it was 50% protective against mild clinical malaria, 75% protective against hospital admission for malaria, and 90% protective against severe or complicated malaria [4]. In an outpatient clinic in Tanzania, the prevalence of malaria parasitemia was 0.64 for AS, 0.72 for SS, and 2.96 for AA hemoglobin [5]. These studies suggest that children in Africa with HbAS have overall improved survival and lower malaria infection rates, and the difference is largely due to HbAS. The estimates of prevalence of HbAS in Africa range from 10 to 40% across equatorial Africa and decrease to between 1 and 2% on the North African coast and <1% in South Africa [6]. In all newborns in the U.S., the HbAS prevalence is 1.3% based on a finding of HbAS in 1 out of 12 African Americans [7]. Worldwide, more than 100 million individuals have HbAS. A recent review of the medical literature reported that HbAS is not completely benign and provided an evaluation of the strength and specificity of the reported associations [8]. “Definite” associations with HbAS were proposed for exercise-related sudden death, exertional rhabdomyolysis, micro- and macroscopic hematuria, loss of renal concentrating ability, protection against severe falciparum malaria, renal medullary cancer, renal papillary necrosis, and splenic infarction in the setting of low oxygen tension at high altitudes. “Probable” associations with HbAS were suggested for pregnancy-related conditions including fetal loss, low birth weight, preeclampsia, traumatic hyphema, and venous thromboembolic disease. Acute chest syndrome, asymptomatic bacteriuria in pregnancy, and proliferative retinopathy were reported as “Possible” associations with HbAS. Sufficient evidence was not found to associate avascular necrosis of the femoral head, cholelithiasis, leg ulcers, priapism, or stroke with HbAS. Aspects of this review, including the authors' conclusions, were addressed by the workshop. Exercise-Related Death Is HbAS an independent risk factor for sudden death in young athletes? What are the etiologies of sudden death? Is sudden death preventable in individuals with HbAS? Can screening for HbAS prevent or mitigate-associated morbidity or mortality? From a definition perspective, exercise-related sudden death in all athletes is generally viewed as an irreversible and terminal dependence upon life support implemented within 1 hr of the onset of symptoms. The causes of sudden death have been described as cardiac (myocardial, anatomic, electrical, and combined disease), pulmonary, neurologic (brain stem injury and vagal reactions), metabolic (rhabdomyolysis and malignant hyperthermia), endocrine, hemorrhagic, and thrombotic. For cardiac or idiopathic sudden death, the US National Registry of Sudden Death in Athletes [9] reports 115 cases per year and the 36th Bethesda Conference on Eligibility Recommendations for Competitive Athletes with Cardiovascular Abnormalities estimated a prevalence of 1 in 33,000–50,000 with a male predominance of 5:1 to 9:1 [10]. The number of reported cases increased by about 6% per year with 0.3% of the deaths attributed to HbAS. Of the cardiovascular deaths, 82% were reported as exertional; 2.4% of the deaths were attributed to heat stroke. The most common cardiac etiology was hypertrophic cardiomyopathy (HCM) (36%) followed by coronary artery anomalies (17%). The average age of those affected was 18 ± 5 years and 89% were reported to be male. Hypertrophic cardiomyopathy, inherited as an autosomal dominant trait, has been attributed to mutations in genes that encode for sarcomere proteins [11]. Thirteen genes account for ∼50% of HCM cases. HCM is disproportionately present in African American athletes. Of the relevant electrical diseases, the long QT Syndrome is the most important. Inherited in either autosomal or dominant fashion, 13 genes have been described that are involved in the timely execution of the cardiac action potential [12]. The utility of ECG screening for athletes continues to be debated and provides some parallels for the current discussions of screening for HbAS [13]. Issues of cost, test sensitivity and specificity, resource utilization and difficulty of program implementation are central to this discussion [14]. Review of the historical athletic participation of individuals from ancestral populations with higher prevalence of HbAS (e.g. athletes of African ancestry, self identified as black or African American), adds perspective. In the 1936 Olympics, 18 black athletes won 14 medals, 25% of those won by US athletes, and dominated the track and field events. In the 1968 Olympics, nearly 19% of the athletes were black and ∼1% (11/1,265) had HbAS. There were no clinically detected adverse events at Mexico City's high altitude (7,350 feet above sea level). Black athletes continue to participate in the National Football League (NFL) (60% of players are black), the National Basketball Association (NBA) (over 80% of players are black), and in college athletics (34% of football players and 45% of male and 33% of female basketball players are black). Many U.S. black athletes compete at high altitude in Denver, Colorado (5,280 feet above sea level), experiencing frequent exposures to reduced oxygen tension, with rare reports of adverse events, although one NFL player with HbAS suffered splenic complications. Acute, intense exercise has multiple effects that could potentially trigger sickling of HbS containing erythrocytes. These effects include a decrease in plasma volume and pH and increases in sympathetic outflow, oxidative stress, heat production, microvascular perfusion, tissue hypoxia, and release of inflammatory mediators. These detrimental effects are balanced by the benefits of chronic physical training which include a reduced resting heart rate and blood pressure, improved autonomic system balance, increased maximal myocardial oxygen uptake, improved endothelial function and vascular compliance, metabolic and neuromuscular modifications, and training-specific muscle adaptations [15]. Skeletal muscle function is fundamental to exercise and is affected by mechanical, metabolic, hormonal, and neuronal stressors. The consequences of these stressors depend on the degree of loading, the number of contractions, and the thresholds of protective mechanisms for stress-induced damage. The threshold is affected by fiber type, number and oxidative content of mitochondria, energy reserves, speed and strength of fiber contraction, and fiber size. The major types of muscle fibers are Type I (slow twitch), Type IIa (fast twitch), and Type IId (x) (fast twitch). Slow twitch fibers have higher aerobic capacity, myoglobin content, and fatigue resistance, whereas fast twitch fibers have higher glycolytic capacity, glycogen content, and sarcoplasmic reticulum (SR) development. Contraction speeds are slower for the fast twitch fibers compared with the slow twitch fibers. The three types of fibers are further distinguished by different myosin heavy chains. Black, African men had significantly more Type IIa fibers (49 vs. 42%) and fewer Type I fibers (33 vs. 41%) than Caucasian men [16]. The muscle activities of glycolytic pathway enzymes were 40 to 76% higher in black than Caucasian men and the average creatine kinase nearly twice as high. Obese black women have been reported to have a higher percentage of Type IIb fibers and a lower percentage of Type I fibers than Caucasian women [17]. A study of young, military recruits with Exertional Heat Illness (EHI) in Taiwan found that 24 of 37 with EHI developed rhabdomyolysis and that the percentage of Type II fibers was 66% in controls, 75.5% in individuals with EHI alone, and 81% in those with EHI and rhabdomyolysis [18]. 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