Malaria in patients with sickle cell anaemia: burden, risk factors and outcome at the Laquintinie hospital, Cameroon.

BACKGROUND: It is believed that the current prevalence of malaria in endemic areas reflects selection for the carrier form of sickle cell trait through a survival advantage. Malaria has been incriminated as a great cause of mortality in people with sickle cell disease (SCD). However, people with SCD, a high-risk group, do not benefit from free or subsisized malaria prevention and treatment in Cameroon unlike other vulnerable groups which may be due to insufficient evidence to guide policy makers. This study aimed at describing clinical and socio-demographic characteristics of patients with malaria, determining the prevalence of malaria in hospitalized children and in those with SCD and without, compare frequency of presentation of malaria related complications (using clinical and laboratory elements that define severe malaria) between children admitted for malaria with SCD and those without and finally, determing the risk factors for death in children admitted for malaria. METHODS: This was a retrospective analysis of admission records of children age 1 to 18 years with a confirmed malaria diagnosis admitted at the Laquintinie Hospital during January 2015 through December 2018. Clinical features, laboratory characteristics and outcome of malarial infections, stratified by SCD status were studied. Patients with HIV infection, malnutrition, renal failure and discharged against medical advice were excluded from the study. Data were analysed using Epi-info 7 software and analysis done. Chi square test, Odds ratios, CI and student's t test were used to determine association between variables. Statistical significance was set at p-value ≤0.05. RESULTS: The prevalence of malaria was lower among children with SCD than it was among children without SCD (23.5% vs 44.9%). Similarly, among those with a positive microscopy, the mean parasite density was significantly lower among children with SCD than it was among children without SCD (22,875.6 vs 57,053.6 parasites/ µl with t-value - 3.2, p-value 0.002). The mean hemoglobin concentration was lower in SCD as compared to non SCD (5.7 g/l vs 7.4 g/l, t-value - 12.5, p-value < 0.001). Overall mortality in SCD was 3.4% and malaria was reponsible for 20.4% of these deaths as compared to the 35.4% in non SCD patients. Convulsion and impaired consciousness were significantly lower in SCD group (OR:0.1, CI: 0.1-0.3, p value < 0.01 and OR:0.1, CI:0.1-0.2, p-value < 0.001 respectively). Death was significantly higher in SCD patients with malaria as compared to SCD patients admitted for other pathologies (3.2% vs 1.5%., OR:2.2, CI:1-5, p-value 0.050). CONCLUSION: The SCD population has a lower mortality related to malaria compared to the non-SCD population. Meanwhile, within the SCD population, those admitted with malaria are twice more likely to die than those admitted for other pathologies. Jaundice, hepatomegaly and splenomegaly were common in SCD with malaria, however no risk factors for malaria severity or malaria related death was identified.

Sickle Cell Trait, Rhabdomyolysis, and Mortality among U.S. Army Soldiers.

BACKGROUND: Studies have suggested that sickle cell trait elevates the risks of exertional rhabdomyolysis and death. We conducted a study of sickle cell trait in relation to these outcomes, controlling for known risk factors for exertional rhabdomyolysis, in a large population of active persons who had undergone laboratory tests for hemoglobin AS (HbAS) and who were subject to exertional-injury precautions. METHODS: We used Cox proportional-hazards models to test whether the risks of exertional rhabdomyolysis and death varied according to sickle cell trait status among 47,944 black soldiers who had undergone testing for HbAS and who were on active duty in the U.S. Army between January 2011 and December 2014. We used the Stanford Military Data Repository, which contains comprehensive medical and administrative data on all active-duty soldiers. RESULTS: There was no significant difference in the risk of death among soldiers with sickle cell trait, as compared with those without the trait (hazard ratio, 0.99; 95% confidence interval [CI], 0.46 to 2.13; P=0.97), but the trait was associated with a significantly higher adjusted risk of exertional rhabdomyolysis (hazard ratio, 1.54; 95% CI, 1.12 to 2.12; P=0.008). This effect was similar in magnitude to that associated with tobacco use, as compared with no use (hazard ratio, 1.54; 95% CI, 1.23 to 1.94; P<0.001), and to that associated with having a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 30.0 or more, as compared with a BMI of less than 25.0 (hazard ratio, 1.39; 95% CI, 1.04 to 1.86; P=0.03). The effect was less than that associated with recent use of a statin, as compared with no use (hazard ratio, 2.89; 95% CI, 1.51 to 5.55; P=0.001), or an antipsychotic agent (hazard ratio, 3.02; 95% CI, 1.34 to 6.82; P=0.008). CONCLUSIONS: Sickle cell trait was not associated with a higher risk of death than absence of the trait, but it was associated with a significantly higher risk of exertional rhabdomyolysis. (Funded by the National Heart, Lung, and Blood Institute and the Uniformed Services University of the Health Sciences.).

D-Dimer in African Americans: Whole Genome Sequence Analysis and Relationship to Cardiovascular Disease Risk in the Jackson Heart Study.

OBJECTIVE: Plasma levels of the fibrinogen degradation product D-dimer are higher among African Americans (AAs) compared with those of European ancestry and higher among women compared with men. Among AAs, little is known of the genetic architecture of D-dimer or the relationship of D-dimer to incident cardiovascular disease. APPROACH AND RESULTS: We measured baseline D-dimer in 4163 AAs aged 21 to 93 years from the prospective JHS (Jackson Heart Study) cohort and assessed association with incident cardiovascular disease events. In participants with whole genome sequencing data (n=2980), we evaluated common and rare genetic variants for association with D-dimer. Each standard deviation higher baseline D-dimer was associated with a 20% to 30% increased hazard for incident coronary heart disease, stroke, and all-cause mortality. Genetic variation near F3 was associated with higher D-dimer (rs2022030, ß=0.284, P=3.24×10-11). The rs2022030 effect size was nearly 3× larger among women (ß=0.373, P=9.06×10-13) than among men (ß=0.135, P=0.06; P interaction =0.009). The sex by rs2022030 interaction was replicated in an independent sample of 10 808 multiethnic men and women (P interaction =0.001). Finally, the African ancestral sickle cell variant (HBB rs334) was significantly associated with higher D-dimer in JHS (ß=0.507, P=1.41×10-14), and this association was successfully replicated in 1933 AAs (P=2.3×10-5). CONCLUSIONS: These results highlight D-dimer as an important predictor of cardiovascular disease risk in AAs and suggest that sex-specific and African ancestral genetic effects of the F3 and HBB loci contribute to the higher levels of D-dimer among women and AAs.

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 (22 December 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.

Sickle cell trait associated with a RR of death of 37 times in National Collegiate Athletic Association football athletes: a database with 2 million athlete-years as the denominator.

BACKGROUND: This study examines sickle cell trait (SCT) as a cause of sudden death in National Collegiate Athletic Association (NCAA) athletes and explores the cost-effectiveness of different screening models. METHODS: The authors reviewed the cause of all cases of sudden death in NCAA student-athletes from January 2004 through December 2008. The authors also explored the cost-effectiveness of screening for this condition in selected populations assuming that identifying athletes with SCT would prevent death. RESULTS: There were 273 deaths and a total of 1 969 663 athlete-participant-years. Five (2%) deaths were associated with SCT. In football athletes, there were 72 (26%) deaths. Of these, 52 (72%) were due to trauma unrelated to sports activity and 20 (28%) were due to medical causes; nine deaths were cardiac (45%), five were associated with SCT (25%). Thirteen of the 20 deaths due to medical causes occurred during exertion; cardiac (6, 46%) SCT associated (5, 39%), and heat stroke unrelated to SCT (2, 15%). All deaths associated with SCT occurred in black Division I football athletes. The risk of exertional death in Division I football players with SCT was 1:827 which was 37 times higher than in athletes without SCT. The cost per case identified varied widely depending on the population screened and the price of the screening test. CONCLUSIONS: Exertional death in athletes with SCT occurs at a higher rate than previously appreciated. More research is needed to (1) understand the pathophysiology of death in SCT-positive athletes and (2) determine whether screening high-risk populations reduces mortality.

Renal medullary carcinoma and its association with sickle cell trait: a case report and literature review.

Renal medullary carcinoma (rmc) is a rare and aggressive renal malignancy that usually presents at an advanced stage, has a poor prognosis, and is associated with sickle cell trait. We present a case of rmc including radiologic and pathology findings, treatment, and outcome. A review of the literature is also presented, with an emphasis on the association of rmc with sickle cell trait, which was an unknown diagnosis in our patient preoperatively.

Physiological responses of sickle cell trait carriers during exercise.

Growing evidence suggests that physiological responses during exercise in sickle cell trait (SCT) carriers might differ from persons with normal haemoglobin. Epidemiological and experimental results support the view that SCT carriers could be advantaged in certain anaerobic activities, but the underlying physiological and bio-cellular mechanisms remain unknown. Maximal aerobic physical fitness (i.e. maximal oxygen consumption and maximal aerobic power) is not affected by SCT; however, recent studies suggest that SCT carriers could be characterized by a lesser aerobic capacity. Discrepancies are frequently reported in the literature concerning lactate metabolism during exercise in this population. While some studies observed higher blood lactate concentration during exercise in individuals carrying SCT compared with subjects with normal haemoglobin, others described lower concentration, which suggests a paradoxical lower lactate production by exercising muscles and/or greater ability to clear circulating lactate in SCT carriers. One of the most debated topics is the clinically benign condition of SCT, particularly during strenuous exercise. SCT carriers are usually involved in physical exercise without developing medical complications; however, several authors have presented case reports of SCT carriers who have collapsed and died unexpectedly during or after exercise. Blood rheological, haemostatic and vascular adhesion mechanism abnormalities in combination with environmental factors, such as heat strain, might play a role in the occurrence of these fatal scenarios. Several physiological differences have been observed between SCT carriers and non-SCT carriers, which make it necessary to consider the former as a specific population in response to exercise.

The Association Between Sickle Cell Trait in U.S. Service Members with Deployment, Length of Service, and Mortality, 1992-2012.

Introduction: Sickle cell trait (SCT) affects an estimated 5.02% of non-Hispanic blacks, 1.08% of Hispanics, and 0.1% of Whites in the U.S. military. Policies for SCT screening and occupational restrictions vary by service. Population-based studies of SCT with quantification of military-relevant outcomes are lacking. Methods: The study design was a retrospective cohort of 15,081 SCT-positive versus 60,320 SCT-negative U.S. active duty personnel enlisted from 1992 to 2012 and followed through 2013. Military-relevant outcome included number and days of deployment, length of service, and cause of death. Results: SCT-positive versus SCT-negative service members experienced more deployments (p < 0.01) and longer number of days deployed for all services, especially the Army (p < 0.001). The median length of service was longer for SCT-positive service members stratified by service and by gender (p < 0.05). The adjusted risk of length of service greater than 5 yr by SCT status was 1.37 (95% confidence interval 1.31-1.43) with greater than a three-fold higher risk in the Navy and Air Force compared with the Army. Crude mortality rate was not significantly different by SCT status, although deaths due to suicide, self-directed violence, and other non-specific causes were more common in SCT-positive service members. Conclusion: We found that SCT-positive service members deployed more frequently, for greater lengths of time, and remained in service longer. No significant difference in crude mortality ratio was discovered. Additional research on military-relevant outcomes and a cost-effectiveness analysis of SCT screening practices are needed to inform evidence-based SCT enlistment policies.

Comparative study of clinical presentation and hematological indices in hospitalized sickle cell patients with severe Plasmodium falciparum malaria.

BACKGROUND: Sickle-cell-gene has a high frequency in malaria endemic regions. In India, though the prevalence of both sickle-cell-gene and malaria are high, no study has been carried out. This study aims to find out the possible differences in hematological and clinical parameters in severe falciparum malaria with respect to sickle cell genotypes. METHODS: Five hundred fourteen adults with severe falciparum malaria hospitalized in Department of Medicine, Veer Surendra Sai Institute of Medical Sciences and Research, Burla, between August, 2010 to December, 2014 were included and categorized on the basis of sickle cell genotypes. The hematological parameters were compared by one-way-analysis-of-variance and incidence of sub-phenotypes of severe malaria was compared by χ2 test across the groups. RESULTS: Patients with sickle cell anemia (HbSS) and severe falciparum malaria had lower hemoglobin level compared to patients with normal ß-globin genotype (HbAA) and sickle cell trait (HbAS). Most of the hematological parameters were homogeneous in patients with HbAA and HbAS and different from patients with HbSS. Incidence of acute renal failure was low (χ2, 9.91; p, 0.002) and jaundice was high (χ2, 5.20; p, 0.022) in patients with HbSS. No clinical difference was observed in patients with HbAA and HbAS. The mortality was low (χ2, 4.33; p, 0.037) and high (χ2, 10.48; p, 0.001) in patients with HbAS and HbSS respectively compared to patients with HbAA. CONCLUSION: Though sickle-cell-gene protects against falciparum infections, the hematological parameters and sub-phenotypes of severe malaria remain unchanged when the infection progresses to a severe form in patients with HbAA and HbAS. Presence of hemolytic anemia in patients with HbSS shows diverse hematological and clinical phenotypes as compared to others. High mortality in patients with HbSS emphasizes the need for a better preventive approach to save valuable lives.

Sickle cell trait and sudden death--bringing it home.

Sickle cell trait continues to be the leading cause of sudden death for young African Americans in military basic training and civilian organized sports. The syndrome may have caused the death of up to 10 college football players since 1974 and, as recently as 2000, was suspected as the cause of death of three U.S. Army recruits. The penal military-style boot camps in the United States and the recent death of two teenagers with sickle cell trait merits renewed vigor in the education of athletic instructors, the military and the public about conditions associated with sudden death in individuals with sickle cell trait.

Preventing Exertional Death in Military Trainees: Recommendations and Treatment Algorithms From a Multidisciplinary Working Group.

Despite aggressive prevention programs and strategies, nontraumatic exertional sudden death events in military training continue to prove a difficult challenge for the Department of Defense. In November 2014, the 559th Medical Group at Joint Base San Antonio-Lackland, Texas, hosted a working group on sudden exertional death in military training. Their objectives were three-fold: (1) determine best practices to prevent sudden exertional death of military trainees, (2) determine best practices to establish safe and ethical training environments for military trainees with sickle cell trait, and (3) develop field-ready algorithms for managing military trainees who collapse during exertion. This article summarizes the major findings and recommendations of the working group.