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Introduction
Skills and Expertise
Publications
Publications (541)
Background: Pregnant and lactating women were not included in the initial large vaccine clinical trials for SARS-CoV-2 (COVID) infection. Delineating the antibody titers in serum and breast milk of lactating women is important to determine the safety and benefits of vaccination in this special population. Objective: To investigate COVID vaccination...
Background:
Cases of malaria and dengue in the Dominican Republic both spiked in 2019, but their rates of codetection are poorly characterized, especially in children.
Methods:
We performed a prospective, observational study in January to December 2019 at the Hospital Infantil Robert Reid Cabral, in the Dominican Republic, enrolling hospitalized...
Background and objective:
The disease burden of sickle cell anemia (SCA) in sub-Saharan African (SSA) countries is substantial, with many children dying without an established diagnosis or proper treatment. The global burden of SCA is increasing each year, making therapeutic intervention a high priority. Hydroxyurea is the only disease-modifying t...
Executive summary
All over the world, people with sickle cell disease (an
inherited condition) have premature deaths and preven
table severe chronic complications, which considerably
affect their quality of life, career progression, and finan
cial status. In addition, these people are often affected by
stigmatisation or structural racism, whic...
Introduction: Hydroxyurea is effective disease-modifying treatment for sickle cell anemia (SCA). Escalation to maximum tolerated dose (MTD) achieves superior benefits without additional toxicities, but requires dose adjustments with serial monitoring. Pharmacokinetic (PK)-guided dosing can predict a personalized optimal dose, which approximates MTD...
Background:
Transcranial Doppler screening with chronic transfusions reduces stroke risk in children with sickle cell anaemia but is not feasible in low-resource settings. Hydroxyurea is an alternative treatment to decrease stroke risk. We aimed to estimate stroke risk in children with sickle cell anaemia in Tanzania and to determine the efficacy...
Data from small clinical trials in the USA and India suggest zinc supplementation reduces infection in adolescents and adults with sickle cell anemia (SCA), but no studies of zinc supplementation for infection prevention have been conducted in young children with SCA living in Africa, who have higher infection rates. We conducted a randomized doubl...
Hydroxyurea is approved for treating children and adults with sickle cell anemia (SCA). Despite its proven efficacy, concerns remain about its mutagenic and carcinogenic potential that hamper its widespread use. Cell culture‐ and animal‐based investigations indicate that hydroxyurea's genotoxic effects are due to indirect clastogenicity in select c...
Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) provides hydroxyurea at maximum tolerated dose (MTD) for children with sickle cell anemia (SCA) in sub-Saharan Africa. Beyond reducing sickle-related clinical events, documented treatment benefits include ~50% malaria incidence. To identify associations and propose mech...
Sickle cell disease (SCD) is a common condition within sub-Saharan Africa and associated with high under-5 (U5) mortality. The American Society of Hematology instituted the Consortium on Newborn Screening in Africa (CONSA) for SCD, a seven-country network of sites to implement standardized newborn hemoglobinopathy screening and early intervention f...
Introduction:
Stroke is a severe complication of sickle cell anemia (SCA), with devastating sequelae. Transcranial Doppler (TCD) ultrasonography predicts stroke risk, but implementing TCD screening with suitable treatment for primary stroke prevention in low-resource environments remains challenging. SPHERE (NCT03948867) is a prospective phase 2 o...
Background: β-thalassemia is rare in sub-Saharan Africa and to our knowledge there has been no case of homozygous β-thalassemia major reported from this region. In a recent cohort study, we identified four β-thalassemia mutations among 83 heterozygous carriers in Kilifi, Kenya. One of the mutations identified was a rare β-globin gene initiation cod...
Background
Recognition of the burden of sickle cell anaemia (SCA) in sub-Saharan African (SSA) countries is increasing, with few therapies available for clinical management. Hydroxyurea is the only disease-modifying therapy that has proven feasible and clinically efficacious in low-income countries in SSA; however, the health economic implications...
Hydroxyurea is efficacious against sickle cell anaemia (SCA)-related complications in African children. Prior studies demonstrated conflicting results on the effect of hydroxyurea on risk of infection, the most common cause of morbidity and mortality in African children with SCA.
We evaluated the incidence of infections before and after starting hy...
Introduction: Many children with sickle cell anemia (SCA) require blood transfusions, which carry risks and utilize a scarce resource globally, particularly in Africa. Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) has documented the safety, feasibility, and benefits of hydroxyurea for children with SCA living in su...
Introduction: L-glutamine (Endari ®, Emmaus Medical, Inc.) is an amino acid approved for the treatment of sickle cell disease (SCD) by the United States Food and Drug Association (FDA) after 2 clinical trials demonstrated a reduction in painful episodes and hospitalizations. L-glutamine has many roles, including de novo synthesis of intracellular g...
Plasmodium falciparum malaria causes morbidity and mortality in African children with sickle cell anemia (SCA), but comparisons of host responses to P. falciparum between children with SCA (HbSS) and HbAA are limited. We assessed parasite biomass and plasma markers of inflammation and endothelial activation in children with HbAA (n=208) or HbSS (n=...
Background:
Sickle cell anaemia is a common global life-threatening haematological disorder. Most affected births occur in sub-Saharan Africa where children usually go undiagnosed and die early in life. Uganda's national sickle cell screening programme was developed in response to a 2014 sickle cell surveillance study that documented a high diseas...
Hydroxyurea (hydroxycarbamide) is an effective treatment for sickle cell anaemia (SCA), but clinical responses depend primarily upon the degree of fetal haemoglobin (HbF) induction and the heterogeneity of HbF expression across erythrocytes. The number and characteristics of HbF-containing cells (F-cells) are not assessed by traditional HbF measure...
There is an immediate need to address long‐standing questions about the reproductive health of girls and women with sickle cell disease (SCD). There are many SCD‐related reproductive risks and uncertainties across girls’ and women’s reproductive life span, with particularly outstanding concerns about menstruation, contraception, fertility and pregn...
EXpanding Treatment for Existing Neurological Disease (EXTEND) investigated whether hydroxycarbamide lowers transcranial Doppler (TCD) velocities in Jamaican children with sickle cell anaemia (SCA) and elevated TCD velocity with or without previous stroke. Forty‐three children (age 2–17 years) with baseline maximum time‐averaged mean velocity (TAMV...
Objectives: Newborn screening in the United States and Europe allows early identification of congenital disorders but does not yet exist in most low-resource settings, especially in sub-Saharan Africa. Newborn screening can identify multiple inherited hematological disorders, but feasibility and effectiveness for Africa are not fully determined.
Me...
Sickle cell anemia (SCA) is a hereditary hemoglobinopathy with a variable phenotype. There is no single biomarker that adequately predicts disease severity and can be used to monitor treatment response in patients in clinical trials and clinical care. The use of clinical outcomes, such as vaso-occlusive crises (VOC), requires long and expensive stu...
Background
Without early initiation of disease‐modifying therapy, the acute and chronic complications of sickle cell anemia (SCA) begin early in childhood and progress throughout life. Hydroxyurea is a safe and effective medication that reduces or prevents most SCA‐related complications. Despite recommendations to prescribe hydroxyurea for all chil...
UNSTRUCTURED
Introduction: Sickle cell anemia (SCA) is a genetic blood disorder that places children at risk for serious medical complications, early morbidity and mortality, and high healthcare utilization. Until recently, hydroxyurea was the only disease-modifying treatment for this life-threatening disease and has remained the only option for ch...
Background
Sickle cell anemia (SCA) is a genetic blood disorder that puts children at a risk of serious medical complications, early morbidity and mortality, and high health care utilization. Until recently, hydroxyurea was the only disease-modifying treatment for this life-threatening disease and has remained the only option for children younger t...
Hydroxyurea, an oral medication with important clinical benefits in the treatment of sickle cell anemia, can be accurately determined in plasma with a transition metal dichalcogenide-based electrochemical sensor. We used a two-dimensional molybdenum sulfide material (MoS2) selectively electrodeposited on a polycrystalline gold electrode via tailore...
Objective:
To determine the regional- and district-level newborn prevalence of sickle cell trait and disease, and the prevalence of haemoglobin variants and genetic modifiers of sickle cell disease, in the nine regions of north-western United Republic of Tanzania.
Methods:
We repurposed dried blood spot samples from children (aged 0-24 months) b...
Background
Severe anemia is common and frequently fatal for hospitalized patients in limited-resource settings. Lack of access to low-cost, accurate, and rapid diagnosis of anemia impedes the delivery of life-saving care and appropriate use of the limited blood supply. The WHO Haemoglobin Colour Scale (HCS) is a simple low-cost test but frequently...
Objective:
Sickle cell disease is an important public health issue that is increasingly recognized as a substantial contributor to morbidity and early childhood mortality in sub-Saharan Africa. We aimed to provide information from large-scale, long-term sickle cell screening efforts in Africa.
Methods:
We used nationally representative data from...
Introduction: Sickle cell anemia (SCA) is a severe and life-threatening disorder that requires treatment to prevent short- and long-term complications and prolong life. The primary disease-modifying therapy for SCA remains hydroxyurea (HU). Due to 30 years of evidence demonstrating safety and efficacy culminating with BABY HUG, the 2014 National He...
Introduction: In low-resource settings, red blood cell (RBC) transfusions for children with sickle cell anemia (SCA) may be cross-matched for only ABO and RhD antigens, so RBC alloimmunization can develop due to differences in Rh and other antigens between donors and recipients. In the Rh system, these differences can include absence of the antigen...
Introduction: Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) is an open-label study of hydroxyurea for children with sickle cell anemia (SCA) in sub-Saharan Africa (Angola, DR Congo, Kenya, and Uganda). Initial results documented the feasibility, safety, and benefits of hydroxyurea for SCA in sub-Saharan Africa but...
Introduction: Sickle cell anemia (SCA) is highly prevalent in sub-Saharan Africa with >300,000 annual births, and substantial morbidity and mortality due to limited resources. The burden of stroke in this population is of particular concern, given the devastating clinical and neurocognitive sequelae of these events. Hydroxyurea, a potent disease mo...
Introduction: Transcranial Doppler (TCD) screening data from Uganda, Tanzania, and Nigeria have documented elevated velocities in >20% of children with sickle cell anemia (SCA) not receiving hydroxyurea treatment. Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) has demonstrated the safety, feasibility, and benefits o...
Introduction: Hydroxyurea is a potent therapeutic agent for sickle cell anemia (SCA), and treatment at maximum tolerated dose (MTD) is becoming the standard of care. Hydroxyurea exerts its disease-modifying effects primarily through induction of fetal hemoglobin (HbF), although the cellular and molecular mechanisms by which hydroxyurea increases Hb...
Introduction: Hydroxyurea has well-described clinical and laboratory benefits in sickle cell anemia (SCA). Traditionally, hemoglobin concentration (Hb) and fetal hemoglobin (HbF) are used to assess treatment response, but these aggregate parameters do not fully capture the range of erythrocyte abnormalities in SCA. Dense red blood cells (DRBCs) are...
Introduction: Elevated levels of fetal hemoglobin (HbF) are known to ameliorate both the morbidity and mortality of sickle cell anemia (SCA). Sustained post-natal HbF expression is heritable and regulated by multiple quantitative trait loci. Previous genomic studies have identified three major gene loci (BCL11A, HBS1L-MYB, and HBG2) that account fo...
Total pancreatectomy with islet autotransplantation is a complex surgical approach for acute recurrent or chronic pancreatitis that frequently triggers extreme thrombocytosis (platelets ≥ 1000 × 109 /L). Thrombocytosis can be prothrombotic, so cytoreductive hydroxyurea is often initiated after this surgery; however, optimal dosing strategy and effi...
In an effort to explore new knowledge and to develop meaningful collaborations for improving child health, the First Pan African Workshop on Newborn Screening was convened in June 2019 in Rabat, Morocco. Participants included an informal network of newborn screening stakeholders from across Africa and global experts in newborn screening and sickle...
Background
Hydroxyurea has proven safety, feasibility, and efficacy in children with sickle cell anemia in sub-Saharan Africa, with studies showing a reduced incidence of vaso-occlusive events and reduced mortality. Dosing standards remain undetermined, however, and whether escalation to the maximum tolerated dose confers clinical benefits that out...
Background
β‐Thalassemia is rare in sub‐Saharan Africa. Previous studies have suggested that it is limited to specific parts of West Africa. Based on hemoglobin A2 (HbA2) concentrations measured by HPLC, we recently speculated that β‐thalassemia might also be present on the East African coast of Kenya. Here, we follow this up using molecular method...
Lactation is contraindicated for women with sickle cell anemia receiving hydroxyurea therapy, despite sparse pharmacokinetics data. In 16 women who were lactating volunteers, we documented hydroxyurea transferred into breastmilk with a relative infant dosage of 3.4%, which is below the recommended 5%-10% safety threshold. Breastfeeding should be pe...
Incident stroke, both primary and recurrent are common in children with sickle cell anemia (SCA) in Jamaica with incidences of 7.8% by 14 years of age and 29/100 person-years respectively. Cerebral vasculopathy manifested by elevated transcranial doppler (TCD) velocity (>170 cm/sec) is the major risk factor for both with a prevalence of 19.8% among...
Introduction. Plasmodium falciparum malaria is a major cause of morbidity in African children with sickle cell anemia (SCA). Factors associated with severe disease and mortality in malaria, including tumor necrosis factor (TNF)-alpha and components of the angiopoietin (Angpt)-Tie-2 system, have also been implicated in the pathogenesis and clinical...
Patients on hydroxyurea who achieve maximum tolerated dose (MTD), defined by a target level of mild myelosuppression, may have greater laboratory and clinical benefits than those maintained on a lower dose. MTD is currently determined by gradual dose escalation, a process that often takes six to twelve months. Using data from a previous cohort of p...
Background
Total pancreatectomy with islet autotransplantation (TPIAT) is a surgical treatment for chronic recurrent pancreatitis that involves splenectomy, pancreatectomy and creation of a Roux-en-Y, followed by re-injection of the pancreatic islets into the portal vein. Postoperatively, patients develop a sustained and extreme thrombocytosis (ExT...
Background: Sickle cell disease (SCD) is a chronic, debilitating disorder caused by a mutation in beta globin, which leads to the production of sickle hemoglobin (HbS). Deoxygenated HbS polymerization results in red blood cell (RBC) sickling, which leads to anemia, hemolysis, vaso-occlusion, and organ damage. Voxelotor a first-in-class therapy in d...
Introduction. The burden of sickle cell anemia (SCA) is high across the Caribbean, including the Dominican Republic where the morbidity of SCA is substantial due to limited resources. Approximately 10% of affected children will develop primary stroke, with serious medical and neurocognitive sequelae. In the US, transcranial Doppler (TCD) ultrasonog...
Background: Hydroxyurea is the standard of care for children with sickle cell anemia (SCA). We have developed and prospectively validated a population pharmacokinetics (PK)-based dosing model to initiate hydroxyurea at a personalized dose that achieves maximum tolerated dose (MTD) quickly and produces a more robust HbF response than traditional wei...
Introduction. Based on sparse historical data, Tanzania ranks fourth globally for the estimated number of annual births with sickle cell disease. Northwest Tanzania is projected to have an especially high burden of sickle cell disease, but no contemporary surveillance data exist to verify this projection. We designed a large prospective study to de...
Introduction. Children with sickle cell anemia enrolled in Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) received open-label hydroxyurea at maximum tolerated dose (MTD) in four countries within sub-Saharan Africa (Tshilolo et al, NEJM 2019;380:121-131). Unlike children in the United States or Europe, a substantial...
Introduction. Hydroxyurea treatment has proven safety, feasibility, and efficacy for children with sickle cell anemia living in sub-Saharan Africa. Even in malaria endemic regions, hydroxyurea is safe and has been shown to reduce vaso-occlusive events and lower mortality. The optimal dosing regimen is not known, however, and specifically whether a...
Introduction. Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) is a prospective multicenter open-label trial that has already demonstrated hydroxyurea treatment at maximum tolerated dose (MTD) is safe, feasible, and offers major benefits for children with sickle cell anemia living in sub-Saharan Africa (Tshilolo et al...
Background:
Sickle cell anemia (SCA) is the most common inherited hemoglobinopathy worldwide. Infection is a major cause of illness and death in children with SCA, especially in sub-Saharan Africa where an estimated 50-90% of affected children die before their fifth birthday. Interventions to reduce the incidence and severity of infections are nee...
Background Sickle cell anemia (SCA) is the most common inherited hemoglobinopathy worldwide. Infection is a major cause of illness and death in children with SCA, especially in sub Saharan Africa where an estimated 50-90% of affected children die before their fifth birthday. Interventions to reduce the incidence and severity of infections are neede...
Background
Deoxygenated sickle hemoglobin (HbS) polymerization drives the pathophysiology of sickle cell disease. Therefore, direct inhibition of HbS polymerization has potential to favorably modify disease outcomes. Voxelotor is an HbS polymerization inhibitor.
Methods
In a multicenter, phase 3, double-blind, randomized, placebo-controlled trial,...
Hydroxyurea is FDA‐approved and now increasingly used for children with sickle cell anemia (SCA), but dosing strategies, pharmacokinetic (PK) profiles, and treatment responses for individual patients are highly variable. Typical weight‐based dosing with step‐wise escalation to maximum tolerated dose (MTD) leads to predictable laboratory and clinica...
Background
The Uganda Sickle Surveillance Study provided evidence for a large sickle burden among HIV‐exposed infants in Uganda. To date, however, no large scale screening program has been developed for Central or East Africa.
Methods
A 3‐year targeted sickle cell screening project in Uganda was designed by the Ministry of Health to (1) determine...