I am a Hematologist/Oncologist whose major interest is in understanding and improving the care of patients with hemoglobinopathies. In particular, my focus has been in conducting multi-center trials to answer therapeutic questions in hematologic and iron overload disorders. I have been a federally funded research investigator for over 30 years and been national principal investigator for many successful trials. In the last decade, I have focused on transfusion therapy and understanding iron metabolism and its consequences in multiple diseases. I have been the principal investigator on several studies related to transfusion therapy, chelation therapy in hemoglobinopathies. For over 25 years, I have focused on alloimmunization, transfusion-induced hemosiderosis, transfusion efficacy, and risks in hematology. In order to do this, I have developed a hemoglobinopathy center, which provides primary through tertiary care to pediatric and adult patients.
Abstract: Cooley's anemia, or thalassemia major, is a blood disorder characterized by a marked increase in F hemoglobin and a decrease in the production of certain oxygen-carrying proteins in red blood cells. Thalassemia major is the most severe form of the chronic familial anemias that result from the premature destruction of red blood cells and is inherited as an autosomal recessive trait. In the years since the Seventh Cooley's Anemia Symposium, held in 1997, major advances have taken place in the understanding and treatment of the disease. The molecular mechanisms responsible for the switch from fetal hemoglobin to adult hemoglobin production have been further clarified, while new drugs to enhance the production of fetal hemoglobin and relieve the anemia of thalassemia have been introduced and studied. Understanding of the relationship between molecular genotype and clinical phenotype has been advanced, and the techniques for molecular diagnosis, including prenatal diagnosis, have been vastly improved. Most importantly, there have been dramatic improvements in teh treatment and prevention of complications of thalassemia. As a result, patients are now living longer, albeit with more disability. Problems such as osteoporosis, heart failure, growth hormone deficiency, pulmonary hypertension, and infertility can now be detected early and treated. This volume not only focuses on the advances over the last six or seven years, but also illuminates many unsolved but critically important issues in the understanding and treatment of thalassemia, thus offering the scientific, clinical, care-giving, and patient communities the most up-to-date exchange on the current and future perspectives of the disease.
Notes: Cooley's Anemia Symposium (8th : 2005 : Lake Buena Vista, Fla.) xD;edited by Elliott P. Vichinsky. xD;ill. (some col.) ; 24 cm. xD;"Eighth Cooley's Anemia Symposium ... held on March 17-19, 2005 in Lake Buena Vista, Florida"--Contents p.
Abstract: The Year Book of Pediatrics brings you abstracts of the articles that reported the year's breakthrough developments in pediatrics, carefully selected from more than 500 journals worldwide. Expert commentaries evaluate the clinical importance of each article and discuss its application to your practice. There's no faster or easier way to stay informed! This annual covers all aspects of pediatric care from infectious diseases and immunology, adolescent medicine, therapeutics and toxicology, child development, dentistry and otolaryngology and neurology and psychiatry. The Year Book of Pediatrics publishes annually in December of the preceding year.
Abstract: Sickle cell disease (SCD) is characterized by progressive vascular injury and its pathophysiology is strikingly similar to that of atherosclerosis. Statins decrease inflammation and improve endothelial function in cardiovascular disease, but their effect in SCD is not known. In this pilot study, we examined the safety and effect of short-term simvastatin on biomarkers of vascular dysfunction in SCD. We treated 26 SCD patients with simvastatin, 20 or 40 mg/d, for 21 d. Plasma nitric oxide metabolites (NOx), C-reactive protein (CRP), interleukin-6 (IL-6), vascular cell adhesion molecule-1 (VCAM-1), tissue factor (TF) and vascular endothelial growth factor (VEGF) were analyzed and responses to simvastatin were compared between the two treatment groups. Simvastatin increased NOx levels by 23% in the low-dose (P =0·01) and 106% in the moderate-dose (P =0·01) groups, and by 52% overall (P=0·0008). CRP decreased similarly in both dose groups and by 68% overall (P =0·02). Levels of IL-6 decreased by 50% (P=0·04) and 71% (P<0·05) in the low- and moderate-dose groups, respectively. Simvastatin had no effect on VEGF, VCAM1 or TF. Simvastatin was well-tolerated and safe. Our preliminary findings showing a dose-related effect of simvastatin on levels of NOx, CRP and IL-6 suggest a potential therapeutic role for simvastatin in SCD.
Abstract: Previous reports using dual x-ray absorptiometry (DXA) suggest that up to 70% of adults with thalassemia major (Thal) have low bone mass. However, few studies have controlled for body size and pubertal delay, variables known to affect bone mass in this population. In this study, bone mineral content and areal density (BMC, aBMD) of the spine and whole body were assessed by DXA, and volumetric BMD and cortical geometries of the distal tibia by peripheral quantitative computed tomography (pQCT) in subjects with Thal (n = 25, 11 male, 10 to 30 years) and local controls (n=34, 15 male, 7 to 30 years). Z-scores for bone outcomes were calculated from reference data from a large sample of healthy children and young adults. Fasting blood and urine were collected, pubertal status determined by self-assessment and dietary intake and physical activity assessed by written questionnaires. Subjects with Thal were similar in age, but had lower height, weight and lean mass index Z-scores (all p < 0.001) compared to controls. DXA aBMD was significantly lower in Thal compared to controls at all sites. Adult Thal subjects (> 18 years, n = 11) had lower tibial trabecular vBMD (p = 0.03), cortical area, cortical BMC, cortical thickness, periosteal circumference and section modulus Z-scores (all p < 0.01) compared to controls. Cortical area, cortical BMC, cortical thickness, and periosteal circumference Z-scores (p = 0.02) were significantly lower in young Thal (≤ 18 years, n = 14) compared to controls. In separate multivariate models, tibial cortical area, BMC, and thickness and spine aBMD and whole body BMC Z-scores remained lower in Thal compared to controls after adjustment for gender, lean mass and/or growth deficits (all p < 0.01). Tanner stage was not predictive in these models. Osteocalcin, a marker of bone formation, was significantly reduced in Thal compared to controls after adjusting for age, puberty and whole body BMC (p=0.029). In summary, we have found evidence of skeletal deficits that cannot be dismissed as an artifact of small bone size or delayed maturity alone. Given that reduced bone density and strength are associated with increased risk of fracture, therapies focused on increasing bone formation and bone size in younger patients are worthy of further evaluation.
Abstract: Children with siblings coping with chronic illness experience stresses and disruptions in daily life as families work together to care for the affected child. Research suggests that children and adolescents with sickle cell disease (SCD) may be at risk for adjustment problems, impaired psychosocial functioning, and reduced quality of life. These potential stressors affect the child with SCD as well as their caregivers and other family members. This study examined the role of family functioning on the psychosocial functioning of healthy siblings of children with SCD.
Abstract: To gain an insight into current transfusion and chelation practice in patients with sickle cell disease (SCD), a survey of international experts has been conducted. The findings demonstrate that general utilization of transfusion therapy is low, the primary barrier to treatment being concerns over resultant iron overload and the subsequent need for iron chelation therapy. Where patients were transfused, many physicians indicated that a high proportion of patients had hemosiderosis. As evidence suggests more patients with SCD could benefit from regular transfusion therapy, it is apparent that greater awareness of the need to monitor and treat iron overload in transfused patients is required.
Abstract: The Thalassemia Clinical Research Network collected adherence information from 79 patients on deferoxamine and 186 on deferasirox from 2007 to 2009. Chelation adherence was defined as percent of doses administered in the last 4 weeks (patient report) out of those prescribed(chart review). Chelation history since 2002 was available for 97 patients currently on deferoxamine and 217 on deferasirox, with crude estimates of adherence from chart review. Self-reported adherence to both deferoxamine and deferasirox were quite high, with slightly higher adherence to the oral chelator (97 vs. 92%). Ninety percent of patients on deferasirox reported at least 90% adherence, compared with 75% of patients on deferoxamine. Adherence to both chelators was highest in children, followed by adolescents and older adults.Predictors of lower deferoxamine adherence were smoking in the past year, problems sticking themselves (adults only), problems wearing their pump, and fewer transfusions in the past year. Predictors of lower deferasirox adherence were bodily pain and depression. Switching chelators resulted in increased adherence, regardless of the direction of the switch, although switching from deferoxamine to deferasirox was far more common. As adherence to deferoxamine is higher than previously reported, it appears beneficial for patients to have a choice in chelators.
Abstract: The pathophysiology of iron-induced compromised fertility in women with thalassemia major (TM) was evaluated in 26 adult TM females. Low gonadotropin secretion resulted in reduced ovarian antral follicle count and ovarian volume, but levels of anti-müllerian hormone (AMH), a sensitive marker for ovarian reserve independent of gonadotropin effect, were mostly normal. AMH correlated with non-transferrin-bound iron (NTBI), suggesting a role of labile iron in the pathogenesis of decreased reproductive capacity, possibly occurring in parallel to cardiac iron toxicity, as cardiac iron was associated with the presence of amenorrhea and with NTBI levels. AMH emerges as an important biomarker for assessment of reproductive capacity in TM, demonstrating that fertility is preserved in the majority of those younger than 30 to 35 years. AMH can be useful in future studies aiming at improved chelation for fertility preservation, whereas NTBI and labile plasma iron may be valuable for monitoring iron effect on the reproductive system.
Abstract: Ineffective erythropoiesis, the hallmark of β-thalassemia, is a result of α/non-α globin chain imbalance.(1) One strategy to redress globin-chain imbalance is to induce γ-globin gene (HBG) expression. Repression of HBG in adult erythroid cells involves DNA methylation and other epigenetic changes. Therefore, the cytosine analog decitabine, which can deplete DNA methyltransferase 1 (DNMT1), can potentially activate HBG. In 5 patients with β-thalassemia intermedia, a dose and schedule of decitabine intended to deplete DNMT1 without causing significant cytotoxicity (0.2 mg/kg subcutaneous 2 times per week for 12 weeks) increased total hemoglobin from 7.88 ± 0.88 g/dL to 9.04 ± 0.77 g/dL (P = .004) and absolute fetal hemoglobin from 3.64 ± 1.13 g/dL to 4.29 ± 1.13 g/dL (P = .003). Significant favorable changes also occurred in indices of hemolysis and red blood cell densitometry. Consistent with a noncytotoxic, differentiation altering mechanism of action, the major side effect was an asymptomatic increase in platelet counts without erythrocyte micronucleus or VDJ recombination assay evidence of genotoxicity. This study was registered at www.clinicaltrials.gov as #NCT00661726.
Abstract: To date, there is a lack of long-term safety and efficacy data for iron chelation therapy in transfusion-dependent patients with sickle cell disease (SCD). To evaluate the long-term safety and efficacy of deferasirox (a once-daily oral iron chelator), patients with SCD completing a 1-year, Phase II, randomized, deferoxamine (DFO)-controlled study entered a 4-year extension, continuing to receive deferasirox, or switching from DFO to deferasirox. Average actual deferasirox dose was 19·4 ± 6·3 mg/kg per d. Of 185 patients who received at least one deferasirox dose, 33·5% completed the 5-year study. The most common reasons for discontinuation were withdrawal of consent (23·8%), lost to follow-up (9·2%) and adverse events (AEs) (7·6%). Investigator-assessed drug-related AEs were predominantly gastrointestinal [including nausea (14·6%), diarrhoea (10·8%)], mild-to-moderate and transient in nature. Creatinine clearance remained within the normal range throughout the study. Despite conservative initial dosing, serum ferritin levels in patients with ≥ 4 years deferasirox exposure significantly decreased by -591 μg/l (95% confidence intervals, -1411, -280 μg/l; P = 0·027; n = 67). Long-term deferasirox treatment for up to 5 years had a clinically acceptable safety profile, including maintenance of normal renal function, in patients with SCD. Iron burden was substantially reduced with appropriate dosing in patients treated for at least 4 years.
Abstract: An elevated tricuspid regurgitant jet velocity (TRV) is associated with hemolysis and early mortality in sickle cell disease, yet risk factors, clinical parameters and mortality associated with this biomarker in thalassemia are poorly defined. This report summarizes the prevalence of an elevated TRV in 325 patients screened by Doppler-echocardiography in the Thalassemia Clinical Research Network. A documented TRV was reported in 148/325 (46%) of patients. Average age was 25.9 years (range 5-56 years) and 97% were transfusion-dependent. Mean TRV was 2.3±0.4 m/s (range 0.2-3.5 m/s). An abnormal TRV≥2.5 m/s was identified in 49/148 (33%) of patients with a documented TRV, 5% (8/148) with a TRV≥3.0 m/s suggesting significant PH risk. Older age was strongly associated with a high TRV, however 16% of children had a TRV≥2.5 m/s. A history of splenectomy, hepatitis C, smoking or high WBC was associated with TRV elevation. In summary, an elevated TRV is noted in 1/3 of transfusion-dependent thalassemia patients with a documented value and develops in both children and adults. Age, splenectomy, hepatitis C and smoking are significant univariate risk factors, with splenectomy surfacing as the dominant risk factor over time. Mortality was low in this cohort. Prospective longitudinal studies are needed. The clinicaltrials.gov identifier is NCT00661804.
Abstract: Although most common in tropical regions, population migration has meant that sickle cell disease is now one of the most prevalent genetic diseases worldwide. The issues and challenges faced by physicians and patients have been discussed by an international group of experts representing 4 key regions: the USA, Europe, Latin America, and the Middle East/Africa. Conclusive evidence to support the use of transfusion therapy for the prevention of stroke has resulted in key changes to patient management in all regions, and increasing numbers of patients are benefiting from this management approach. However, it is apparent that transfusion therapy is still under-utilized, largely due to concerns over iron overload, alloimmunization, limited blood supplies, and, sometimes, due to parental refusal. Once transfused, assessment and management of body iron levels can be poor, particularly in patients who are intermittently transfused. Compliance with chelation therapy regimens is a significant challenge, but new therapeutic options are likely to overcome some of the current barriers. Key requirements in all regions were considered to be the following: to provide greater physician, patient, and family education; to ensure effective transition from pediatric to adult care; and to establish national guidelines in order to ensure best practice is consistently applied.
Abstract: Red blood cell (RBC) transfusion is the primary treatment for severe forms of thalassaemia. Pre-storage screening has resulted in decreased transfusion-transmitted infections, but anti-RBC antibodies remain a major problem. We report on 697 participants who had ever received transfusions. Allo- and autoantibody rates were compared with respect to splenectomy status, ethnicity, diagnosis, duration of transfusions, treatment centre, and age at transfusion initiation, together with rates before and after 1990, when leucoreduction methods were routine at thalassaemia treatment centres. Allo- and autoantibodies were reported in 115 (16·5%) and 34 (4·9%) subjects, respectively. Splenectomized patients were more likely to have alloantibodies [odds ratio (OR) = 2·528, P ≤ 0·0001], or autoantibodies (OR = 2·590, P = 0·0133). Alloantibodies occurred in 19 of 91 (21%) splenectomized subjects who started transfusion after 1990, and only 18 of 233 (7·7%) nonsplenectomized subjects (P < 0·001). Data from this study demonstrate that RBC antibodies continue to develop in chronically transfused thalassaemia patients at a high rate. Splenectomy preceded the development of antibodies in most cases. Increased rates of RBC sensitization among splenectomized patients is concerning and deserves further study.
Abstract: The 2009 novel influenza A (H1N1) pandemic has had profound public health implications all over the world. The majority of patients infected with the novel strain have recovered uneventfully. However, certain populations have been defined who appear to be at increased risk of complications due to H1N1 infections. This review summarizes the clinical course of five patients with sickle cell, four of whom had confirmed H1N1 infection, and one whom had a presumed H1N1 infection.
Abstract: Early diagnosis during newborn screening or infancy has enabled the observation of the natural history of hemoglobin H disease, a subtype of α-thalassemia.
Abstract: There is still a clinical need for a well-tolerated and safe iron chelator for the treatment of transfusional iron overload. We describe the pharmacokinetic properties and safety data after 7 days of dosing of FBS0701, a novel oral, once-daily iron chelator.
Abstract: Hemoglobin E thalassemia accounts for about one-half of all cases of severe beta thalassemia. There is marked variability in its clinical severity ranging from an asymptomatic to a transfusion-dependent phenotype. The phenotypic variability and inadequate longitudinal data present challenges in determining the optimal management of patients. This article summarizes findings on the natural history of Hemoglobin E thalassemia and some factors responsible for its clinical heterogeneity. Major genetic factors include the type of beta thalassemia mutation, the co-inheritance of alpha thalassemia, and polymorphisms associated with increased synthesis of fetal hemoglobin. Other factors, including response to anemia, and the influence of infection with malaria and other environmental influences, may be important. The remarkable variation and instability of clinical phenotypes in Hemoglobin E thalassemia require individual management plans for each patient, which should be reassessed over time.
Abstract: Preserving fertility, preventing early menopause, and predicting reproductive ability have become crucial for many adult thalassemia major females. Luteinizing hormone/follicle-stimulating hormone (LH/FSH) and estradiol, commonly used for assessment of fertility potential in thalassemia, have a poor predictive value. Current reproductive practice uses markers of ovarian reserve testing, which were not yet studied in thalassemia women. We explored the relationship between liver iron concentration (LIC) and fertility status in 26 females (mean 30 years old). Seventeen (65%) of them experienced primary or secondary amenorrhea. Levels of LH/FSH and estradiol were low or undetectable in 48% and 35% of patients, respectively and did not correlate with age, presence of amenorrhea, and LIC. This further addresses the need for utilization of current available methods for assessment of fertility capacity in thalassemia, which will also allow future correlation with pituitary iron measures by MRI as well as early intervention for fertility preservation.
Abstract: Pulmonary hypertension (PH) has been reported with nearly all forms of the inherited as well as the acquired hemolytic anemias. Recent research investigating the pathophysiology of PH in sickle cell disease and thalassemia has helped elucidate the central role of hemolysis-mediated endothelial dysfunction in the development of PH in these populations. Although the most appropriate treatment of PH in patients with hemolytic anemia is not clearly defined, the associated significant increased risk of death underscores the need for randomized clinical trials in this area.
Abstract: Hemoglobin Constant Spring (HbCS) is the most common nondeletional alpha-thalassemia variant causing HbH disease, making its detection crucial in populations at risk. Universal newborn screening for HbH is carried out in California. Identification of alpha-thalassemia genotypes responsible for HbH and HbH-CS requires rapid, accurate and cost-effective genotyping methods suitable for population screening. We incorporated the HbCS mutation into our existing seven-plex genotyping assay for common alpha-thalassemia deletions. To assess the feasibility and diagnostic utility of this expanded multiplex gap-PCR assay, we determined genotypic frequencies of HbCS in samples referred for alpha-thalassemia testing between 1 January 2006 and 31 December 2008. During the 3-year study period, 1436 samples were genotyped for alpha-thalassemia. HbH-CS accounted for 23 (13%) of the 176 cases of HbH disease identified. In a subset of 145 newborns referred by the California NBS program with an elevated Hb Bart's level at birth, HbH disease was confirmed in 134 (93%) and HbH-CS identified in 13 (10%) of these. This expanded genotyping assay has proven to be a rapid, reliable and clinically useful diagnostic tool for the detection of HbH-CS disease.
Abstract: Patients with sickle cell disease (SCD) are concerned with emergency department care, including time to treatment and staff attitudes and knowledge. Providers are concerned about rapid access to patient information and SCD treatment protocols. A software application that stores and retrieves encrypted personal medical information on a plastic credit card-sized Chart Card was designed.
Abstract: A magnetic resonance imaging cardiac magnetic susceptometry (MRI-CS) technique for assessing cardiac tissue iron concentration based on phase mapping was developed. Normal control subjects (n=9) and thalassemia patients (n=13) receiving long-term blood transfusion therapy underwent MRI-CS and MRI measurements of the cardiac relaxation rate R2*. Using MRI-CS, subepicardium and subendocardium iron concentrations were quantified exploiting the hemosiderin/ferritin iron specific magnetic susceptibility. The average of subepicardium and subendocardium iron concentrations and R2* of the septum were found to be strongly correlated (r=0.96, P<.0001), and linear regression analysis yielded CIC (microg Fe/g(wet tissue))=(6.4+/-0.4).R2* (septum) (s(-1)) - (120+/-40). The results demonstrated that septal R2* indeed measures cardiac iron level.
Abstract: Over 70,000 people live with sickle cell disease (SCD) in the United States and multitudes worldwide. About 2000 afflicted babies are born in this country each year. In African countries such as Nigeria, over 100,000 babies are born with the disease each year. Great strides have been made in the conservative management of SCD. However, the medical and psychosocial cost of supporting patients with this chronic illness is enormous and spans a lifetime. Hematopoietic stem cell transplantation (HSCT) can abrogate SCD manifestations, and is the best option for cure today. Yet, this treatment modality is underutilized as less than 500 transplants are reported in the Center for International Blood and Marrow Transplant Research (CIBMTR) database because of its significant risk of morbidity and mortality. There is growing understanding of the pathophysiology of the disease, and this, coupled with advances in transplantation and new approaches to therapy, continue to improve care of patients with SCD both in children and during adulthood. Continuing investigation seeks to predict the course of the disease and to determine timing and modality of therapy in order to optimize outcomes.
Abstract: Alpha thalassemia, the most common genetic disorder of hemoglobin synthesis, affects up to 5% of the world's population. It represents a group of conditions with reduced or absent synthesis of one to all four of alpha globin genes. Deletional or nondeletional mutations occur on chromosome 16. Its severity ranges from asymptomatic to fatal in utero. Hemoglobin H disease, a mutation of three alpha globin genes, is more severe than previously recognized. Anemia, hypersplenism, hemosiderosis, growth failure, and osteoporosis are commonly noted as the patient ages. Alpha thalassemia major, a usually fatal in utero disease, is now recognized to have a complex molecular and phenotypic expression with increasing births being reported. Surviving newborns without intrauterine transfusion often have congenital anomalies and neurocognitive injury. Serious maternal complications often accompany pregnancy. Doppler ultrasonography with intrauterine transfusion ameliorates these complications. The high incidence in many populations mandates population screening and prenatal diagnosis of at-risk couples. Universal newborn screening has been adopted in several regions with DNA confirmatory testing. These advances have resulted in ethical dilemmas for the family and the provider.
Abstract: Renal papillary necrosis in sickling hemoglobinopathies can lead to significant complications, including hemorrhage, obstruction, and infection. Despite its frequency, there are limited therapies for protracted hemorrhage. In the past, massive hemorrhage was managed with nephrectomy. Here, we report a patient with hemoglobin SC disease and prolonged, life-threatening hemorrhage from papillary necrosis successfully treated with oral, low-dose epsilon aminocaproic acid (EACA). Although further study is warranted, this case illustrates the need to consider EACA in the conservative management of renal papillary necrosis and significant hemorrhage in sickle cell hemoglobinopathies.
Abstract: In this study, the authors examined a possible role of measurements of end-tidal carbon monoxide (CO), corrected for inhaled CO (ETCOc), as a noninvasive screening tool for hemoglobinopathies and as an indicator for when transfusions would be required in patients receiving chronic transfusions. ETCOc measurements were obtained in subjects with sickle cell disease (n = 18), thalassemia (n = 21), and healthy controls (n = 62). ETCOc values less than 3 parts per million (ppm) yielded a positive predictive value of 93% and negative predictive value of 94% in identifying hemoglobinopathies. Subsequently, 7 subjects with thalassemia had laboratory parameters and ETCOc measured over 2 transfusion cycles. ETCOc values were 4.90 +/- 0.32 ppm (mean +/- SD), with 89% of values being above normal (>or=3 ppm). Pretransfusion ETCOc levels significantly correlated with pretransfusion reticulocyte count (r = .96, P <.001), but not with pretransfusion hemoglobin (r = .44, P = .16) or pretransfusion soluble transferrin receptors (sTfR, r = .52, P = .10). In conclusion, we found that patients with hemoglobinopathies have ETCOc values above the range for healthy controls and ETCOc measurements can be used as an adjunct to hemoglobin measurements to determine the proper timing of transfusions.
Abstract: Certain beta globin gene mutations produce a thalassemia major phenotype in the heterozygous state. While most such patients have thalassemia intermedia, we describe a young Guatemalan child with a de novo mutation in the beta globin gene, codon 31 T --> G (Hemoglobin Hakkari), who developed severe anemia at the age of 10 months and remains transfusion-dependent. The substitution of B13 leucine with arginine in the beta globin results in alteration of a critical heme contact point resulting in an extremely unstable variant hemoglobin and a clinical picture that is characterized by ineffective erythropoiesis and numerous intracytoplasmic inclusions within the erythrocyte precursors of the bone marrow. .
Abstract: Advances in the management of thalassemia have resulted in increased life expectancy and new challenges. We conducted the first survey of education and employment status of people with thalassemia in North America.
Abstract: Pulmonary hypertension (PH) is common in thalassemia and contributes to mortality. Advancing age and a history of splenectomy are major risk factors in this population. The etiology of PH is multifactorial, involving a complex interaction of platelets, the coagulation system, erythrocytes, and endothelial cells along with inflammatory and vascular mediators. The long-term effect of splenectomy, red cell membrane pathology, coagulation abnormalities, low nitric oxide (NO) bioavailability, excess arginase activity, platelet activation, oxidative stress, iron overload, and chronic hemolysis play a role. The process of hemolysis disables the arginine-NO pathway through the simultaneous release of erythrocyte arginase and cell-free hemoglobin. Both NO and its obligate substrate arginine are rapidly consumed. The biological consequences of hemolysis on NO bioavailability ultimately translate into the clinical manifestations of PH. Guidelines for the management of PH in thalassemia have not yet been established; however, clinical trials are ongoing in an effort to guide future therapy.
Abstract: Sickle cell anemia (SCA) is a chronic illness causing progressive deterioration in quality of life. Brain dysfunction may be the most important and least studied problem affecting individuals with this disease.
Abstract: The highest approved dose of deferasirox is currently 30 mg/kg per d in many countries; however, some patients require escalation above 30 mg/kg per d to achieve their therapeutic goals. This retrospective analysis investigated the efficacy (based on change in serum ferritin levels) and safety of deferasirox >30 mg/kg per d in adult and paediatric patients with transfusion-dependent anaemias, including beta-thalassaemia, sickle cell disease and the myelodysplastic syndromes. In total, 264 patients pooled from four clinical trials received doses of >30 mg/kg per d; median exposure to deferasirox >30 mg/kg per d was 36 weeks. In the overall population there was a statistically significant median decrease in serum ferritin of 440 microg/l (P < 0.0001) from pre-dose-escalation to the time-of-analysis; significant decreases were also observed in adult and paediatric patients, as well as beta-thalassaemia patients. The adverse event profile in patients who received deferasirox doses of >30 mg/kg per d was consistent with previously published data. There was no worsening of renal or liver function following dose escalation. Deferasirox >30 mg/kg per d effectively reduced iron burden to levels lower than those achieved prior to dose escalation in patients with transfusion-dependent anaemias. This has important implications for patients who are heavily transfused and may require higher doses to reduce body iron burden.
Abstract: This review highlights recent advances in iron metabolism that are relevant to sickle cell disease (SCD). SCD is a common hemoglobinopathy that results in chronic inflammation. Improved understanding of how iron metabolism is controlled by proteins such as hepcidin, ferroportin, hypoxia-inducible factor 1, and growth differentiation factor 15 have revealed how they are involved in the organ toxicity of SCD. SCD patients have lower levels of non-transferrin-bound iron (NTBI) relative to other hemoglobinopathies, such as thalassemia. Care for SCD now commonly uses transfusion that results in iron overload and necessitates the need for chelation. New oral chelation therapy using deferasirox (Exjade/ICL670) appears to be safe and may even lower the amount of toxic free NTBI and enhance patient compliance. Finally, we suggest that iron metabolism and trafficking is different in SCD compared to other hemoglobinopathies. The high levels of inflammatory cytokines in SCD may enhance macrophage/reticuloendothelial cell iron and/or renal cell iron retention. This makes the tissues that retain iron different in SCD, and thus the organs that fail in SCD are different from those of other hemoglobinopathies, such as the cardiomyopathy or endocrinopathies of thalassemia.
Abstract: Chronic blood transfusion is increasingly indicated in patients with sickle cell disease. Measuring resulting iron overload remains a challenge. Children without viral hepatitis enrolled in 2 trials for stroke prevention were examined for iron overload (STOP and STOP2; n = 271). Most received desferrioxamine chelation. Serum ferritin (SF) changes appeared nonlinear compared with prechelation estimated transfusion iron load (TIL) or with liver iron concentrations (LICs). Averaged correlation coefficient between SF and TIL (patients/observations, 26 of 164) was r = 0.70; between SF and LIC (patients/observations, 33 of 47) was r = 0.55. In mixed models, SF was associated with LIC (P = .006), alanine transaminase (P = .025), and weight (P = .026). Most patients with SF between 750 and 1500 ng/mL had a TIL between 25 and 100 mg/kg (72.8% +/- 5.9%; patients/observations, 24 of 50) or an LIC between 2.5 and 10 mg/g dry liver weight (75% +/- 0%; patients/observations, 8 of 9). Most patients with SF of 3000 ng/mL or greater had a TIL of 100 mg/kg or greater (95.3% +/- 6.7%; patients/observations, 7 of 16) or an LIC of 10 mg/g dry liver weight or greater (87.7% +/- 4.3%; patients/observations, 11 of 18). Although SF changes are nonlinear, levels less than 1500 ng/mL indicated mostly acceptable iron overload; levels of 3000 ng/mL or greater were specific for significant iron overload and were associated with liver injury. However, to determine accurately iron overload in patients with intermediately elevated SF levels, other methods are required. These trials are registered at www.clinicaltrials.gov as #NCT00000592 and #NCT00006182.
Abstract: This study aimed to determine differences in the rates of growth, endocrine- and calcium-related abnormalities in the various thalassemia syndromes in North America treated with current therapies. Medical history, physical examinations and blood and urine collections were obtained from patients with all thalassemia syndromes age 6 years and older in the Thalassemia Clinical Research Network. 361 subjects, 49% male, mean age 23.2 years (range 6.1-75 years) were studied. Approximately 25% of children and adults, regardless of the thalassemia syndrome, had short stature. Overall growth in children was mildly affected. Final height was close to midparental height (z = -0.73 +/- 1.24). Patients with beta thalassemia major (TM) had higher rates of hypogonadism, multiple endocrinopathies, worse hyperglycaemia, subclinical hypoparathyroidism and hypercalciuria. Hypogonadism remained the most frequent endocrinopathy and was frequently under-treated. 12.8% of the subjects had 25 vitamin D concentrations less than 27 nmol/l and 82% less than 75 nmol/l, regardless of the thalassemia syndrome. Adolescents had lower 25 vitamin D levels than children and adults. Compared to patients with other thalassemia syndromes, those with beta TM suffered from higher rates of multiple endocrinopathies, abnormal calcium metabolism and hypercalciuria. Vitamin D abnormalities were high among adolescents.
Abstract: Adults with beta thalassemia major frequently have low BMD, fractures, and bone pain. The purpose of this study was to determine the prevalence of low BMD, fractures, and bone pain in all thalassemia syndromes in childhood, adolescence, and adulthood, associations of BMD with fractures and bone pain, and etiology of bone disease in thalassemia. Patients of all thalassemia syndromes in the Thalassemia Clinical Research Network, > or =6 yr of age, with no preexisting medical condition affecting bone mass or requiring steroids, participated. We measured spine and femur BMD and whole body BMC by DXA and assessed vertebral abnormalities by morphometric X-ray absorptiometry (MXA). Medical history by interview and review of medical records, physical examinations, and blood and urine collections were performed. Three hundred sixty-one subjects, 49% male, with a mean age of 23.2 yr (range, 6.1-75 yr), were studied. Spine and femur BMD Z-scores < -2 occurred in 46% and 25% of participants, respectively. Greater age, lower weight, hypogonadism, and increased bone turnover were strong independent predictors of low bone mass regardless of thalassemia syndrome. Peak bone mass was suboptimal. Thirty-six percent of patients had a history of fractures, and 34% reported bone pain. BMD was negatively associated with fractures but not with bone pain. Nine percent of participants had uniformly decreased height of several vertebrae by MXA, which was associated with the use of iron chelator deferoxamine before 6 yr of age. In patients with thalassemia, low BMD and fractures occur frequently and independently of the particular syndrome. Peak bone mass is suboptimal. Low BMD is associated with hypogonadism, increased bone turnover, and an increased risk for fractures.
Abstract: Alpha thalassemia disorders are a group of hereditary anemias caused by absent or decreased production of the alpha chain of hemoglobin. Hemoglobin Bart's hydrops fetalis is usually a fatal in-utero disease caused by absence of the alpha genes. However, the molecular and genotypic expression of hemoglobin Bart's varies and increasing numbers of births are being reported. Population screening and prenatal diagnosis of at-risk couples is essential but often not performed. Most affected pregnancies are often undetected, resulting in severe fetal and maternal complications. Noninvasive monitoring by Doppler ultrasonagraphy with intrauterine transfusion therapy has changed the prognosis for this disorder. These advances in intrauterine and postnatal therapy have resulted in ethical dilemmas for the family and the provider.
Abstract: BACKGROUND: Newborn screening (NBS) for hemoglobinopathies facilitates early identification of affected individuals to ensure the prompt institution of comprehensive medical care for affected newborns in California. When linked to extensive follow-up and education, NBS has been shown to significantly reduce mortality in children with sickle cell disease. Due to changing immigration patterns from Asia and Latin America, the State of California has witnessed an increased prevalence of clinically significant hemoglobin (Hb) disorders, including those resulting from novel genotypes. In 1999, newborn screening for Hb H disorders was incorporated in the statewide hemoglobinopathy screening program. PROCEDURE: Primary screening for hemoglobin variants was performed using high performance liquid chromatography. Confirmatory testing on hemoglobinopathy mutations was performed by electropheresis techniques and genotyping methods. RESULTS: Of 530,000 newborn samples screened annually in California, 2,118 samples were referred to the Hemoglobin Reference Laboratory (HRL) for confirmatory testing between January 1, 1998 and June 30, 2006 (0.05%). Sickle cell disease was most frequently observed (1 in 6,600 births) followed by alpha-thalassemia (1 in 9,000 births) and beta-thalassemia disease (1 in 55,000 births). The confirmatory analysis modified the initial screening in 5% of cases and revealed 25 rare or new genotypes. Diverse ethnicities were associated with hemoglobin mutations including Southeast Asian, Black, Indian/Asian, Middle Eastern, and Hispanic. CONCLUSIONS: The California hemoglobinopathy screening program provides accurate diagnosis of hemoglobinopathies. Increasing incidence of diverse mutations require new strategies of laboratory screening, counseling, and patient management.
Abstract: AIM: To investigate the application of an expanded Transactional Stress and Coping Model for the psychological adjustment of non-chronically ill, African-American siblings of children with sickle cell disease (SCD). METHODS: Ninety-seven siblings (M = 11.24 years) from 65 families who care for a child with SCD participated. Primary caregivers completed the Coping Health Inventory for Parents, the Family Relations Scale and the Child Behaviour Checklist, while siblings completed the Kidcope, the Children's Self-Efficacy for Peer Interaction Scale, and the Social Support Scale for Children. RESULTS: Family processes were predictive of sibling adjustment, revealing that family coping, expressiveness and support improved adjustment, while family conflict predicted poor adjustment. CONCLUSION: Findings suggest that family-centered interventions stressing family expressiveness and support, while minimizing conflict, will contribute to sibling psychological adjustment.
Abstract: BACKGROUND: We assessed whether oxidant-stress and inflammation in beta-thalassemia could be controlled by the novel oral iron chelator deferasirox as effectively as by deferoxamine. DESIGN AND METHODS: Forty-nine subjects were enrolled from seven sites and studied at baseline, and after 1, 6, and 12 months of therapy. Malondialdehyde, protein carbonyls, vitamins E and C, total non-transferrin bound iron, transferrin saturation, C-reactive protein, cytokines, serum ferritin concentration and liver iron concentration were measured. RESULTS: Liver iron concentration and ferritin declined significantly in both treatment groups during the study. This paralleled a significant decline in the oxidative-stress marker malondialdehyde (deferasirox -22%/year, deferoxamine -28%/year, average decline p=0.006). The rates of decline did not differ between treatment groups. Malondialdehyde was higher in both treatment groups than in a group of 30 non-thalassemic controls (p < 0.001). The inflammatory marker high-sensitivity C-reactive protein decreased significantly only in the group receiving deferasirox (deferasirox -51%/year, deferoxamine +8.5%/year, p = 0.02). This result was confounded by a chance difference in the level of high-sensitivity C-reactive protein between the two groups at baseline, but analyses controlling for this difference suggested an equally large treatment effect. CONCLUSIONS: Iron chelation therapy with deferoxamine or with deferasirox was equally effective in decreasing iron burden and malondialdehyde. The possible differential effect of the two chelators on inflammation warrants further investigation.
Abstract: BACKGROUND/AIMS: There is increasing evidence demonstrating the value of transfusions in sickle cell disease (SCD). However, resultant iron overload can be life threatening if untreated. Chelation therapy with deferoxamine requires parenteral infusions that can negatively impact quality of life and adherence to treatment. METHODS: As part of a phase II trial, SCD patient-reported outcomes were evaluated. One hundred and ninety-five patients were randomized (2:1) to receive oral deferasirox (5-30 mg/kg/day) or deferoxamine (20-50 mg/kg, 5 days per week); 121 had previously received deferoxamine. RESULTS: At each time point, significantly more patients who had previously received deferoxamine were 'satisfied/very satisfied' with deferasirox, or found treatment to be 'convenient/very convenient' compared with deferoxamine (p < 0.001). In these patients, fewer hours were lost from daily activities with deferasirox than deferoxamine treatment. Most patients (77%) preferred deferasirox, and more were willing to continue taking deferasirox than deferoxamine at end-of-study (84 vs. 11%, respectively). CONCLUSIONS: Patients with SCD are therefore more satisfied with deferasirox, which has a lower impact on daily activities than deferoxamine. Given the high levels of satisfaction, it is likely that quality of life will be improved. These results also suggest that treatment adherence with deferasirox may be better than with deferoxamine, which should lead to improved long-term outcomes.
Abstract: Sickle cell disease continues to cause significant morbidity and mortality despite increases in life expectancy. This review looks at recent translational research in sickle cell disease, covering the red cell membrane, the vascular endothelium, local and systemic inflammation and the potentially pivotal role of nitric oxide as a key regulator of sickle cell complications. Clinical research reviewed includes pulmonary hypertension, which is emerging as a particularly deadly scourge of adults with any haemolytic anaemia, and newer insights into older, more established complications and treatments, such as red cell transfusions, the need for and use of iron chelation and avascular necrosis. Finally, recent studies about those factors that affect the day-to-day lives of persons with sickle cell disease, pain and neuropsychiatric functioning, are discussed.
Abstract: Antiviral treatment of hepatitis C virus in thalassemia has raised concerns of ribavirin-induced hemolysis and increased iron loading. This study examined the change in liver iron concentration, transfusion requirement, virological response, and iron-related toxicities after pegylated interferon alpha-2a/ribavirin treatment in patients with thalassemia. Median transfusions increased by 44%. However, only 29% (4/14) of patients showed an increase of liver iron concentration > 5mg/g dry wt. and overall liver iron remained stable. One of 4 patients with genotype 2 or 3 demonstrated sustained viral response, compared with 50% with genotype 1 (6/12). No patient developed cardiac, liver or endocrine toxicities, although neutropenia occurred in 52%. The molar efficacy of deferoxamine improved with reduction in liver inflammation on biopsy (p=0.001). In conclusion, antiviral treatment is safe if transfusion requirement, iron toxicities and neutropenia are monitored.
Abstract: The current study aims to compare positive and negative measures of psychosocial functioning among children with sickle cell disease (SCD) and their healthy siblings. Participants were 41 African-American children with SCD, 97 healthy siblings, and their primary caregivers. Primary caregivers completed self-report questionnaires assessing child behavioral problems, while children with SCD and siblings completed self-report questionnaires assessing coping, self-efficacy, and perceived social support. No significant differences were noted between children with SCD and their siblings on all measures. Both groups reported self-efficacy and perceived social support within the normative range, and endorsed significantly greater use of Positive/Approach coping. In general, both groups of children do not have clinically significant behavioral problems. However, secondary exploratory analyses identified that a greater percentage of children from both groups scored above the established clinical cutoff on the behavioral summary scores. Number of visits to the emergency room was related to behavioral problems in children with SCD. While previous reports have been mixed in their findings that children with SCD are at greater risk for psychosocial and other behavioral problems, the current report finds that children with SCD and their healthy siblings endorse positive psychosocial functioning and as a group do not have clinically significant behavioral problems. Nonetheless, ongoing psychosocial evaluation for children receiving treatment for SCD is vital.
Abstract: Senicapoc, a novel Gardos channel inhibitor, limits solute and water loss, thereby preserving sickle red blood cell (RBC) hydration. Because hemoglobin S polymerization is profoundly influenced by intracellular hemoglobin concentration, senicapoc could improve sickle RBC survival. In a 12-week, multicenter, phase 2, randomized, double-blind, dose-finding study, we evaluated senicapoc's safety and its effect on hemoglobin level and markers of RBC hemolysis in sickle cell anemia patients. The patients were randomized into 3 treatment arms: placebo; low-dose (6 mg/day) senicapoc; and high-dose (10 mg/day) senicapoc. For the primary efficacy end point (change in hemoglobin level from baseline), the mean response to high-dose senicapoc treatment exceeded placebo (6.8 g/L [0.68 g/dL] vs 0.1 g/L [0.01 g/dL], P < .001). Treatment with high-dose senicapoc also produced significant decreases in such secondary end points as percentage of dense RBCs (-2.41 vs -0.08, P < .001); reticulocytes (-4.12 vs -0.46, P < .001); lactate dehydrogenase (-121 U/L vs -15 U/L, P = .002); and indirect bilirubin (-1.18 mg/dL vs 0.12 mg/dL, P < .001). Finally, senicapoc was safe and well tolerated. The increased hemoglobin concentration and concomitant decrease in the total number of reticulocytes and various markers of RBC destruction following senicapoc administration suggests a possible increase in the survival of sickle RBCs. This study is registered at http://clinicaltrials.gov as NCT00040677.
Abstract: Deferasirox (Exjade, ICL670) is a once-daily, oral iron chelation agent that is now widely available for the treatment of transfusional hemosiderosis in adult and pediatric patients aged > or =2 years of age. Clinical evaluation has established the efficacy and safety of this novel agent in patients with a variety of chronic anemias. Deferasirox represents a significant advance in the treatment of iron overload, as the availability of an effective oral therapy has the potential to relieve many patients from the burden of frequent parenteral therapy with the previous reference standard iron chelator, deferoxamine. The most common drug-related adverse events seen in the core registration trials were gastrointestinal disturbances, rash, mild and nonprogressive increases in serum creatinine levels, and elevations in liver enzyme levels. Most events were transient, mild-to-moderate in severity, and easily managed without discontinuation of treatment. As with any new agent, it is important that treating physicians are familiar with the adverse event profile of deferasirox and how the associated effects can be readily managed to ensure optimal use of this important treatment.
Abstract: BACKGROUND: Transfusion therapy is frequently used to prevent morbidity in sickle cell disease (SCD), and subsequent iron overload is common. The objective of this study was to evaluate the current standard of care in monitoring iron overload and related complications in patients with SCD compared to thalassemia (Thal). STUDY DESIGN AND METHODS: A cross-sectional study was conducted at 31 hematology clinics in the United States, Canada, or the United Kingdom. Patients who received transfusions with a mean serum ferritin level of least 2000 ng per mL were eligible. A total of 199 patients with SCD (113 female; 24.9 +/- 13.2 years) and 142 with Thal (66 female; 25.8 +/- 8.1 years) were recruited, and data were collected between 2001 and 2003 by interview and medical record review. RESULTS: Although both groups were recruited on the basis of significant iron overload, the likelihood of performing a liver biopsy for routine iron monitoring was significantly higher (odds ratio [OR], 3.4; 95% confidence interval [CI], 2.2-5.3) in Thal than SCD. Thal patients were also more likely to be screened for iron-related organ injury including an echocardiograph for cardiomyopathy (OR, 2.6; p < 0.001; 95% CI, 1.6-4.2), alanine aminotransferase for liver function (OR, 8.3; CI, 1.05-64.4), and thyroid-stimulating hormone for hypothyroidism (OR, 12.3; CI, 7.0-21.5). For adult SCD patients, those maintained on simple transfusion with a serum ferritin level of greater than 2500 ng per mL were the least likely to have a liver biopsy (p < 0.03). CONCLUSIONS: These data highlight the unsystematic monitoring of iron and related organ injury in SCD. Until the relationship between iron and related comorbidities is better understood, routine monitoring of iron overload in SCD patients who receive transfusions should be considered a standard part of clinical care.
Abstract: In thalassemia, fetal hemoglobin (HbF) augmentation with hydroxycarbamide (also known as hydroxyurea) is not always successful. The expected parallel effects on red cell (RBC) membrane deformability, cell hydration, and membrane phospholipid organization, all important for extending RBC life span and increasing Hb, have been infrequently examined. We analyzed these characteristics in 15 nontransfused E/beta(0) thalassemia patients treated with HU (mean 10.2 months). Membrane deformability and cell hydration mildly improved in association with increased HbF levels approaching statistical significance (r = 0.51, P = 0.06). All measures improved considerably in splenctomized patients. These findings underscore the disappointing results of hydroxyurea treatment in clinical trials and the importance of examining the effect on RBC characteristics for the development and understanding of HbF-enhancing agents.
Abstract: Transfusional iron overload leads to gonadal failure and low bone mass in patients with thalassemia (Thal). However, gonadal failure is rarely reported in transfused patients with sickle cell disease (SCD) and the literature regarding fracture prevalence in SCD is limited. The objective of this study was to assess self-reported fracture prevalence and its relationship to endocrinopathy in transfused Thal or SCD subjects and compare to non-transfused subjects with SCD (NonTxSCD). Eligibility was based on age> or =12 years and liver iron concentration> or =10 mg/g dry wt or serum ferritin> or =2000 ng/mL (Thal or TxSCD) or for NonTxSCD, ferritin<500 ng/mL. Data were collected by patient interview and chart review at 31 clinical centers in the U.S., Canada and the U.K. 152 subjects with Thal (52% Male; 25.6+/-0.7 years), 203 subjects with TxSCD (44% Male, 24.7+/-0.9 years: Mean+/-SE), and 65 NonTxSCD (50% Male, 22.2+/-1.3 years) were enrolled. Overall, male subjects with Thal were more likely to have sustained a fracture in their lifetime (51%) compared to TxSCD (28%) or NonTxSCD (32%) (p=0.005). There was no difference in fracture prevalence among women (Thal: 26%, TxSCD 17%, NonTxSCD: 16%). Fracture was most frequently reported in the upper extremities (53.3% of all fractures) while spine and pelvic fractures were relatively common for such a young cohort: 10.6%. Though overall fracture prevalence was not distinctly different from published healthy cohorts, fewer fractures occurred during the adolescent years. In multivariate analysis, the significant predictors of fracture prevalence were Thal diagnosis (Odds Ratio: 2.3; 1.2-4.6; 95%CI), male gender (OR: 2.6; 1.5-4.5), hypothyroidism (OR: 3.3; 1.1-9.8) and age (OR: 1.1; 1.03-1.08). These data suggest that despite similar iron burden, transfused patients with Thal are at greater risk for fracture than subjects with SCD. Male subjects with Thal and hypothyroidism are at particular risk for fracture, in contrast, transfused subjects with SCD had no greater risk of fracture compared to non-transfused SCD. Though ethnic differences in fracture risk cannot be ignored, endocrinopathy is rare in TxSCD which may also provide some protection from fracture.
Abstract: Pulmonary hypertension (PHT) is an important co-morbidity in sickle cell disease (SCD). Despite increasing research in adults, the prevalence and implication of this condition in children is unknown. Charts of 362 SCD patients followed at the Children's Hospital & Research Center Oakland were reviewed to determine clinical variables associated with obtaining echocardiographic screening for PHT, clinical associations of PHT, and associated mortality following diagnosis in adults and children with SCD. In this cohort, patients with underlying lung abnormalities or those on chronic transfusions were more likely to have echocardiograms, however the diagnosis of PHT was often unrecognized. A different clinical phenotype for PHT in adults versus children was identified. Associations with PHT for adults included age, renal and lung disease, hepatitis C, chronic transfusions, and a history of acute chest syndrome (ACS), with ACS being protective. Surprisingly, for children, a history of sepsis, along with a history of ACS, or obstructive lung disease were associated with PHT. Survival analysis found significant mortality for PHT, with a hazard ratio of 17.3 (95% confidence interval 4.9-60.4). The divergent clinical spectrum for PHT between adults and children may point to different age-specific mechanisms or biological expression of PHT.
Abstract: OBJECTIVES/METHODS: This 1-yr prospective phase II trial evaluated the efficacy of deferasirox in regularly transfused patients aged 3-81 yrs with myelodysplastic syndromes (MDS; n = 47), Diamond-Blackfan anaemia (DBA; n = 30), other rare anaemias (n = 22) or beta-thalassaemia (n = 85). Dosage was determined by baseline liver iron concentration (LIC). RESULTS: In patients with baseline LIC > or = 7 mg Fe/g dry weight, deferasirox initiated at 20 or 30 mg/kg/d produced statistically significant decreases in LIC (P < 0.001); these decreases were greatest in MDS and least in DBA. As chelation efficiency and iron excretion did not differ significantly between disease groups, the differences in LIC changes are consistent with mean transfusional iron intake (least in MDS: 0.28 +/- 0.14 mg/kg/d; greatest in DBA: 0.4 +/- 0.11 mg/kg/d). Overall, LIC changes were dependent on dose (P < 0.001) and transfusional iron intake (P < 0.01), but not statistically different between disease groups. Changes in serum ferritin and LIC were correlated irrespective of disease group (r = 0.59), supporting the potential use of serum ferritin for monitoring deferasirox therapy. Deferasirox had a safety profile compatible with long-term use. There were no disease-specific safety/tolerability effects: the most common adverse events were gastrointestinal disturbances, skin rash and non-progressive serum creatinine increases. CONCLUSIONS: Deferasirox is effective for reducing iron burden with a defined, clinically manageable safety profile in patients with various transfusion-dependent anaemias. There were no disease-specific adverse events. Once differences in transfusional iron intake are accounted for, dose-dependent changes in LIC or serum ferritin are similar in MDS and other disease groups.
Abstract: BACKGROUND: While it is appropriate to treat transfusional iron overload to limit end-organ injury after bone marrow transplantation (BMT) for beta-thalassemia major (TM), this approach after BMT for sickle cell disease (SCD) and hematological malignancies has not been studied. PROCEDURE: Fifteen children with SCD (n = 4), TM (n = 6), or acute myelogenous leukemia (AML, n = 5) underwent HLA-identical sibling BMT between 2000 and 2003. Prospective evaluations of iron biomarkers were performed and the three groups were compared. RESULTS: The pre-BMT duration and volume of RBC transfusions varied among the three groups, but baseline ferritin and liver iron concentration (LIC) were similar. In contrast, liver histology differed. Liver inflammation was present in four TM patients and portal fibrosis was observed in five TM and one SCD patient. Hepatic veno-occlusive disease (VOD) developed in 5 of 15 patients. VOD was not associated with age, ferritin, ALT, or transfusions, but an association with liver inflammation and elevated LIC was suggested. Phlebotomy was performed in five patients after BMT. Changes in LIC were minimal in non-phlebotomized patients (P = 0.02). CONCLUSION: Iron biomarkers demonstrated significant iron overload before BMT in patients with malignant and non-malignant disorders. However, iron overload was associated with liver inflammation and VOD primarily in TM patients. The clinical significance of iron overload in patients after BMT remains uncertain, but this is the first study to suggest that VOD may be associated with transfusional iron burden.
Abstract: Erythrocyte glutathione depletion has been linked to hemolysis and oxidative stress. Glutamine plays an additional antioxidant role through preservation of intracellular nicotinamide adenine dinucleotide phosphate (NADPH) levels, required for glutathione recycling. Decreased nitric oxide (NO) bioavailability, which occurs in the setting of increased hemolysis and oxidative stress, contributes to the pathogenesis of pulmonary hypertension (PH) in sickle cell disease (SCD). We hypothesized that altered glutathione and glutamine metabolism play a role in this process. Total glutathione (and its precursors) and glutamine were assayed in plasma and erythrocytes of 40 SCD patients and 9 healthy volunteers. Erythrocyte total glutathione and glutamine levels were significantly lower in SCD patients than in healthy volunteers. Glutamine depletion was independently associated with PH, defined as a tricuspid regurgitant jet velocity (TRV) of at least 2.5 m/s. The ratio of erythrocyte glutamine:glutamate correlated inversely to TRV (r = -0.62, P < .001), plasma arginase concentration (r = -0.45, P = .002), and plasma-free hemoglobin level (r = -0.41, P = .01), linking erythrocyte glutamine depletion to dysregulation of the arginine-NO pathway and increased hemolytic rate. Decreased erythrocyte glutathione and glutamine levels contribute to alterations in the erythrocyte redox environment, which may compromise erythrocyte integrity, contribute to hemolysis, and play a role in the pathogenesis of PH of SCD.
Abstract: Sickle cell disease continues to cause significant morbidity and mortality despite increases in life expectancy. This review looks at recent translational research in sickle cell disease, covering the red cell membrane, the vascular endothelium, local and systemic inflammation and the potentially pivotal role of nitric oxide as a key regulator of sickle cell complications. Clinical research reviewed includes pulmonary hypertension, which is emerging as a particularly deadly scourge of adults with any haemolytic anaemia, and newer insights into older, more established complications and treatments, such as red cell transfusions, the need for and use of iron chelation and avascular necrosis. Finally, recent studies about those factors that affect the day-to-day lives of persons with sickle cell disease, pain and neuropsychiatric functioning, are discussed.
Abstract: Sickle cell disease (SCD) is associated with increased risk of stroke and cognitive impairment. This study describes a retrospective review of 65 patients who underwent routine neuropsychological testing and MRI during treatment at a comprehensive sickle cell center. It was hypothesized that (1) children with no evidence of CVA would perform lower than expected on cognitive tasks compared to population-based normative data, (2) children with strokes and children with silent infarcts would perform lower on cognitive tasks and motor skills as compared to patients with no evidence of CVA, and (3) children with evidence of silent infarcts would perform better than children with known overt strokes. This final hypothesis has not been studied previously, as children with known overt stroke and silent infarct were grouped together. Sixty-five children with SCD who were sent for routine neuropsychological testing and brain MRI were identified via retrospective chart review. Patients had been administered neuropsychological tests to assess cognitive, executive and motor function. Brain MRI was obtained from each patient and was analyzed for evidence of cerebrovascular accident (CVA). Based on MRI analysis, 27% of patients with SCD had experienced a stroke and 13% a silent infarct. The majority (59%) of patients diagnosed with stroke or infarct sustained cortical damage to the frontal lobe. Patients with SCD and no evidence of CVA functioned normally on tests of cognitive ability and achievement, but patients with CVA displayed impairments in cognitive function and comparatively lower scores on verbal and performance scales. Neuropsychological testing can identify impairments in patients with SCD with no known cerebrovascular accident. Investigations of neurocognitive functioning will help characterize patterns of deficits and can inform the ability to implement comprehensive care strategies for patients with SCD and cognitive impairment.
Abstract: Serum ferritin (SF) and liver iron concentration (LIC), as measured by SQUID biosusceptometry, were assessed in a convenience sample of transfusion independent thalassemia patients (nTx-Thal, n=26), regularly transfused thalassemia (Tx-Thal, n=89), or sickle cell patients (SCD, n=45) to investigate the severity of iron overload and the relationship between SF and LIC in nTx-Thal compared to SCD and Tx-Thal. SF correlated with LIC (RS=0.53, P<0.001), but was found to be a poor predictor for LIC. SF was significantly lower (P<0.001) in nTx-Thal patients than in other groups, despite similar LIC values. The SF-to-LIC ratio was significantly lower in nTx-Thal compared to Tx-Thal and SCD patients (median of 0.32, 0.87, and 1.2, respectively: P<0.001). Due to underestimation of LIC by ferritin levels, chelation treatment may be delayed or misdirected in patients with thalassemia intermedia.
Abstract: The most widely used drug for iron chelation is deferoxamine (DFO) mesylate. While effective in promoting iron excretion, it requires prolonged daily infusions, often resulting in poor compliance. A clinical trial was conducted using starch-conjugated DFO (S-DFO; 40SD02), a high-molecular-weight iron chelator possessing prolonged vascular retention. Single doses of S-DFO were infused intravenously into groups of four transfusion-dependent patients with beta-thalassaemia at doses of 150, 300, 600 and 900 mg/kg. Urinary iron excretion and various pharmacologic parameters were evaluated for 1 week and safety for 3 weeks. No drug-related effects were observed on clinical chemistries, haematological and coagulation parameters, urinalyses, vital signs or electrocardiograms. Drug-related adverse events were limited to four urticarial reactions, none requiring termination of the infusion. The drug stimulated clinically significant urinary iron excretion, with the highest dose (900 mg/kg) inducing excretion of 1.31 mg of iron/kg (range 0.79-1.90 mg/kg) over 1 week, with residual iron-binding capacity present in the plasma for over 6 d. In summary, treatment with S-DFO, administered weekly, has the potential to achieve iron balance in the poorly compliant patient.
Abstract: Deferasirox is a once-daily, oral iron chelator developed for treating transfusional iron overload. Preclinical studies indicated that the kidney was a potential target organ of toxicity. As patients with sickle cell disease often have abnormal baseline renal function, the primary objective of this randomised, open-label, phase II trial was to evaluate the safety and tolerability of deferasirox in comparison with deferoxamine in this population. Assessment of efficacy, as measured by change in liver iron concentration (LIC) using biosusceptometry, was a secondary objective. A total of 195 adult and paediatric patients received deferasirox (n = 132) or deferoxamine (n = 63). Adverse events most commonly associated with deferasirox were mild, including transient nausea, vomiting, diarrhoea, abdominal pain and skin rash. Abnormal laboratory studies with deferasirox were occasionally associated with mild non-progressive increases in serum creatinine and reversible elevations in liver function tests. Discontinuation rates from deferasirox (11.4%) and deferoxamine (11.1%) were similar. Over 1 year, similar dose-dependent LIC reductions were observed with deferasirox and deferoxamine. Once-daily oral deferasirox has acceptable tolerability and appears to have similar efficacy to deferoxamine in reducing iron burden in transfused patients with sickle cell disease.
Abstract: A natural history study was conducted in 142 Thalassemic (Thal), 199 transfused Sickle Cell Disease (Tx-SCD, n = 199), and 64 non-Tx-SCD subjects to describe the frequency of iron-related morbidity and mortality. Subjects recruited from 31 centers in the US, Canada or the UK were similar with respect to age (overall: 25 +/- 11 years, mean +/- SD) and gender (52% female). We found that Tx-SCD subjects were hospitalized more frequently compared with Thal or non-Tx-SCD (P < 0.001). Among those hospitalized, Tx-SCD adult subjects were more likely to be unemployed compared with Thal (RR = 1.6, 95% CI 1.0-2.5) or non-Tx-SCD (RR = 3.1, 95% CI 1.3-7.3). There was a positive relationship between the severity of iron overload, assessed by serum ferritin, and the frequency of hospitalizations (r= 0.20; P = 0.009). Twenty-three deaths were reported (6 Thal, 17 Tx-SCD) in 23.5 +/- 10 months of follow-up. Within the Tx-SCD group, those who died began transfusion (25.3 vs. 12.4 years, P < 0.001) and chelation therapy later (26.8 vs. 14.2 years, P = 0.01) compared with those who survived. The unadjusted death rate in Thal was lower (2.2/100 person years) compared with that in Tx-SCD (7.0/100 person years; RR = 0.38: 95% CI 0.12-0.99). However, no difference was observed when age at death was considered. Despite improvements in therapy, death rate in this contemporary sample of transfused adult subjects with Thal or SCD is 3 times greater than the general US population. Long term follow-up of this unique cohort of subjects will be helpful in further defining the relationship of chronic, heavy iron overload to morbidity and mortality.
Abstract: Hypertransfusional (>8 transfusions/year) iron in liver biopsies collected immediately after transfusions in beta-thalassemia and sickle cell disease correlated with increased expression (RNA) for iron regulatory proteins 1 and 2 (3-, 9- to 11-fold) and hepcidin RNA: (5- to 8-fold) (each p <.01), while ferritin H and L RNA remained constant. A different H:L ferritin ratio in RNA (0.03) and protein (0.2-0.6) indicated disease-specific trends and suggests novel post-transcriptional effects. Increased iron regulatory proteins could stabilize the transferrin receptor mRNA and, thereby, iron uptake. Increased hepcidin, after correction of anemia by transfusion, likely reflects excess liver iron. Finally, the absence of a detectable change in ferritin mRNA indicates insufficient oxidative stress to significantly activate MARE/ARE promoters.
Abstract: BACKGROUND: Providing home care for a child with a chronic illness can be stressful for the family. The purpose of this paper is to examine patterns of caregiving and the associated psychological impact on maternal caregivers of children with sickle cell disease (SCD). PROCEDURE: Fourteen maternal caregivers of children with SCD were interviewed as part of a larger study of maternal caregivers of children with chronic illness. Forty-four caregivers of children with HIV and 36 caregivers of healthy children were included as comparison groups. Interviews included questions regarding amount of time spent providing care for the child (technical care, non-technical care, health care management), hospitalization, emergency room visits, illness stigma, and mental health of the caregiver. RESULTS: Children with SCD had significantly lower functional status and significantly more hospitalizations in the previous 3 months than children with HIV. Caregivers of children with SCD were more likely to work full-time and had higher incomes than caregivers of children with HIV. The three caregiving groups did not differ significantly on amount of total care, although caregivers of children with SCD and caregivers of children with HIV both reported significantly more time spent in technical care than caregivers of healthy children. Despite lower functional status of the children in the SCD group, when group comparisons on caregiving time variables were adjusted for child's functional status, the differences between groups increased. This appeared to be due to the fact that caregivers in the HIV group spent more time in all caregiving categories except skin, crisis, and other care. In terms of caregiver mental health, caregivers of children with HIV and SCD had significantly higher depressive mood scores than caregivers of healthy children but the groups did not differ on caregiving burden. CONCLUSIONS: The perceived care burden of caregivers of children with SCD may be related to the unpredictable nature of the crisis care they provide. Additional attention is warranted to developing adequate resources for caregivers of children with SCD to mitigate the stress of unexpected crises.
Abstract: BACKGROUND: Iron chelation therapy (ICT) with deferoxamine (DFO), the current standard for the treatment of iron overload in patients with transfusion-dependent disorders such as beta-thalassemia, requires regular subcutaneous or intravenous infusions. This can lead to reduced quality of life and poor adherence, resulting in increased morbidity and mortality in iron-overloaded patients with beta-thalassemia. Deferasirox is an orally administered iron chelator that has been approved for use in the United States, Switzerland, and other countries. OBJECTIVE: This analysis was conducted to compare patient-reported outcomes (PROs) during receipt of DFO infusions or once-daily oral therapy with deferasirox (ICL670). METHODS: PROs were prospectively evaluated as part of a randomized, Phase III study comparing the efficacy and safety profile of DFO 20 to 60 mg/kg per day with those of deferasirox 5 to 30 mg/kg per day in patients (age > or =2 years) with beta-thalassemia who were receiving regular transfusions and had a liver iron concentration of > or =2 mg/g dry weight. PRO questionnaires were completed by patients or a parent or legal guardian at baseline, week 4, week 24, and end of study (EOS). Patients assessed their level of satisfaction with study treatment (very satisfied, satisfied, neutral, dissatisfied, or very dissatisfied) and rated its convenience (very convenient, convenient, neutral, inconvenient, or very inconvenient). Time lost from normal activities due to ICT in the previous 4 weeks was recorded using a single global assessment. At week 4, patients who had previous experience with DFO were asked to indicate their preference for treatment (ICT received before the study, ICT received during the study, no preference, or no response) and the reason for that preference. At EOS, all patients were asked if they would be willing to continue using the ICT they had received during the study. All study analyses were performed in all patients who received at least 1 dose of study medication. RESULTS: Five hundred eighty-six patients (304 females, 282 males; age range, 2-53 years) received treatment with DFO (n = 290) or deferasirox (n = 296). Significantly more patients treated with deferasirox reported being very satisfied or satisfied with treatment compared with those treated with DFO (week 4: 92.0% vs 50.4%, respectively; week 24: 89.6% vs 44.0%; EOS: 85.1% vs 38.7%; all, P < 0.001). At the same time points, the majority of those treated with deferasirox reported that treatment was very convenient or convenient compared with those treated with DFO (95.5% vs 21.3%, 91.7% vs 17.4%, and 92.7% vs 11.3%, respectively; all, P < 0.001). Among patients who had previously taken DFO and were randomized to receive deferasirox during the study, 96.9% reported a preference for deferasirox over DFO. At EOS, the proportion of patients indicating a willingness to continue study therapy was significantly greater in those receiving deferasirox than in those receiving DFO (85.8% vs 13.8%; P < 0.001). CONCLUSIONS: In this study, patient-reported satisfaction and convenience were significantly higher for the once-daily, oral ICT deferasirox than for DFO infusions. Among patients who had received DFO before the study, the majority indicated a preference for deferasirox over DFO. Most patients receiving deferasirox indicated that they would be willing to continue taking it. These results suggest that deferasirox had a positive impact on patients' daily lives.
Abstract: Hemoglobin (Hb) E is one of the world's most common and important mutations. It results in a heterogeneous group of disorders whose phenotype range from asymptomatic to severe. Hb E trait and Hb EE are mild disorders. The combination of Hb E and Hb S (Hb SE) results in a sickle cell disease syndrome similar to sickle beta(+) thalassemia. It is important to distinguish Hb E disorders diagnostically because of this marked difference in clinical course among different genotypes. Screening tests, including hemoglobin electrophoresis and high-pressure liquid chromatography (HPLC), may suggest other mutations, unless one is familiar with the findings. E beta-thalassemia, the most serious form of E syndromes, affects a million people worldwide and is increasing in North America. Its phenotype ranges from mild anemia to severe transfusion-dependent thalassemia major. Several genetic modifiers affect the phenotype, including the type of beta-thalassemia mutation, Hb F levels, and co-inheritance of alpha-thalassemia. However, the cause of the phenotypic variability is largely unknown. A prospective natural history study of E beta-thalassemia in Sri Lanka suggests that environmental modifiers are prognostically important. The clinical course of E beta-thalassemia is punctuated by acute and chronic complications that may cause serious morbidity and mortality. Recent studies indicate these patients are at high risk for thromboembolism secondary to a hypercoagulable state increased by splenectomy. Morbidity from iron overload in nontransfused patients secondary to increased gastrointestinal iron absorption is common. Cardiopulmonary disease, including pulmonary hypertension, requires ongoing monitoring and is secondary to iron overload, thromboembolism, and hemolysis-induced nitric oxide deficiency. These patients are excellent candidates for Hb F-modulating agents because moderate changes in hemoglobin may result in marked improvement in phenotype. Recent studies with hydroxyurea indicate 40% of patients will clinically improve with hydroxyurea.
Abstract: Iron-overload associated endocrinopathy is the most frequently reported complication of chronic transfusion therapy in patients with thalassaemia (Thal). This study compared iron-overloaded subjects with Thal (n = 142; 54%M; age 25.8 +/- 8.1 years) and transfused sickle-cell disease (Tx-SCD; n = 199; 43%M, 24.9 +/- 13.2 years) to non-transfused SCD subjects (non-Tx-SCD; n = 64, 50%M, 25.3 +/- 11.3 years), to explore whether the underlying haemoglobinopathy influences the development of endocrinopathy. Subjects were recruited from 31 centres in the USA, Canada and the UK. Subjects with Thal had more evidence of diabetes (13% vs. 2%, P < 0.001), hypogonadism (40% vs. 4%, P < 0.001), hypothyroidism (10% vs. 2%, P = <0.001) and growth failure (33% vs. 7%, P < 0.001), versus Tx-SCD. Fifty-six per cent of Thal had more than one endocrinopathy compared with only 13% of Tx-SCD (P < 0.001). In contrast, Tx-SCD was not different from non-Tx-SCD. Multivariate analysis indicated that endocrinopathy was more likely in Thal than SCD [Odds Ratio (OR) = 9.4, P < 0.001], with duration of chronic transfusion a significant predictor (OR = 1.4 per 10 years of transfusion, P = 0.04). Despite iron overload, endocrinopathy was not increased in Tx-SCD versus non-Tx-SCD, suggesting that the underlying disease may modulate iron-related endocrine injury. However, because transfusion duration remained a significant predictor of endocrinopathy, these data should be confirmed in SCD subjects that have been chronically transfused for longer periods of time.
Abstract: BACKGROUND: Osteonecrosis of the femoral head is a common complication in patients with sickle cell disease, and collapse of the femoral head occurs in 90% of patients within five years after the diagnosis of the osteonecrosis. However, the efficacy of hip core decompression to prevent the progression of osteonecrosis in these patients is still controversial. METHODS: In a prospective multicenter study, we evaluated the safety of hip core decompression and compared the results of decompression and physical therapy with those of physical therapy alone for the treatment of osteonecrosis of the femoral head in patients with sickle cell disease. Forty-six patients (forty-six hips) with sickle cell disease and Steinberg Stage-I, II, or III osteonecrosis of the femoral head were randomized to one of two treatment arms: (1) hip core decompression followed by a physical therapy program or (2) a physical therapy program alone. Eight patients withdrew from the study, leaving thirty-eight who participated. RESULTS: Seventeen patients (seventeen hips) underwent decompression combined with physical therapy, and no intraoperative or immediate postoperative complications occurred. Twenty-one patients (twenty-one hips) were treated with physical therapy alone. After a mean of three years, the hip survival rate was 82% in the group treated with decompression and physical therapy and 86% in the group treated with physical therapy alone. According to a modification of the Harris hip score, the mean clinical improvement was 18.1 points for the patients treated with hip core decompression and physical therapy compared with 15.7 points for those treated with physical therapy alone. With the numbers studied, the differences were not significant. CONCLUSIONS: In this randomized prospective study, physical therapy alone appeared to be as effective as hip core decompression followed by physical therapy in improving hip function and postponing the need for additional surgical intervention at a mean of three years after treatment.
Abstract: The pathogenesis of pulmonary hypertension (PAH), a serious complication in thalassemia, is not well understood. Thromboembolism has been postulated as one of the causative factors; however, there are currently limited specific data on its role. To examine whether increased platelet activation and hypercoagulability are linked to PAH, 25 beta-thalassemia major and beta-thalassemia intermedia patients were evaluated with Doppler echocardiograms for estimation of pulmonary artery pressure and with laboratory assays for indications of a prothrombotic state. The association of clinical variables and abnormal coagulation assays with PAH was determined. PAH was identified in 17 (68%) patients; mean pulmonary artery systolic pressure was 39.8 +/- 5.4 mm Hg. PAH was significantly associated with prior splenectomy, older age, and evidence for chronic hemolysis, diagnosed in both transfused (n = 10) and nontransfused (n = 7) patients. Increased platelet activation, measured by P-selectin, was significantly associated with PAH (P = 0.001). Increased thrombin-antithrombin III level was more prevalent in the presence of PAH, but increased fibrinolysis or low protein C levels were not. This study underscores the role of platelet activation in the development of PAH and stresses its occurrence even among patients who are regularly transfused, especially those who are older and have had splenectomies.
Abstract: Historically, fractures are cited as a frequent problem in patients with Thalassemia prior to optimization of transfusion and chelation regimens. The aim of this study was to determine the prevalence of fractures in a contemporary sample of North American patients with Thalassemia. The North American Thalassemia Clinical Research Network (TCRN) database registry was used to gather historical data on 702 patients with common alpha and beta-Thalassemia diagnoses including Thalassemia Major (TM), Intermedia (TI), E/Beta, homozygous alpha Thalassemia (AT), Hemoglobin H disease (HbH) and HbH with Constant Spring (HbH/CS), who consented to a medical record chart review. Bone mineral density (BMD) measurements by DXA were available for review in a subgroup of patients (n = 312). The overall fracture prevalence among all Thalassemia syndromes was 12.1%, equally distributed between females (11.5%) and males (12.7%). Fractures occurred more frequently in TM (16.6%) and TI (12.2%) compared to E/Beta (7.4%) and alpha (2.3%). Prevalence increased with age (2.5% ages 0-10 years, 7.4% ages 11-19 years, 23.2% ages >20 years) and with use of sex hormone replacement therapy (SHRT) (P < 0.01). On average, BMD Z and T scores were 0.85 SD lower among patients with a history of fractures (mean Z/T score -2.78 vs. -1.93, 95% CI for the difference -0.49 to -1.22 SD, P = 0.02). Presence of other endocrinopathies (i.e. hypothyroidism, hypoparathyroidism and diabetes mellitus), anthropometric parameters, heart disease or hepatitis C were not significant independent predictors of fractures. These data indicate that fractures remain a frequent complication among the aging patients with both TM and TI beta-Thalassemia. However, the fracture prevalence has improved compared to published reports from the 1960s to 1970s. In addition, children with Thalassemia appear to have low fracture rates compared to the general population.
Abstract: OBJECTIVES: To evaluate knowledge, perceptions and the effectiveness of different sources of information about sickle cell trait (SCT) and sickle cell disease (SCD); to determine individual knowledge of SCT status. METHODS: 28 individuals participated in three focus groups (healthcare providers, people affected by SCD or SCT, and community members). Surveyors interviewed 282 respondents within their neighborhoods. RESULTS: Common themes across the focus groups included the limited general awareness of SCD and SCT, the emphasis on the benign nature of SCT rather than on future implications, and the need for public health education campaigns about SCD and SCT involving media strategies. The majority of community survey respondents (n = 243, 86.2%) had correct general knowledge about the genetic basis and severity of SCD, but only 16% (n = 45) knew their own trait status. When respondents had received information about SCD from friends and acquaintances, they were three times more likely to know their SCT status, compared with respondents who had not received information from a personal source (p < 0.01). CONCLUSIONS: Despite a screening history in the 1970s fraught with controversy, sickle cell disease management and detection can be a model for the empowerment of communities in making informed decisions about theirs and their families' futures, given the burgeoning of genetic information.
Abstract: Blood transfusion therapy is life-saving for patients with beta-thalassaemia and sickle cell disease (SCD), but often results in severe iron overload. This pilot study examined whether the biomarkers of tissue injury or inflammation differ in these two diseases. Plasma malondialdehyde (MDA) was significantly increased 1.8-fold in thalassaemia relative to control patients. In contrast, MDA in SCD was not significantly different from controls. In multivariate analysis, the strongest predictors of elevated MDA were liver iron concentration (P < 0.001) and specific diagnosis (P = 0.019). A significant 2-fold elevation of non-transferrin bound iron (NTBI) was observed in thalassaemia relative to SCD. NTBI was not a significant predictor of high MDA in multivariate analysis. SCD patients showed a significant 2.2-fold elevation of the inflammatory marker interleukin (IL)-6 relative to controls, and a 3.6- and 1.7-fold increase in IL-5 and IL-10 relative to thalassaemia. Although alpha-tocopherol was significantly decreased by at least 32% in both thalassaemia and SCD, indicating ongoing oxidant stress and antioxidant consumption, gamma-tocopherol, a nitric oxide-selective antioxidant, was increased 36% in SCD relative to thalassaemia. These results demonstrate that thalassaemia patients have increased MDA and circulating NTBI relative to SCD patients and lower levels of some cytokines and gamma-tocopherol. This supports the hypothesis that the biology of SCD may show increased inflammation and increased levels of protective antioxidants compared with thalassaemia.
Abstract: Advances in molecular diagnostics have led to an increased interest in expanding population-based screening to include genetic diseases that occur outside the newborn period. Hereditary hemochromatosis may be a candidate for large-scale screening in populations with a high prevalence of the common HFE mutations. To determine race-specific frequencies of the HFE mutations, C282Y and H63D, the authors applied an automated, high-throughput genotyping method to dried blood spot samples from a representative population of California newborns. In this sample of 3989 newborns, C282Y and H63D allele frequencies were highest in white (C282Y: 5.5 +/- 0.5%; H63D: 13.4 +/- 0.76%) and Hispanic (C282Y: 1.8 +/- 0.29%; H63D: 11.9 +/- 0.72%) newborns, and lowest in black (C282Y: 1.3 +/- 0.25%; H63D: 3.0 +/- 0.38%) and Asian (C282Y 0.5 +/- 0.16%; H63D 2.9 +/- 0.37%) newborns. The estimated prevalence of C282Y homozygotes in this multiracial population is 1.4/1000. As additional genetic and environmental risk factors for HHC are identified, neonatal screening may become an acceptable strategy to follow susceptible individuals and prevent clinical disease.
Abstract: Pulmonary hypertension is common in adults with thalassaemia and other haemolytic anaemias. It was hypothesised that regular transfusions in thalassaemia major should both decrease the chronic haemolytic rate and be protective from pulmonary hypertension (PHT). To reduce the contribution of existing cardiac disease to PHT, the subjects were limited to patients with normal left ventricular shortening fractions. Associations with multiple laboratory markers of haemolysis, serum ferritin levels, chest X-rays findings and splenectomy status were also considered. We found no biochemical, transfusional, or clinical (except gender) differences in transfused thalassaemia patients with or without pulmonary hyper tension.
Abstract: STUDY OBJECTIVE: To determine the dose tolerance, safety, and pharmacokinetics of a single oral dose of ICA-17043 in patients with sickle cell disease. DESIGN: Phase I, randomized, double-blind, placebo-controlled, single-dose, dose-escalation study. SETTING: Four university medical centers. PATIENTS: Twenty-eight patients with sickle cell disease, aged 18-60 years, who were otherwise healthy and in a noncrisis state. INTERVENTION: Patients in three separate dose cohorts--50 mg, 100 mg, and 150 mg--received single doses of ICA-17043 or placebo. MEASUREMENTS AND MAIN RESULTS: The mean area under the concentration-time curve from time zero extrapolated to infinity (AUC(0-infinity)) for ICA-17043 increased in a dose-related manner (11,827, 19,697, and 30,676 ng.hr/ml for 50, 100, and 150 mg, respectively). Overall mean half-life was 12.8 days. Mean peak plasma concentrations rose between the 50- and 100-mg dose levels but plateaued at 150 mg (59.1, 108.7, and 109.1 ng/ml, respectively). Weekly pharmacokinetic and safety assessments were conducted in each patient during the follow-up phase for 56 days. No dose-limiting adverse events were noted in any of the patients. CONCLUSION: Total systemic exposure of ICA-17043 after a single oral dose, as measured by AUC(0-infinity), increased nearly proportionally with the dose. The rate of absorption, however, appeared to be delayed at doses greater than 100 mg. With the long half-life of ICA-17043 demonstrated in this study, once-daily dosing is probably adequate to maintain steady-state plasma concentrations. In addition, single doses of ICA-17043 were well tolerated.
Abstract: PURPOSE: We evaluated bone mineral density (BMD) and risk factors for poor bone mineralization in children with sickle cell anemia (SCA). PATIENTS AND METHODS: Twenty-five children with severe manifestations of SCA (frequent hospitalizations, growth delay, or need for chronic red cell transfusions) were enrolled. Bone density was assessed at lumbar spine and proximal femur with dual-energy X-ray absorptiometry (DXA), and Z-scores were calculated by comparison with age, sex, and ethnicity-specific reference data. RESULTS: The median age of the study population was 12.8 years (10.2-19.8 years). Calcium intake was inadequate in 60%, and serum 25-hydroxy vitamin D (25-OHD) level <50 nM in 74% of patients. Median Z-scores for lumbar spine (-2.3) and proximal femur (-1.7) were markedly reduced, and 64% (95% confidence interval, 43%-82%) of patients had low bone density. Z-scores were not related to age, growth delay, chronic transfusions, or ferritin level. CONCLUSION: Our results suggest that children with severe manifestations of SCA have low BMD, and possess significant deficits in dietary calcium and circulating vitamin D.
Abstract: OBJECTIVE: To establish the validity and reliability of the Children's Hospital Oakland Hip Evaluation Scale (CHOHES), a modification of the Harris Hip Score, for the evaluation of avascular necrosis (AVN) in sickle cell disease (SCD). DESIGN: Nonrandomized test-retest. SETTING: Outpatient clinic. PARTICIPANTS: Forty patients with SCD and 3 healthy controls participated. Twenty-six SCD patients (15 males, 11 females; mean age, 25 y) had been diagnosed with AVN. This group was compared with 14 SCD patients without AVN and 3 healthy controls (8 males, 9 females; mean age, 16 y). INTERVENTION: On average, subjects were assessed by 2 physical therapists by using the CHOHES on 3 separate outpatient visits within a 2-week period. MAIN OUTCOME MEASURES: A mixed model with random effects was constructed to compare patient scores on the CHOHES with disease severity as estimated by Ficat staging on plain radiographs. Correlations between and within physical therapists using the CHOHES were calculated to assess intra- and interrater reliability. RESULTS: From the random effects model, the CHOHES mean score was 88 for Ficat stage 0, 75 for Ficat stage I or II, and 61 for Ficat stages III or IV (P < .05). Intrarater reliability estimates for the total CHOHES score were very good (r > or = .87) as were interrater reliability estimates (r > or = .90) between therapists who measured hips with a wide range of CHOHES scores. CONCLUSIONS: The CHOHES appears to be an easy-to-use, valid, and reliable assessment tool and should be considered for use in the routine clinical evaluation of SCD patients with AVN.
Abstract: Patients with E/beta(0) thalassaemia, the most common haemoglobinopathy in many Asian countries, might benefit from drugs that increase fetal and total haemoglobin and thereby decrease the need for transfusions. The long-term clinical efficacy and safety of such therapy is unknown, limiting its use in countries where resources for safe and regular transfusion are scarce. In this study, 45 patients were treated with hydroxyurea (18-20 mg/kg) for 24+/-9 months, hydroxyurea with sodium phenyl butyrate (n=8) and hydroxyurea with erythropoietin (n=9), each for approximately 6 months, and followed for 3 years from study exit. Hydroxyurea had minimal toxicity, resulted in a mean 1.3 g/dl steady-state increase in haemoglobin in 40% of patients, and a milder response (<OR=1 g/dl) in the others. Baseline haemoglobin F was significantly associated with an increase in haemoglobin (P<0.001). Combined treatment with erythropoietin benefited selected patients, but the addition of sodium phenyl butyrate had no effect. Of the 27/45 patients who discontinued regular transfusions before the study, 13 remained transfusion independent during long-term follow-up, 6/13 continued hydroxyurea. Hydroxyurea moderately increased steady-state haemoglobin in a sub-group of E/beta(0) thalassaemia patients and can be considered for patients with intermediate severity disease, thus delaying or avoiding the need for life-long transfusions. Continuous monitoring of toxicity and growth is required.
Abstract: OBJECTIVE: Changing patterns of immigration to North America, along with improved treatment, have altered the clinical spectrum of thalassemia, one of the world's most common genetic diseases. The new demography of the disease, with its widely variable phenotypes, has implications for its diagnosis, counseling, and management. Characterization of the new spectrum of this ancient disease, now predominated by minority groups, is essential for optimizing survival. METHODS: The National Institutes of Health-sponsored North American Thalassemia Clinical Research Network (TCRN) conducted a cross-sectional study of 721 patients with thalassemia syndromes. A detailed chart review was undertaken to define the relationships between ethnic origins, genotype, and phenotype. These results were compared with 3 previous surveys of similar regions. To determine if the TCRN patient epidemiology is representative of North American patients, 87 additional programs were reviewed, and hemoglobinopathy programs from the 2 largest thalassemia regions, Ontario and California, were analyzed. RESULTS: A total of 721 patients completed analysis in the TCRN study, including 389 (54%) patients with beta-thalassemia major, 105 (15%) patients with beta-thalassemia intermedia, 95 (13%) patients with hemoglobin E-beta-thalassemia, and 132 (18%) patients with alpha-thalassemia. beta-Thalassemia predominated in Eastern North America. Hemoglobin E-beta-thalassemia and alpha-thalassemia were common on the Western continent. Genotype broadly correlated with the clinical phenotype. However, there was marked heterogeneity in clinical phenotype among patients with similar globin mutations. In beta-thalassemia disorders, coinheritance of the alpha-thalassemia trait, triplication of alpha-thalassemia genes, and heterozygosity for the dominant beta-thalassemia allele affected the clinical phenotype. In alpha-thalassemia disorders, structural mutations such as hemoglobin H-Constant Spring resulted in a severe hemoglobin H phenotype. Sixty percent of patients received regular transfusions, and 86% received regular iron-chelation therapy. Increased survival and decreasing birth rates of Mediterranean patients resulted in an aging Greek/Italian population being replaced by a young Asian/Middle Eastern population. Now, Asian patients account for >50% of the thalassemia population. Evidence of increasing survival is reflected in an advancing mean age of white patients with thalassemia major (25 years, up from 11 years in 1974). The results of the non-TCRN thalassemia survey confirm these observations and describe a young multiethnic thalassemia population distributed throughout North America. Newborn-screening results suggest that thalassemia births in North America are increasing and reflect the change in genotype and phenotype observed in the TCRN populations. CONCLUSIONS: The epidemiology of thalassemia in North America reflects a heterogeneous group of diseases with new ethnicities, genotypes, and phenotypes. In these communities, physicians will need to provide education, prenatal diagnosis, counseling, and management of this newly diverse group of patients.
Abstract: A long-term observational study of Hb E-beta-thalassemia in Sri Lanka is beginning to define some of the genetic and environmental factors that are responsible for its remarkable phenotypic variability. In this population there is a very small difference between the steady-state hemoglobin levels between the mild and severe phenotypes, and it has been possible to stop transfusion in many of those who have been on long-term treatment of this kind. These preliminary observations, made over the last 7 years, provide directions for future research into this increasingly important disease.
Abstract: BACKGROUND AND PURPOSE: Ischemic stroke occurs in at least 11% of patients with homozygous sickle cell anemia (SCD) by the time they turn 20 years old. High risk associated with distal intracranial internal carotid (ICA) and proximal middle cerebral artery (MCA) stenosis can be detected by transcranial Doppler (TCD). TCD screening offers the possibility of reducing the risk of first stroke significantly based on a paradigm tested and proven to be effective in a stroke prevention trial in sickle cell anemia (STOP). Children with high flow velocity in the ICA and MCA of 200 cm/s time average mean of the maximum (TAMM) or higher had a 10% per year risk of first stroke that was reduced to <1% with regular red cell transfusion (reduction of hemoglobin S <30%). The clinical application of the STOP results could be enhanced if criteria for treatment could be found that are based on peak systolic velocity (PSV), the measure more commonly used in vascular ultrasound practice. OBJECTIVE: To compare PSV and end diastolic velocity (EDV) with TAMM for prediction of stroke and to derive PSV cutpoints for STOP protocol definitions of conditional and abnormal TCD. Using the STOP TCD and stroke outcome data to compare PSV and TAMM in terms of stroke prediction, PSV cutpoints comparable to those based on TAMM and used in STOP were derived. Because of their familiarity to the vascular ultrasound community, PSV cutpoints should be an important alternative to TAMM and may increase availability of screening and risk stratification for children with this disease. MATERIALS AND METHODS: Data from 1,937 baseline TCD studies from STOP were correlated with stroke outcome in those not treated with transfusion. Stroke prediction was assessed with survival analysis using TAMM, PSV and EDV as continuous variables individually and then pair-wise in the same model, which contained 53 stroke events. RESULTS: PSV and EDV were highly correlated to the TAMM velocity (r=0.94). The multivariate model for prediction indicated that TAMM velocity was a better predictor than EDV, and PSV and TAMM were approximately equivalent. PSV cutpoints defining the two relevant STOP risk categories--"conditional," which should lead to increased TCD surveillance, and "abnormal," which should lead to strong consideration for treatment according to STOP--were derived taking into consideration known differences in measurements between the dedicated Doppler systems (TCD) used in STOP and the transcranial Doppler imaging (TCDI) systems commonly used in clinical practice. The recommended PSV cutpoint for conditional TCD is 200 cm/s, and for abnormal TCD triggering consideration for treatment is 250 cm/s. CONCLUSION: Assuming TCDI equipment is used and the STOP protocol is applied, a PSV cutpoint of 200 cm/s is recommended as the threshold for increased TCD surveillance (comparable to a TCD TAMM of 170 cm/s in STOP); a PSV of 250 cm/s is recommended as the cutpoint at which, if confirmed in a second examination, chronic transfusion should be considered. Assuming the STOP scanning protocol is used, PSV is at least as good as TAMM and can be used to select children with SCD for treatment or increased surveillance to prevent first stroke.
Abstract: Bone and joint disorders are the most common cause of chronic pain in patients who have sickle cell disease. The femoral head is the most common area of bone destruction in sickle cell patients, although other disease-related problems include avascular necrosis of the humeral head, changes in the thoracic and lumbar spine, infection with encapsulated organisms (Salmonella and Staphylococcus aureus are the most common), bone marrow disturbances, and dental effects. Complications can occur at any location: epiphyseal, metaphyseal, or diaphyseal. The location and the extensiveness of the problems determine the pain and structural damage. The hip joint is particularly vulnerable in sickle cell disease. This article highlights aspects of sickle cell disease that affect healthy bone and joint function and discusses treatment options.
Abstract: Although it is life saving, transfusion therapy has resulted in the majority of sickle cell anemia and thalassemia patients being at risk for hemosiderosis-induced organ damage. It is unknown whether the complications of iron overload are affected by the underlying disease. In order to address this problem, we compared the prevalence of organ dysfunction in both groups of patients receiving chronic transfusion therapy (beta thalassemia, N = 30; sickle cell anemia, N = 43). Both groups had similar quantitative liver iron. Thalassemia patients had greater cardiac disease (20% vs. 0%), growth failure (27% vs. 9%), and endocrine failure (37% vs. 0%). The strongest predictors of combined endocrine and cardiac disease in multivariate analysis were duration of chronic transfusion (P = 0.03) and diagnosis (P = 0.03). Quantitative liver iron concentration on a single liver biopsy was not predictive of cardiac or endocrine injury. Viral hepatitis is the strongest predictor of hepatocellular damage (P = 0.009), while the development of liver fibrosis is more closely related to liver iron concentration (P = 0.04). In conclusion, sickle cell anemia and thalassemia differ in the prevalence of organ injury. This difference is related to the duration of iron exposure and the specific hemoglobinopathy. A prospective study with a larger number of subjects is needed to confirm the relationships between specific diagnosis, liver iron concentration over time, and organ dysfunction.
Abstract: In patients with sickle cell disease or beta-thalassemia receiving RBC transfusions for a long period, a precise knowledge of the liver iron concentration (LIC) is essential for treatment. Patients underwent LIC and liver pathology assessment by duplicate biopsies in 2 passes from the same local liver site. Fresh tissue cores in trace element-free containers and tissues from dissolved paraffin-embedded cores were analyzed. LIC measurements in each of 2 paraffin-embedded cores did not differ significantly (median, 12,455 vs 12,153 microg/g dry weight; n = 29). A significant difference was observed when 1 fresh tissue sample and 1 paraffin-embedded core were analyzed (median, 11,716 vs 12,864 microg/g dry weight; n = 16; P < .001) with a median disagreement between LIC measurements of 23.0%. We found high agreement in LICs between liver biopsy specimens processed by the paraffin-embedding technique but overestimation of LICs in comparison with desiccated fresh tissue samples.
Abstract: BACKGROUND: We hypothesized that child cognitive disability would be a significant risk factor for non-adherence with home deferoxamine (DFO) administration and that a factor that would contribute to improved adherence would be sharing of responsibilities for chelation between parents and patients. We explored the influences on adherence of behavioral and psychological adjustment; family stress; perceived convenience of and satisfaction with the DFO regimen; and parent and patient knowledge about DFO. PROCEDURE: Fifteen pediatric patients with sickle cell disease (SCD) who had evidence of excessive iron stores, and their parents, were interviewed about adherence and responsibility for chelation therapy. A neuropsychological assessment battery was administered to the patients. Family stress, the child's emotional and behavioral status, knowledge about chelation and iron overload were explored. Adherence was rated objectively using pharmacy refill patterns and observable signs of chelation. RESULTS: Sharing of responsibilities for chelation between parents and children was related to better adherence while neuropsychological status bore a complex relation to adherence. Of the exploratory variables, low family stress were related to better adherence while satisfaction with the home care regimen and convenience ratings were not useful in predicting adherence. No one element of adherence, even objective measures, was capable of classifying adherence, while a multifactorial scheme categorizing adherent, partially adherent and non-adherent groups demonstrated good face validity. CONCLUSIONS: Supporting developmentally appropriate sharing of responsibilities for self-care is critical, taking patient neurocognitive status into consideration. Clinicians should evaluate adherence using a multifactorial model that highlights the most salient targets for intervention.
Abstract: CONTEXT: Sickle cell disease is characterized by a state of nitric oxide resistance and limited bioavailability of l-arginine, the substrate for nitric oxide synthesis. We hypothesized that increased arginase activity and dysregulated arginine metabolism contribute to endothelial dysfunction, pulmonary hypertension, and patient outcomes. OBJECTIVE: To explore the role of arginase in sickle cell disease pathogenesis, pulmonary hypertension, and mortality. DESIGN: Plasma amino acid levels, plasma and erythrocyte arginase activities, and pulmonary hypertension status as measured by Doppler echocardiogram were prospectively obtained in outpatients with sickle cell disease. Patients were followed up for survival up to 49 months. SETTING: Urban tertiary care center and community clinics in the United States between February 2001 and March 2005. PARTICIPANTS: Two hundred twenty-eight patients with sickle cell disease, aged 18 to 74 years, and 36 control participants. MAIN OUTCOME MEASURES: Plasma amino acid levels, plasma and erythrocyte arginase activities, diagnosis of pulmonary hypertension, and mortality. RESULTS: Plasma arginase activity was significantly elevated in patients with sickle cell disease, with highest activity found in patients with secondary pulmonary hypertension. Arginase activity correlated with the arginine-ornithine ratio, and lower ratios were associated with greater severity of pulmonary hypertension and with mortality in this population (risk ratio, 2.5; 95% confidence interval [CI], 1.2-5.2; P = .006). Global arginine bioavailability, characterized by the ratio of arginine to ornithine plus citrulline, was also strongly associated with mortality (risk ratio, 3.6; 95% CI, 1.5-8.3; P<.001). Increased plasma arginase activity was correlated with increased intravascular hemolytic rate and, to a lesser extent, with markers of inflammation and soluble adhesion molecule levels. CONCLUSIONS: These data support a novel mechanism of disease in which hemolysis contributes to reduced nitric oxide bioavailability and endothelial dysfunction via release of erythrocyte arginase, which limits arginine bioavailability, and release of erythrocyte hemoglobin, which scavenges nitric oxide. The ratios of arginine to ornithine and arginine to ornithine plus citrulline are independently associated with pulmonary hypertension and increased mortality in patients with sickle cell disease.
Abstract: Accumulating evidence supports the existence of a condition involving hemolysis-associated pulmonary hypertension (PHT). Hemolysis-induced release of cell-free hemoglobin and red blood cell arginase, resulting in impaired nitric oxide bioavailability, endothelial dysfunction, and PHT, has been reported in sickle cell disease. Since thalassemia is also a condition of chronic hemolysis, these patients are at risk. The data demonstrate that hemolysis-induced dysregulation of arginine metabolism and PHT also occurs in thalassemia. Erythrocyte release of arginase during hemolysis contributes to the development of PHT. Therapies that maximize arginine and nitric oxide bioavailability may benefit patients with thalassemia.
Abstract: Iron-mediated oxidative stress plays an important role in the pathophysiology of thalassemia. Oxidative stress can cause lesions in DNA, including double-strand breaks. DNA damage, which is a cause of cancer (although not the only one), is recognized as deleterious. Unlike cancer, DNA damage can be assayed easily and relatively inexpensively in humans. In this study, a sensitive micronucleus assay was used to measure the frequency of chromosomal breaks in patients with alpha- and beta-thalassemia. The micronucleus test is based on the observation that a secondary nucleus (micronucleus) is formed around a chromosomal fragment, outside the main nucleus of a dividing cell. Micronuclei are readily apparent in red blood cells (RBCs), which otherwise lack DNA. We combined an immunomagnetic separation technique with single-laser flow cytometry to isolate and analyze reticulocytes in peripheral blood for the presence of micronuclei before these cells are removed by the spleen. Blood samples were obtained from patients with thalassemia and healthy volunteers. After immunomagnetic enrichment of CD71-positive reticulocytes, the cells were stained for micronuclei using the DNA dye 7-aminoactinomycin D (7-AAD) and evaluated by flow cytometry. Our findings indicate that higher levels of micronuclei frequencies are present in thalassemic RBCs.
Abstract: The impact of thalassemia major and thalassemia intermedia and their associated complications on quality of life (QOL) is largely unknown. Determining the degree of health impairment as perceived by the patient is essential information needed to recommend suitable therapy. The objective of this study was to evaluate QOL in transfusion-independent patients with thalassemia (non-Tx) compared with that in transfused patients (Tx) and to identify the factors that affect QOL in thalassemia. A convenient sample of 48 thalassemia patients (29 Tx and 19 non-Tx) with mean age of 14.6 years (SD = 7.5 years) were selected during a comprehensive visit to complete a Dartmouth Primary Care Cooperative Information Chart System (COOP) questionnaire. Patients rated QOL from excellent (1) to poor (5) on five dimensions of health status. Scores of 4 or 5 represent major limitations. These results were augmented by a brief medical history and chart review. Forty-one percent of Tx patients and 47% of non-Tx patients reported severe impairments in 1-6 and 1-2 domains, respectively. The most commonly reported affected domains were feelings such as anxiety, depression, and concern of overall health status or indications of recent deterioration in health. In contrast with previous beliefs, transfusion-independent thalassemia patients also suffer serious impairment in QOL. Presented data suggest that all patients with thalassemia undergo QOL assessment so that interventions focused on affected domains can be implemented.
Abstract: Thalassemia is a growing global public health problem with an estimated 900,000 births of clinically significant thalassemia disorders expected to occur in the next 20 years. This growth will occur in disorders previously uncommon in many parts of the world. In particular, hemoglobin (Hb) E-beta-thalassemia and Hb H disease account for much of the projected increases in thalassemia. Worldwide, Hb E-beta-thalassemia is one of the most frequent hemoglobinopathies. The incidence of Hb E approaches 60% of the populations in many regions of Southeast Asia. In coastal regions of North America, its prevalence is rapidly growing. The severity of Hb E-beta-thalassemia ranges from a complete lack of symptoms to transfusion dependence. alpha-Thalassemia diseases, often considered benign, are now recognized to be more severe than originally reported. Hb H, Hb H-Constant Spring (CS), and homozygous alpha-thalassemia affect at least a million people worldwide. California considers Hb H disease a public health problem and has initiated a neonatal screening program for Hb H and particularly Hb H-CS. Homozygous alpha-thalassemia, usually fatal, is also being more commonly detected. Several regions have initiated universal prenatal screening programs to address homozygous alpha-thalassemia. In summary, the prognosis for thalassemia disorders is improving, but prenatal diagnosis and neonatal screenings are needed. Comprehensive services that address language and social barriers as well as access to Hb F-enhancing agents and transfusions are needed.
Abstract: Cardiac arrhythmias are among the leading causes of morbidity and mortality of transfusion-dependent, iron-overloaded beta-thalassemia patients. Routine screening with Holter electrocardiogram has been recommended; however, infrequent electrocardiographic changes limit its clinical usefulness. The purpose of this study was to determine the diagnostic yield of Holter electrocardiogram monitoring and its correlation with patient symptoms and disease status. A retrospective analysis was performed on 27 transfusion-dependent thalassemia patients who underwent cardiac questionnaire and Holter screening yearly, in addition to echocardiogram and quantitative iron-level determination. Four patients had clinically significant arrhythmias detected on Holter screening, while 2 patients developed severe cardiac complications secondary to arrhythmias within 1 year of follow-up of normal Holter screening. Early detection of cardiac events among transfusion-dependent thalassemia patients with Holter electrocardiography is not clinically effective. Other screening modalities, including the transtelephonic event recorder, should be evaluated in arrhythmia surveillance.
Abstract: Adherence to deferoxamine (DFO) is vital for the long-term survival of patients with thalassemia; however, currently no measure exists to quantify adherence directly. In this study, 90 patients with thalassemia major underwent liver iron concentration (LIC) assessment by SQUID biosusceptometer, were asked to rate their adherence to DFO using a Numerical Likert Scale (NLS), and were educated about complications of iron overload. Of 38% (n = 28) of patients who rated themselves as very compliant, 19 had elevated LIC related to inadequate dosing of DFO and nine reported nonadherence in the past. Adherence improved after counseling and LIC decreased by 25% (7-60%) in eight previously noncompliant patients who returned for subsequent LIC over 15 months. In conclusion, the NLS seems to be a simple but reliable tool to assess patients' adherence to DFO. Education and frequent noninvasive LIC assessments can improve adherence and iron burden. Elevated LIC does not necessarily reflect concurrent noncompliance; however, it can be an indication of nonadherence in the past.
Abstract: Patients with hemoglobin E (Hb E)-beta 0-thalassemia, one of the most common hemoglobinopathies worldwide, could benefit from drugs that increase fetal and total hemoglobin levels and thereby decrease the need for transfusions. The long-term clinical outcome of such therapy, its hematologic effects, and which patients are likely to benefit from treatment are unknown. Consequently, the use of such drugs for Hb E-beta 0-thalassemia is limited, and countries where resources for safe and regular transfusion are scarce cannot benefit from them. In a multicenter trial of 42 patients treated with hydroxyurea for two years, almost half the patients demonstrated a significant increase in steady-state hemoglobin level. Drug toxicity was minimal. Combined treatment of hydroxyurea with erythropoietin benefited selected patients, but the addition of sodium phenyl butyrate was ineffective. After 5 years of follow-up, a subset of patients remained off transfusions. Hydroxyurea should be considered for a subset of Hb E-beta 0-thalassemia patients.
Abstract: Treatment of hepatitis C virus (HCV) in the general population has improved over the last decade. Patients treated with peginterferon alfa (PegIFN) and ribavirin (RBV) combination therapy demonstrate overall 50-55% sustained viral response (SVR) with rates as high as 80% in patients with genotypes 2 and 3. Because RBV induces hemolysis and subsequently increases blood transfusion requirements, combination therapy has been considered contraindicated for hemoglobinopathies. This report reviews the response to interferon alfa and RBV (IFN/RBV) and PegIFN/RBV combination therapies in patients treated in the Northern California Comprehensive Thalassemia Center. A total of six thalassemia major patients were treated with IFN/RBV (n = 5; age: 4-38 years) or with PegIFN/RBV (n = 1; age: 26 years). Quantitative HCV RNA polymerase chain reaction and liver iron level assessment were completed. Transfusion volumes were obtained from patients' medical records. On IFN/RBV combination, four of five patients demonstrated SVR. The one patient on PegIFN/RBV showed end-treatment viral response after 6 months of therapy (genotype 3), but subsequently relapsed. Liver iron pretreatment level ranged from 0.2 to 22 mg/g dry weight, with a mean +/- SD of 7.9 +/- 7.7. Transfusion requirement increased by a median of 43.5% (range: 32-137%). Five of the six patients had liver iron measurements within 1 year following completion of treatment, with quantitative liver iron increasing in two patients by 2.5 mg/g dry weight, decreasing in two patients by 3 and 14 mg/g dry weight, and remaining unchanged in one patient. All patients were able to complete combination therapy, although dose reductions were required. Patients with thalassemia and high iron overload can obtain SVR after combination therapy with rates similar to those in the general population and without significant complications. Although transfusion requirements increased in most patients, iron burden was not necessarily increased.
Abstract: Thalassemia is one of the most common single-gene disorders that can be cured by hematopoietic stem cell transplantation (HCT) from a human leukocyte antigen (HLA)-identical sibling donor. In families that have an affected child, preimplantation genetic diagnosis (PGD) can be used to select an unaffected, HLA-identical embryo. In brief, this procedure requires in vitro fertilization, oocyte retrieval, fertilization, and blastomere biopsy for identification of unaffected HLA-identical embryos. After delivery, umbilical cord blood from the sibling donor is collected for HCT. The objective of this study was to determine the outcomes of families using PGD therapy for cure of beta-thalassemia and to review the limitations of PGD therapy. Families affected with beta-thalassemia who attempted PGD therapy were retrospectively identified and reviewed for indication, attempted cycles, successful pregnancy, and transplantation outcomes. Eight identified families affected by thalassemia underwent PGD. The diagnosis of their affected children included six cases of beta-thalassemia major and two cases of transfusion-dependent hemoglobin E-beta-thalassemia patients. A total of 14 cycles of PGD were attempted, ranging from one to four attempts per family. Following successful identification of HLA-identical cells, two pregnancies occurred, of which one resulted in engraftment of a beta-thalassemia child. PGD therapy offers the possibility of recruiting a suitable donor for HCT, yet is limited by financial cost due to labor-intensive techniques, low probability of obtaining an HLA-matched unaffected embryo, variable implantation capacity, and significant emotional impact. Improvements in PGD therapy's efficacy and cost will make this a more viable option for affected families.
Abstract: New developments in the epidemiology, treatment and prognosis of thalassemia have dramatically altered the approach to the care of affected patients, and these developments are likely to have an even greater impact in the next few years. Demographic changes have required an awareness and understanding of the unique features of thalassemia disorders that were previously uncommon in North America but are now seen more frequently in children and recognized more consistently in adults. New methods for measuring tissue iron accumulation and new drugs to remove excessive iron are advancing two of the most challenging areas in the management of thalassemia as well as other transfusion-dependent disorders. Improved survival of patients with thalassemia has given new importance to adult complications such as endocrinopathies and hepatitis that have a major impact on the quality of life. This chapter describes how these changes are redefining the clinical management of thalassemia. In Section I, Dr. Renzo Galanello describes recent advances in iron chelation therapy. Several new chelators are either licensed in some countries, are in clinical trials or are in the late stages of preclinical development. Some of these iron chelators, such as deferiprone (DFP) and ICL670, are orally active. Others, such as hydroxybenzyl-ethylenediamine-diacetic acid (HBED) and starch deferoxamine, require parenteral administration but may be effective with less frequent administration than is currently required for deferoxamine. Chelation therapy employing two chelators offers the possibility of more effective removal of iron without compromising safety or compliance. Other strategies for chelation therapy may take advantage of the ability of particular chelators to remove iron from specific target organs such as the heart and the liver. In Section II, Dr. Dudley Pennell addresses cardiac iron overload, the most frequent cause of death from chronic transfusion therapy. The cardiac complications related to excessive iron may result from long-term iron deposition in vulnerable areas or may be due to the more immediate effects of nontransferrin-bound iron. Cardiac disease is reversible in some patients with intensive iron chelation therapy, but identification of cardiac problems prior to the onset of serious arrhythmias or congestive heart failure has proven difficult. New methods using magnetic resonance imaging (MRI) have recently been developed to assess cardiac iron loading, and studies suggest a clinically useful relationship between the results using these techniques and critical measures of cardiac function. Measurements such as T2* may help guide chelation therapy in individual patients and may also enhance the assessment of new chelators in clinical trials. The use of MRI-based technology also holds promise for wider application of non-invasive assessment of cardiac iron in the management of patients with thalassemia. In Section III, Dr. Melody Cunningham describes some of the important complications of thalassemia that are emerging as patients survive into adulthood. Hepatitis C infection is present in the majority of patients older than 25 years. However, antiviral therapy in patients with thalassemia has been held back by the absence of large clinical trials and concern about ribavirin-induced hemolysis. More aggressive approaches to the treatment of hepatitis C may be particularly valuable because of the additive risks for cirrhosis and hepatocellular carcinoma that are posed by infection and iron overload. Thrombosis is recognized with increasing frequency as a significant complication of thalassemia major and thalassemia intermedia, and pulmonary hypertension is now the focus of intense study. Risk factors for thrombosis such as splenectomy are being identified and new approaches to anticoagulation are being initiated. Pregnancies in women with thalassemia are increasingly common with and without hormonal therapy, and require a better understanding of the risks of iron overload and cardiac disease in the mother and exposure of the fetus to iron chelators. In Section IV, Dr. Elliott Vichinsky describes the dramatic changes in the epidemiology of thalassemia in North America. Hemoglobin E-beta thalassemia is seen with increasing frequency and poses a particular challenge because of the wide variability in clinical severity. Some affected patients may require little or no intervention, while others need chronic transfusion therapy and may be appropriate candidates for hematopoietic stem cell transplantation. Enhancers of fetal hemoglobin production may have a unique role in Hb E-beta thalassemia since a modest increase in hemoglobin level may confer substantial clinical benefits. Alpha thalassemia is also being recognized with increasing frequency in North America, and newborn screening for Hemoglobin Barts in some states is leading to early detection of Hb H disease and Hb H Constant Spring. New data clarify the importance of distinguishing these two disorders because of the increased severity associated with Hb H Constant Spring. The use of intrauterine transfusions to sustain the viability of fetuses with homozygous alpha thalassemia has created a new population of patients with severe thalassemia and has raised new and complex issues in genetic counseling for parents with alpha thalassemia trait.
Abstract: Liver iron measurements using biosusceptometers have been validated on two low-TC SQUID (Superconducting Quantum Interference Device) systems (New York and Hamburg) built in the 1980's. Recently, two new instruments have been installed in Torino, Italy (2001), and Oakland, California (2003). The design of the Oakland system is similar to those in Hamburg and Torino. Improvements were made to adjust for significant environmental noise, moreover, an active electronic noise cancellation, a computer controlled water coupling reference system using a pressure feedback and a faster data acquisition system using software lockin amplifiers have been implemented. All 3 systems (Hamburg, Torino, Oakland) are using the same standardized operational protocol. Presented herein are the data collected from 276 patients measured with the SQUID biosusceptometer at Oakland since installation. The results from 149 patients with beta-thalassemia (beta-Thal, age: 2-66 y), 76 patients with sickle-cell disease (SCD, age: 5-55 y), 35 patients with various rare diseases (RD, age: 2-80 y), and 16 patients with hereditary hemochromatosis (HHC, age: 6-74 y) are reported. The liver iron concentration in the different groups are 222 - 7570 (beta-Thal), 518 - 7918 (SCD), 511 - 6234 (RD), 258 - 2041 (HHC) microg/g-liver (in vivo wet weight). The long-term reproducibility (12 months) in a patient on constant treatment regimen demonstrated a mean liver iron of 1141 +/- 133 microg/g-liver. The new SQUID Ferritometer located on the US West coast will give more patients access to this non-invasive liver iron assessment.
Abstract: Augmentation of fetal hemoglobin (HbF) synthesis can reduce the severity of beta-thalassemia by improving the imbalance between alpha- and non-alpha-globin chains. However, previous clinical trials of pharmacologic induction of HbF in thalassemia produced inconsistent results. Striking responses in HbF and total hemoglobin synthesis were occasionally observed, but in most patients, the increase in gamma-globin synthesis was inadequate to influence the clinical course of thalassemia. A small number of patients treated with azacytidine demonstrated a consistent response, but the development of this drug was abandoned due to concerns over toxicity. Decitabine, an analog of azacytidine, is a more potent inhibitor of DNA methyltransferase, and may be less toxic in clinical use. Trials in sickle cell anemia have confirmed that decitabine is effective in patients refractory to hydroxyurea. The clinical trials of decitabine in thalassemia must carefully evaluate the dose and route of administration, and address concerns about long-term side effects.
Abstract: The thalassemias pose an increasing burden for health-care services in many Asian countries. In order to conserve rare resources, it is essential to determine the reasons for the remarkable phenotypic heterogeneity and natural history of these disorders so that the most cost-effective methods for their control and management can be established. A long-term observational study of patients with different forms of thalassemia in Sri Lanka suggests that in addition to the well-defined primary, secondary and tertiary genetic modifiers, environmental factors, particularly malaria, and variation in the ability to adapt to the profound anaemia which characterizes these conditions, may play a significant role in determining their clinical severity. These findings may have important implications for the control and management of thalassemia in Asian populations.
Abstract: Stroke is a devastating complication of sickle cell anemia (SCA), affecting up to 30% of children with the disease. Despite the relative frequency of stroke in SCA, few predictors of risk exist. Because stroke in SCA is likely a multifactorial disease, analysis of the combined effect of multiple genetic variants may prove more successful than evaluation of individual candidate genes. We genotyped 230 children with SCA for 104 polymorphisms among 65 candidate vascular genes to identify risk associations with stroke. Patients were phenotyped based on magnetic resonance imaging/angiography (MRI/MRA) findings into large-vessel (LV) versus small-vessel (SV) disease stroke subgroups. Specific polymorphisms in the IL4R 503, TNF (-308), and ADRB2 27 genes were independently associated with stroke susceptibility in the LV stroke subgroup, while variants in the VCAM1 (-1594) and LDLR NcoI genes were associated with SV stroke risk. The combination of TNF (-308)GG homozygosity and the IL4R 503P variant carrier status was associated with a particularly strong predisposition to LV stroke (odds ratio [OR] = 5.5; 95% confidence interval [CI] = 2.3-13.1). We show that several candidate genes may play a role in predisposition to specific stroke subtypes in children with SCA. If confirmed, these results provide a basis for population screening and targeted intervention to prevent stroke in SCA.
Abstract: An increasing number of Southeast Asian immigrants have come to North America. Physicians who care for this population should be aware of the high prevalence of hematologic disorders and develop an approach to their diagnosis and management. Malaria and the hematologic sequelae, glucose-6-phophate dehydrogenase deficiency, the thalassemia syndromes, Southeast Asian ovalocytosis, visceral leishmaniasis, HIV infection, and iron-deficiency anemia, all of which may pertain to these patients, are reviewed in this article.
Abstract: The Stroke Prevention Trial in Sickle Cell Anemia (STOP) was a randomized multicenter controlled trial comparing prophylactic blood transfusion with standard care in sickle cell anemia (SCA) children aged 2 to 16 years selected for high stroke risk by transcranial Doppler (TCD). More than 2000 children were screened with TCD to identify the 130 high-risk children who entered the randomized trial. A total of 5613 TCD studies from 2324 children were evaluated. We also collected information on stroke. We describe the changes in TCD with repeated testing and report the outcome without transfusion in the STOP screened cohort. Risk of stroke was higher with abnormal TCD than with normal or conditional TCD (P <.001) or inadequate TCD (P =.002), and risk with conditional TCD was higher than with normal TCD (P <.001). Repeated TCD in 1215 children showed that the condition of 9.4% of children became abnormal during observation. Younger patients and those with higher initial flow velocities were most likely to convert to abnormal TCDs. Screening in STOP confirmed the predictive value of TCD for stroke. Substantial differences in the probability of conversion to abnormal TCD were observed, with younger children and those with higher velocity more likely to have an abnormal TCD with rescreening.
Abstract: Rates and severity of pneumococcal infections in children with sickle cell disease were examined before licensure of pneumococcal-conjugated vaccine (PVC). Rates of peak invasive infection rates in 1-year-old children with hemoglobin SS and mortality in those 0 to 10 years of age were 36.5 to 63.4 and 1.4 to 2.8 per 1000 person-years, respectively (>10 and 100 times as frequent as in the general population). Overall, 71% of serotyped isolates (n=80) were PVC serotypes and 71% of nonvaccine serotype strains were penicillin-sensitive. Clinical presentation in children with hemoglobin SS (n=71; more with hypotension) and hemoglobin SC (n=18; more with acute chest syndrome, otitis media) differed. Penicillin nonsusceptibility (38% of isolates) varied between geographic study sites. Penicillin prophylaxis appeared less effective against intermediate and resistant strains. Of all infected children, meningitis developed in 20% and 15% died (hemoglobin SS, n=15 and 11; hemoglobin SC, n=1 each). Factors associated with death included age >4 years (58%), serotype 19F, and not being followed by a hematologist (42% each). The pneumococcal-polysaccharide vaccine was 80.4% effective within 3 years after vaccination (95% CI, 39.7, 93.6). Children with sickle cell disease of all ages may benefit from PVC boosted with polysaccharide vaccination.
Abstract: Children with sickle cell anemia (SCA) carry a 200-fold increased risk for cerebral infarction. Stroke can be the result of small-vessel (SV) or large-vessel (LV) disease. However, it is unknown whether these subtypes result from the same pathophysiologic processes. Complete HLA genotyping was performed on 231 eligible children previously enrolled in the Cooperative Study of Sickle Cell Disease (CSSCD). Cerebral infarction on magnetic resonance imaging (MRI) was documented in 71 patients, and 160 patients had negative findings on MRI. Based on MRI/magnetic resonance angiography (MRA) findings, infarct size, and location, 36 patients were classified as having LV stroke and 35 as having SV stroke. When comparing the total MRI+ group with the MRI- group, HLA DPB1*0401 was associated with increased stroke risk (P =.01), whereas DPB1*1701 (P =.02) conferred protection from stroke. These DPB1 associations with stroke were attributed to the SV stroke group, in whom DPB1*0401 was associated with susceptibility (P =.003) and DPB1*1701 with protection from stroke (P =.06). In the LV stroke subgroup, HLA-A*0102 (P =.02) and -A*2612 (P =.007) conferred susceptibility, whereas -A*3301(P =.04) protected from stroke. These results suggest that specific HLA alleles influence stroke risk and appear to contribute differently to SV and LV stroke subtypes. The distinct HLA associations with SV and LV stroke suggest that different pathologic processes may be involved in the development of stroke in children with SCA. If these results are confirmed in a larger study, HLA type may serve as a useful marker for the early identification of SCA patients at high risk for stroke.
Abstract: PURPOSE Few studies address the association of Chlamydia pneumoniae infection with pulmonary disease and outcome in patients with underlying pathology such as sickle cell disease (SCD). SCD patients are susceptible to the pulmonary disorder known as acute chest syndrome (ACS), where the etiology remains ill defined. The purpose of this study was to analyze the clinical course and outcome of C. pneumoniae-associated ACS among SCD patients as part of the National Acute Chest Syndrome Study. PATIENTS AND METHODS: This was a longitudinal study of SCD patients presenting with ACS to multiple U.S. medical centers. Two hundred ninety-six SCD patients who developed ACS were tested by PCR for C. pneumoniae and by standard techniques for other respiratory pathogens. These infections were evaluated for association with ACS, clinical course, and complications. RESULTS: Forty-one (14%) patients with first episodes of ACS were PCR positive for C. pneumoniae. Compared with other infections, C. pneumoniae-infected patients were older, were more likely to present with chest pain, and had higher hemoglobin levels at diagnosis. Both groups had similar rates of respiratory failure and prolonged hospitalization. Of the 89 patients with single-pathogen infections, 27 (30%) were due to C. pneumoniae, 21% to Mycoplasma pneumoniae, 10% to RSV, 4% to Staphylococcus aureus, and 3% to Streptococcus pneumoniae. CONCLUSIONS: C. pneumoniae was the most prevalent pathogen in this study of ACS and was responsible for significant morbidity. Additional research is required to develop effective treatment guidelines for ACS.
Abstract: CONTEXT: Hydroxyurea increases levels of fetal hemoglobin (HbF) and decreases morbidity from vaso-occlusive complications in patients with sickle cell anemia (SCA). High HbF levels reduce morbidity and mortality. OBJECTIVE: To determine whether hydroxyurea attenuates mortality in patients with SCA. DESIGN: Long-term observational follow-up study of mortality in patients with SCA who originally participated in the randomized, double-blind, placebo-controlled Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH), conducted in 1992-1995, to determine if hydroxyurea reduces vaso-occlusive events. In the MSH Patients' Follow-up, conducted in 1996-2001, patients could continue, stop, or start hydroxyurea. Data were collected during the trial and in the follow-up period. SETTING: Inpatients and outpatients in 21 sickle cell referral centers in the United States and Canada. PATIENTS: Two-hundred ninety-nine adult patients with frequent painful episodes enrolled in the follow-up. Follow-up data through May 2001 were complete for 233 patients. INTERVENTION: In the MSH, patients were randomly assigned to receive hydroxyurea (n = 152) or placebo (n = 147). MAIN OUTCOME MEASURE: Mortality, HbF levels, painful episodes, acute chest syndrome, and blood cell counts. The randomized trial was not designed to detect specified differences in mortality. RESULTS: Seventy-five of the original 299 patients died, 28% from pulmonary disease. Patients with reticulocyte counts less than 250 000/mm3 and hemoglobin levels lower than 9 g/dL had increased mortality (P =.002). Cumulative mortality at 9 years was 28% when HbF levels were lower than 0.5 g/dL after the trial was completed compared with 15% when HbF levels were 0.5 g/dL or higher (P =.03 ). Individuals who had acute chest syndrome during the trial had 32% mortality compared with 18% of individuals without acute chest syndrome (P =.02). Patients with 3 or more painful episodes per year during the trial had 27% mortality compared with 17% of patients with less frequent episodes (P =.06). Taking hydroxyurea was associated with a 40% reduction in mortality (P =.04) in this observational follow-up with self-selected treatment. There were 3 cases of cancer, 1 fatal. CONCLUSIONS: Adult patients taking hydroxyurea for frequent painful sickle cell episodes appear to have reduced mortality after 9 of years follow-up. Survival was related to HbF levels and frequency of vaso-occlusive events. Whether indications for hydroxyurea treatment should be expanded is unknown.
Abstract: BACKGROUND: Acute chest syndrome (ACS) is the leading cause of hospitalization, morbidity, and mortality in patients with sickle cell disease. Radiographic and clinical findings in ACS resemble pneumonia; however, etiologies other than infectious pathogens have been implicated, including pulmonary fat embolism (PFE) and infarction of segments of the pulmonary vasculature. The National Acute Chest Syndrome Study Group was designed to identify the etiologic agents and clinical outcomes associated with this syndrome. METHODS: Data were analyzed from the prospective study of 671 episodes of ACS in 538 patients with sickle cell anemia. ACS was defined as a new pulmonary infiltrate involving at least 1 complete segment of the lung, excluding atelectasis. In addition, the patients had to have chest pain, fever >38.5C, tachypnea, wheezing, or cough. Samples of blood and deep sputum were analyzed for evidence of bacteria, viruses, and PFE. Mycoplasma pneumoniae infection was determined by analysis of paired serologies. Detailed information on patient characteristics, presenting signs and symptoms, treatment, and clinical outcome were collected. RESULTS: Fifty-one (9%) of 598 episodes of ACS had serologic evidence of M pneumoniae infection. Twelve percent of the 112 episodes of ACS occurring in patients younger than 5 years were associated with M pneumoniae infection. At the time of diagnosis, 98% of all patients with M pneumoniae infection had fever, 78% had a cough, and 51% were tachypneic. More than 50% developed multilobar infiltrates and effusions, 82% were transfused, and 6% required assisted ventilation. The average hospital stay was 10 days. Evidence of PFE with M pneumoniae infection was seen in 5 (20%) of 25 patients with adequate deep respiratory samples for the PFE assay. M pneumoniae and Chlamydia pneumoniae was found in 16% of patients with diagnostic studies for C pneumoniae. Mycoplasma hominis was cultured in 10 (2%) of 555 episodes of ACS and occurred more frequently in older patients, but the presenting symptoms and clinical course was similar to those with M pneumoniae. CONCLUSIONS: M pneumoniae is commonly associated with the ACS in patients with sickle cell anemia and occurs in very young children. M hominis should be considered in the differential diagnosis of ACS. Aggressive treatment with broad-spectrum antibiotics, including 1 from the macrolide class, is recommended for all patients as well as bronchodilator therapy, early transfusion, and respiratory support when clinically indicated.
Abstract: Neonatal hemochromatosis is an enigmatic disease. Little is known about iron metabolism in this disease, including the tissue concentration of ferritin or its H and L subunit ratio. The authors report the tissue iron, ferritin, and ferritin subunit content of a child who died at 5 weeks of neonatal hemochromatosis. The child was born at 29 weeks gestation to a mother with lupus, sickle cell trait, and gestational diabetes. The child's severe liver dysfunction led to the clinical diagnosis of neonatal hemochromatosis at 1 week of age. Despite aggressive support, including red cell transfusions and chelation, the child died of an intracranial hemorrhage. Autopsy showed liver fibrosis and iron staining characteristic of neonatal hemochromatosis. Autopsy liver tissue was compared to age-matched control tissue. Soluble protein was analyzed by the Bradford method. Soluble iron (over 90% of total iron) was analyzed by the o-phenanthroline complex. Tissue ferritin and human ferritin controls (Calzyme) were analyzed by Western blotting after SDS-PAGE, identified with sheep anti-human ferritin antibodies (The BindingSite) secondary antibody-fluorescence for detection, and quantified using the Molecular Dynamics Storm 840 phosphorimager and ImageQuant software. Protein, iron, and total ferritin were similar in the normal and neonatal hemochromatosis liver tissues. Ferritin subunits, however, showed an increased H/L-subunit ratio compared to an age-matched control. This first report of a marked increase in the ferritin H/L-subunit ratio may point to an underlying mechanism of disease in this enigmatic disorder.
Abstract: Pulmonary hypertension is a life-threatening complication of sickle cell disease. L-Arginine is the nitrogen donor for synthesis of nitric oxide, a potent vasodilator that is deficient during times of sickle cell crisis. This deficiency may play a role in pulmonary hypertension. The enzyme arginase hydrolyzes arginine to ornithine and urea, and thus, it may compete with nitric oxide synthase, leading to decreased nitric oxide production. Nitric oxide therapy by inhalation has improved pulmonary hypertension associated with acute chest syndrome in sickle cell disease, and several studies demonstrate therapeutic benefits of arginine therapy for primary and secondary pulmonary hypertension. We sought to determine the effects of arginine therapy on pulmonary hypertension in patients with sickle cell disease. Arginase activity was also determined. Oral arginine produced a 15.2% mean reduction in estimated pulmonary artery systolic pressure (63.9 +/- 13 to 54.2 +/- 12 mm Hg, p = 0.002) after 5 days of therapy in 10 patients. Arginase activity was elevated almost twofold (p = 0.07) in patients with pulmonary hypertension and may limit arginine bioavailability. With limited treatment options and a high mortality rate for patients with sickle cell disease who develop pulmonary hypertension, arginine is a promising new therapy that warrants further investigation.
Abstract: PURPOSE: Recent data suggest that hydroxyurea (HU) increases the production of nitric oxide (NO), a potent vasodilator. NO is normally metabolized from l-Arginine (Arg). However, in vitro and animal experiments suggest that HU is the NO donor itself. In contrast, a recent study indicates that nitric oxide synthase (NOS) may play a role. Since adults with sickle cell disease (SCD) are Arg-deficient, Arg availability may limit the ability of HU to maximally impact NO production if an NOS mechanism is involved. The authors have previously shown that Arg supplementation alone induces a paradoxical decrease in NO metabolite (NO(x)) production. METHODS: The authors studied the effects of HU and Arg supplementation on NO(x) production. HU alone or HU + Arg was administered to patients with SCD at steady state, and sequential levels of Arg, serum NO(x) and exhaled NO were followed over 4 hours. RESULTS: After HU + Arg, all patients demonstrated a significant increase in serum NO(x) production within 2 hours. When the same patients were treated with HU alone (5.1 +/- 2 micromol/L), a mixed response occurred. NO(x) levels increased in four patients and decreased in one patient (-23.3 micromol/L). CONCLUSIONS: While Arg alone does not increase serum NO(x) production in SCD patients at steady state, it does when given together with HU. Hence, co-administration of Arg with HU may augment the NO(x) response in SCD and improve utilization of Arg in patients at steady state.
Abstract: In this update, selected clinical features of sickle cell disease and their management are reviewed. In addition, the current status of interventions that have curative potential for sickle cell disease is discussed, with particular attention focused on indications, methodology, recent results, and challenges to wider clinical application. In Section I, Dr. Nienhuis describes recent improvements in vector technology, safety, and replacement gene expression that are creating the potential for clinical application of this technology. In Section II, Dr. Vichinsky reviews our current understanding of the pathophysiology and treatment of pulmonary injury in sickle cell disease. The acute and chronic pulmonary complications of sickle cell disease, modulators and predictors of severity, and conventional and novel treatment of these complications are discussed. In Section III, Dr. Walters reviews the current status of hematopoietic cell transplantation for sickle cell disease. Newer efforts to expand its availability by identifying alternate sources of stem cells and by reducing the toxicity of transplantation are discussed.
Abstract: OBJECTIVES: Although hydroxyurea is effective in treating adults with sickle-cell anemia (SCA), there is concern that it may adversely affect growth in children. We report the growth characteristics of patients in the Phase I-II pediatric hydroxyurea trial (HUG-KIDS) before and during treatment at the maximum tolerated dose for one year. STUDY DESIGN: Children and adolescents with SCA (n = 68), aged 5 to 16 years at baseline, reached the maximum tolerated dose and had serial height, weight, and Tanner stage measurements. Data from the Cooperative Study of Sickle Cell Disease (CSSCD) were used for comparison. Mixed-effects models were used to compare serial measurements as a function of age and group. RESULTS: In girls, there were no significant differences in height or weight among the pretreatment, on-treatment, and CSSCD groups. Compared with the CSSCD group, HUG-KIDS boys were heavier starting at age 9 years, and pretreatment HUG-KIDS boys were taller starting at age 7 years. The Tanner stage transitions took place at appropriate ages. CONCLUSIONS: Hydroxyurea treatment had no adverse effect on height or weight gain or pubertal development in school-aged children with SCA.
Abstract: Hypothermia has been demonstrated to induce pancytopenia in animals, but whether this association exists in humans is unknown. The authors report the case of an 8-year-old girl in whom hypothermia (temperature 33 degrees C-35 degrees C) is the cause of pancytopenia. The patient developed thermoregulatory dysfunction subsequent to surgical resection of a craniopharyngioma. Her recurrent cytopenias could not be explained by any etiology except chronic hypothermia. The pancytopenia improved upon rewarming the patient to a temperature of 36 degrees C. This association between hypothermia and pancytopenia has rarely been reported in humans and may be underdiagnosed especially in cases of transient or milder presentations. The authors recommend careful hematologic monitoring of patients with thermoregulatory dysfunction.
Abstract: Children with sickle cell anemia (HbSS) are at high risk for neurologically overt cerebral infarcts associated with stroke and neurologically silent cerebral infarcts correlated with neuropsychometric deficit. We used complete magnetic resonance imaging (MRI) histories from 266 HbSS children, aged 6 through 19 years, who were enrolled in the Cooperative Study of Sickle Cell Disease (CSSCD) to examine silent infarct prevalence, localization, recurrence, and progression. We report a baseline prevalence of 21.8%, marginally higher than previously reported due to improved imaging technologies. Although we observed no overall sex difference in prevalence, most lesions in girls occurred before age 6, whereas boys remained at risk until age 10. Silent infarcts were significantly smaller and less likely to be found in the frontal or parietal cortex than were infarcts associated with stroke. Children with silent infarct had an increased incidence of new stroke (1.03/100 patient-years) and new or more extensive silent infarct (7.06/100 patient-years) relative to stroke incidence among all children in our cohort (0.54/100 patient-years). Both events were substantially less frequent than the risk of stroke recurrence among children not provided chronic transfusion therapy. Although chronic transfusion is known to decrease occurrence of new silent infarcts and strokes in children with elevated cerebral arterial blood flow velocity, further study is required to determine its risk-benefit ratio in children with silent infarct and normal velocities. Until safe and effective preventive strategies against infarct recurrence are discovered, MRI studies are best reserved for children with neurologic symptoms, neuropsychometric deficits, or elevated cerebral artery velocities.
Abstract: OBJECTIVES: To examine the body composition of children and adolescents with sickle cell disease (SCD) using bioelectrical impedance analysis and to determine if the impedance parameters resistance, reactance, and phase angle are able to distinguish between subjects with SCD and age- and gender matched controls. STUDY DESIGN: Total body resistance and reactance were obtained for a total of 53 subjects with SCD (27 male and 26 female) between 10 and 18 years of age and 49 control subjects (23 male and 26 female). The fat-free mass, body cell mass, phase angle, and capacitance were also determined. Group comparisons were made using the 2-sample t test. RESULTS: Male subjects with SCD had significantly lower fat-free mass (37.5 +/- 8.8 vs 43.9 +/- 12.3 kg, P =.04), body cell mass (17.4 +/- 4.3 vs 21.7 +/- 5.8 kg,P =.005), and body fat (3.7 +/- 2.6 vs 6.6 +/- 4.7 kg, P =.008) compared with controls. No significant differences in any body composition components were found for the female subjects. Both male and female subjects had significantly lower phase angle measurements (P <.001 and.006, respectively) than their respective controls, indicating possible alterations in cell membrane properties because of an imbalance in membrane composition or function. CONCLUSIONS: Bioelectrical impedance analysis can be used to determine body composition differences in children with SCD. The phase angle may provide a useful method to monitor the efficacy of therapeutic interventions in patients with SCD.
Abstract: The objectives of this study were to describe and compare the characteristics of pain experienced by children and young adults with sickle cell disease (SCD) in inpatient and outpatient settings. The Adolescent Pediatric Pain Tool (APPT), a multidimensional self-report pain assessment, was completed by African American children and young adults (mean age 15.39 +/- 4.32) with SCD during a clinic visit (n = 52), day hospital visit (n = 29), or during the first 24 hours of an inpatient stay (n = 72). Multiple linear regression revealed that pain intensity, number of body areas with pain, and the quality of pain were related to age, sex, and care setting. Pain intensity, location, and quality were of greater magnitude than previous reports of early postoperative pain in children. Examining the specific dimensions of pain intensity, location, and quality and the influencing factors of age, sex, and care setting may lead to more effective treatments for SCD pain.
Abstract: OBJECTIVE: To evaluate the impact of a quality improvement approach to implementing developmentally appropriate pain assessment guidelines for pediatric inpatients. Patient and staff satisfaction with pain assessment and management, and staff documentation were evaluated one year following the implementation of the revised pain assessment guidelines. DESIGN: Quasi-experimental design. SETTING: The pediatric hematology/oncology unit of a regional children's hospital. Study participants. A convenience sample of 36 children and 68 staff at time 1 (TI) and 49 children and 82 staff at time 2 (T2). INTERVENTIONS: Staff were educated on the use of pediatric pain assessment tools and a standardized pain assessment protocol was put into practice. Children or their primary caregivers were interviewed, using a questionnaire modified from the American Pain Society quality assurance guidelines, regarding their experiences with pain assessment and management on the unit at T1, just prior to the staff education, and one year later at T2. Multidisciplinary unit staff completed a parallel questionnaire at T1 and T2. MAIN OUTCOME MEASURES: Patient and staff satisfaction with pain assessment and management, and chart audit of compliance with pain assessment documentation. RESULTS: Patients, family members, and staff reported increased pain assessment, improved staff responsiveness to patients' pain and greater satisfaction with assessment tools between TI and T2. Increased compliance with the assessment guidelines was confirmed by chart audit. CONCLUSIONS: Improved pain assessment and management practices with resultant increase in patient and staff satisfaction can be achieved and sustained over time using quality improvement strategies.
Abstract: PURPOSE: Chronic red cell transfusion has been used for prevention of recurrent stroke in patients with sickle cell disease for three decades, and its effectiveness in primary prevention was recently shown. Iron overload, the inevitable result of chronic transfusion, is commonly monitored with serum ferritin concentration. PATIENTS AND METHODS: Sixty-one patients at high risk for stroke received chronic transfusion in a clinical trial of stroke prevention. A serum ferritin level of less than 500 ng/mL was required for study entry. Ferritin levels were obtained quarterly. Fifty patients who had four or more ferritin measurements were included in this analysis. Transfusions were administered as exchange or simple, with washed, reconstituted, or packed red blood cells, at the discretion of the site investigator. RESULTS: Serum ferritin levels increased linearly with cumulative transfusion volume during the first four ferritin measurements, but the rate of increase varied widely among patients. Rates of increase varied similarly among 23 patients who received exclusively simple transfusion with packed red cells and in five patients who received exchange transfusions. Thirty-two patients received a total transfusion volume of more than 250 mL/kg. Ferritin continued to increase linearly after the first four measurements in 14, but the remaining 18 experienced a plateau before the level reached 3,000 ng/mL. Six of those with a linear increase never reached a ferritin level of 3,000 ng/dL. CONCLUSIONS: There was strong intrapatient correlation between serum ferritin levels and volume transfused but wide interpatient variability early during chronic transfusion therapy. Intrapatient correlation declined at transfusion volumes of more than 250 mL/kg. Direct iron store assessment is needed to determine the clinical significance of serum ferritin variability.
Abstract: A review of patients with sickle cell disease (SCD) and central venous catheters (CVCs) was performed to evaluate the frequency of catheter complications (infections, thrombotic events, and premature CVC removal. Fifteen evaluable patients were identified during our review of a 7.5-year period. The median age was 18 years (range, 1.5-30 years); 14 were African American, and 1 was Latino; 5 were male, and 10 were female. Forty-one CVCs were placed (36 Mediport and 5 Broviac catheters) for a total of 12,120 CVC days. We observed a median of 2 CVCs per patient (range, 1-8 CVCs per patient) with 67 discrete episodes of CVC-associated infection (range, 0-18 per patient) involving 10 patients. The rate of CVC-associated infection for patients with SCD at our institution was 5.5 infections per 1,000 CVC days; this rate was significantly higher than the rate of CVC-associated infection in our patients with cancer (P < 0.001). We also determined that the rate of CVC-associated thrombosis was 0.99 events per 1,000 CVC days and involved 33% of the patients with SCD; the rate of premature CVC removal was 3.15 per 1,000 CVC days, and 78% of CVCs were removed prematurely. We conclude that patients with SCD are at high risk for CVC-related complications, and improved care and close monitoring of CVCs should be encouraged to decrease morbidity in these chronically ill patients.
Abstract: CONTEXT: New therapies have evolved from our improved understanding of the biology of sickle cell disease (SCD) and the availability of a useful transgenic animal model. Several therapeutic options are available that interrupt the sickling process at various key pathways. Nitric oxide (NO)is a critical factor in the pathophysiology of SCD and is a promising antisickling agent with vasodilation properties. NO regulates blood vessel tone, endothelial adhesion, and the severity of ischaemia-reperfusion injury and anaemia in SCD. Although NO is difficult to administer, its precursor, L-arginine, is an oral supplement. STARTING POINT: J R Romero and colleagues recently demonstrated in sickle transgenic mice that oral arginine supplementation induced NO production and reduced red-cell density by inhibiting the Gardos channel, which modulates cell hydration and polymerisation of haemoglobin S (Blood 2002; 99:1103-08). Haemoglobinopathies can be cured by stem-cell transplantation. This therapy is now accepted treatment in symptomatic children. However, most patients lack a genotypically identical family donor. G La Nasa and colleagues demonstrated unrelated-donor stem-cell transplantation may give similar results to related-donor stem-cell transplantation when extended phenotypic matching is used (Blood 2002; 99: 4350-56). This pilot study offers the possibility of cure to patients without a family donor. WHERE NEXT: Although potential opportunities to prevent morbidity in SCD through new therapies are exciting, most patients do not have access to standard multidisciplinary specialty care. Patients require both.
Abstract: A multicenter investigation of allogeneic BMT for children with symptomatic SCD was conducted between 1991 and April 2000. Fifty-nine patients ranging in age from 3.3 to 15.9 (median, 10.1) years received HLA-identical sibling marrow allografts following conventional myeloablative preparation with busulfan, cyclophosphamide and antithymocyte globulin. Currently, 55 patients survive, and 50 survive free of sickle cell disease with a median follow-up of 4.2 (range, 1.2 to 9.6) years after BMT. The Kaplan-Meier probabilities of survival and event-free survival are 93% and 85%, respectively, and the cumulative incidence of disease recurrence is 8%. Among the 55 surviving patients, one patient with disease recurrence experienced a second stroke after BMT. The remaining survivors (3 of whom had disease recurrence) are free of stroke after BMT, including patients who had a clinical stroke (N=29), 'silent' stroke (N=9), other sickle-related central nervous system (CNS) abnormality (N=1) or no CNS disease (N=15) before BMT. After BMT, patients were also evaluated for the impact of this treatment on pre-existing CNS lesions. Forty-eight of 55 surviving patients had cerebral magnetic resonance imaging (MRI) examinations performed after BMT with a median interval follow-up of 24.4 (range, 2.7 - 71.3) months between pre- and post-BMT exams. One patient with graft rejection had changes consistent with a second stroke, but in the remaining patients, follow-up exams had a stable appearance, and in 3 cases that included 2 with stroke, there was evidence of improvement in areas of prior abnormality. Pre- and post-transplantation cerebral magnetic resonance angiography (MRA) examinations among 11 patients were analyzed in a blinded review. Of these, 8 had similar imaging technique and thus were evaluable for comparison. Four of the 8 had a history of stroke and 1 had subclinical abnormalities by cerebral MRI ('silent stroke'), and the remainder had normal baseline exams. With a median follow-up interval of 23.9 months (range, 7.6 - 55.1 months) between pre- and post-BMT MRA exams, there were no significant changes in the appearance of cerebral arteries or in the lumenal diameters noted after BMT. Together, these observations support the notion that SCD patients who are successfully allografted do not experience sickle-related CNS complications and this clinical benefit correlates with evidence of stabilization of CNS disease by cerebral magnetic resonance imaging. These data support the hypothesis that the risk of stroke is mitigated by replacement of sickle with donor erythropoiesis after BMT. As the natural history of stroke in high-risk patients and the role of RBC transfusions are more completely defined, it is appropriate that BMT from HLA-matched sibling donors should also be considered as a suitable primary treatment intervention to prevent stroke.
Abstract: Diseases of iron metabolism are likely to be both more frequent than expected, and exhibit a wider range of clinic severity and effects. Some present without evidence of anemia. Unexplained diseases of end organs that are affected by iron (liver, heart, pancreas, kidney, adrenals, and cerebellum) should have an iron metabolism disorder considered. Review of the blood indices and serum iron and ferritin markers may alert the clinician to most disorders. Further research is likely to define the scope and approach to clinical diagnosis of the diseases of iron metabolism.
Abstract: The Stroke Prevention Trial has confirmed that utilization of transcranial Doppler ultrasonography (TCD), which examines blood flow in large intracranial vessels, can identify children with sickle cell disease (SCD) who are at high risk of developing a premature stroke. It is not known to what extent the vasculopathy in SCD involves small vessels and whether the abnormalities, if present, correlate with large-vessel vasculopathy. Eighteen children with SCD were examined with TCD to determine middle cerebral artery (MCA) velocity and computer-assisted intravital microscopy (CAIM) to determine bulbar conjunctival vessel velocity during the same visit for vasculopathy correlation. High MCA velocity (> or = 200 cm/sec) was found by TCD in 4 patients who also showed abnormal conjunctival velocity (< 0.2 mm/sec or intermittent trickle flow) by CAIM. Three patients had conditional (> or = 170 cm/sec and < 200 cm/sec) MCA velocity: 2 showed abnormal (trickle) and 1 showed normal conjunctival velocity (1.9 mm/sec). One patient with unmeasurable MCA velocity had abnormal (trickle) conjunctival velocity. Of the remaining 10 patients who had normal MCA velocity, 2 showed abnormal (0.05 mm/sec and 0.1 mm/sec) and 8 showed normal conjunctival velocities (1.1-2.4 mm/sec). The MCA velocities correlated significantly with bulbar conjunctival flow velocities (P < or =.008, Fisher exact test). A correlation exists between MCA (large-vessel) and conjunctival (small-vessel) flow velocities. CAIM is a noninvasive quantitative technique that might contribute to the identification of SCD patients at high risk of stroke. Small-vessel vasculopathy might be an important pathological indicator and should be further explored in a large-scale study. (Blood. 2001;97:3401-3404)
Abstract: BACKGROUND: A substantial minority of neurologically normal children with sickle cell disease have lesions consistent with cerebral infarction as seen on magnetic resonance imaging (MRI). OBJECTIVES: To determine if transfusion therapy affects the rate at which silent infarcts develop and to evaluate the contribution of MRI of the brain to stroke prediction by transcranial Doppler (TCD) ultrasonography. STUDY DESIGN: Children with elevated TCD ultrasonographic velocity were randomized to receive long-term transfusion therapy or standard care. Magnetic resonance imaging of the brain was obtained at randomization, annually, and with clinical neurologic events. The risk for new silent lesions and/or stroke was compared for each treatment arm. RESULTS: Among the 37% of subjects with silent infarcts, those receiving standard care were significantly more likely to develop new silent lesions or stroke than were those who received transfusion therapy. For subjects receiving standard care, those with lesions at baseline were significantly more likely to develop stroke or new silent lesions than those whose MRI studies showed no abnormality. CONCLUSIONS: Transfusion therapy lowers the risk for new silent infarct or stroke for children having both abnormal TCD ultrasonographic velocity and silent infarct. However, those with both abnormalities who are not provided transfusion therapy are at higher risk for developing a new silent infarct or stroke than are those whose initial MRI showed no abnormality. The finding of a silent infarct reinforces the need for TCD ultrasonographic screening and consideration of transfusion therapy if the abnormalities are seen. Similarly, elevated TCD ultrasonographic velocity warrants MRI of the brain because children with both abnormalities seem to be at increased risk for developing new silent infarct or stroke.
Abstract: Newborn screening is an accepted public health measure to ensure that appropriate health care is provided in a timely manner to infants with hereditary/metabolic disorders. Alpha-thalassemia is a common hemoglobin (Hb) disorder, and causes Hb H (beta4) disease, and usually fatal homozygous alpha(0)-thalassemia, also known as Hb Bart's (gamma4) hydrops fetalis syndrome. In 1996, the State of California began to investigate the feasibility of universal newborn screening for Hb H disease. Initial screening was done on blood samples obtained by heel pricks from newborns, and stored as dried blood spots on filter paper. Hb Bart's levels were measured as fast-moving Hb by automated high-performance liquid chromatography (HPLC) identical to that currently used in newborn screening for sickle cell disease. Subsequent confirmation of Hb H disease was done by DNA-based diagnostics for alpha-globin genotyping. A criterion of 25% or more Hb Bart's as determined by HPLC detects most, if not all cases of Hb H disease, and few cases of alpha-thalassemia trait. From January, 1998, through June, 2000, 89 newborns were found to have Hb H disease. The overall prevalence for Hb H disease among all newborns in California is approximately 1 per 15,000. Implementation of this program to existing newborn hemoglobinopathy screening in populations with significant proportions of southeast Asians is recommended. The correct diagnosis would allow affected infants to be properly cared for, and would also raise awareness for the prevention of homozygous alpha(0)-thalassemia or Hb Bart's hydrops fetalis syndrome.
Abstract: We describe a novel multilocus genotyping assay permitting simultaneous identification of 60 candidate markers for stroke in sickle cell anaemia (SCA). Based on cerebral magnetic resonance imaging (MRI), 69 patients were divided into stroke and control groups. The variant allele, CBS 278thr, showed protection from stroke, whereas the apoE3 allele showed a trend towards association with increased stroke risk. Several other variant alleles [TNFalpha (-308)A, CETP (-628)A, apoCIII (-641)A] showed a trend towards significant associations with stroke risk. These preliminary results on a small group of patients suggest that a multilocus genotyping assay may be valuable in identifying genes that increase the risk of stroke in SCA.
Abstract: OBJECTIVES: To compare the results of serial neuropsychologic testing in children with sickle cell disease with the results of serial magnetic resonance imaging (MRI) examinations, particularly to evaluate neuropsychologic function in the absence of overt stroke. STUDY DESIGN: In the Cooperative Study of Sickle Cell Disease, serial neuropsychologic and MRI tests were performed in 373 patients (255 with hemoglobin SS and 118 with hemoglobin SC), 6 to 18 years of age. MRI of the brain and a neuropsychologic battery that included the Wechsler Intelligence Scale for Children (WISC-R or WISC-III) and the Woodcock-Johnson Math and Reading Achievement Tests were performed concurrently and repeated every 2 to 3 years. A silent infarct was defined as an MRI finding of increased signal intensity on T(2) imaging in a patient without a history of stroke. RESULTS: Twenty-seven patients, all with hemoglobin SS, had overt strokes and 62 had silent infarcts (52 with hemoglobin SS). Patients with hemoglobin SS and silent infarcts had significantly lower scores for math and reading achievement, Full-Scale IQ, Verbal IQ, and Performance IQ, when compared with those with normal MRI findings. In children with hemoglobin SS and normal MRI findings, the scores for Verbal IQ, math achievement, and coding (a subscale of Performance IQ) declined with increasing age. CONCLUSIONS: School-aged children with sickle cell disease had compromised neuropsychologic function in the presence of silent infarcts. In addition, they had declines in performance in certain areas of function over time. Therapeutic interventions that prevent or lessen cognitive impairment are needed before school entry for children with sickle cell disease.
Abstract: A multicenter investigation of allogeneic bone marrow transplantation for children with sickle cell disease was conducted that included 27 European and North American transplant centers. Fifty-nine patients who ranged in age from 3.3 to 15.9 years (median, 10.1 years) received HLA-identical sibling marrow allografts between September 1991 and April 2000. Fifty-five patients survive, and 50 survive free from sickle cell disease, with a median follow-up of 42.2 months (range, 11.8 to 115 months) after transplantation. Of the 50 patients with successful allografts, 13 developed stable mixed donor-host hematopoietic chimerism. The level of donor chimerism, measured > or =6 months after transplantation in peripheral blood, varied between 90% and 99% in 8 patients. Five additional patients had a lower proportion of donor cells (range, 11% to 74%). Among these 5 patients, hemoglobin levels varied between 11.2 and 14.2 g/dL (median, 11.3 g/dL; mean, 12.0 g/dL). In patients who had donors with a normal hemoglobin genotype (Hb), the Hb S fractions were 0%, 0%, and 7%, corresponding to donor chimerism levels of 67%, 74%, and 11%, respectively. Among patients who had donors with sickle trait, the Hb S fractions were 36% and 37%, corresponding to donor chimerism levels of 25% and 60%, respectively. Thus, allograft recipients with stable mixed chimerism had Rb S levels similar to donor levels, and only 1 patient required a red blood cell transfusion beyond 90 days posttransplantation. None of the patients have experienced painful events or other clinical complications related to sickle cell disease after transplantation. These observations strongly suggest that patients with sickle cell disease who develop persistent mixed hematopoietic chimerism after transplantation experience a significant ameliorative effect.
Abstract: With increased recognition of the profound morbidity of sickle cell disease and with growing evidence of the efficacy of transfusion therapy in prevention and treatment of sickle cell complications, most patients now receive intermittent transfusion therapy. The purpose of this report is to review blood component therapy and Its risks for sickle cell patients. Packed red cells are the preferred blood component. Leukocyte-reduced units should be standard because of their beneficial effects in reducing alloimmunization, transfusion reactions, platelet refractoriness, and infection transmission. The use of washed, frozen, or Irradiated units is limited to specific problems. Sickle trait-positive units function normally, but because of difficulties with calculating hemoglobin S percentages and leukocyte filters, they are not routinely used. Transfusion-acquired infections have shown a marked decrease but still present a major risk. Viral hepatitis transmission is currently low, but at least 10% of adult sickle cell patients are hepatitis C positive, and they often have liver damage. Although bacterial infections are rare, they account for 16% of transfusion-related fatalities. Patients who are iron overloaded are particularly vulnerable to Yersina enterocolitica. Red cell alloimmunization is a serious problem that could potentially affect 50% of transfused patients. However, preventive phenotypic matching for common antigens can minimize alloimmunization; limited matching for at least E, C, and K has become the standard of care. Recently, more patients are being identified who have developed red cell autoantibodies, which can mask alloantibodies and occasionally are hemolytic. Careful laboratory evaluation of all cases is essential. Transfusions also may trigger sickle cell events, including pain crises, stroke, and acute pulmonary deterioration. In part, these are induced by blood viscosity and increased blood pressure. Diuretic therapy and close monitoring of transfusion volume and vital signs can minimize these events. In summary, transfusion therapy carries risks, but the routine use of leukocyte-reduced, phenotypically matched units in conjunction with close monitoring of patients can make transfusion therapy safer.
Abstract: BACKGROUND: Most sickle cell anemia patients undergo transfusion therapy to prevent complications. The Stroke Prevention Trial in Sickle Cell Anemia showed that transfusion therapy is effective in the primary prevention of stroke. Despite its efficacy, transfusion therapy is limited by alloimmunization. The purpose of this study was to determine if a multicenter trial could implement a transfusion program utilizing phenotypically matched blood to reduce alloimmunization. STUDY DESIGN AND METHODS: One hundred thirty children underwent RBC phenotyping and antibody screening with review of blood bank records. The protocol required use of WBC-reduced RBCs, which were matched for E, C, and Kell. Monthly alloantibody testing and review of transfusion forms were performed to determine compliance and the occurrence of any adverse events. RESULTS: Patient RBCs expressed a low frequency of Kell (2%), E (20%), and C (25%) antigens. Sixty-one patients received 1830 units. Ninety-seven percent of all units were WBC reduced. Only 29 units were inadvertently not matched for E, C, and Kell. Five patients (8%) developed a clinically significant alloantibody. Four developed a single antibody to E or Kell. Three patients (5%) developed a warm autoantibody. There were 11 transfusion reactions and 8 transfusion-associated events. Transfusion reactions included 6 febrile reactions (0.33%/unit), 3 allergic (0.16%/unit), and 2 hemolytic (0.11%/unit). Associated events included 4 episodes of hypertension (0.22%/unit), 3 crises (0.16%/unit), and 1 transient ischemic attack (0.05%/unit). CONCLUSION: This is the first multicenter study to show that extended RBC phenotyping can be implemented nationwide. Compared to studies, the alloimmunization rate dropped from 3 percent to 0.5 percent per unit, and hemolytic transfusion reactions dropped by 90 percent. It is recommended that all transfused sickle cell anemia patients be antigen matched for E, C, and Kell. Patients should be closely monitored during transfusions to avoid preventable risks.
Abstract: Since the genetic basis of sickle cell anemia was discovered over 50 years ago, many therapies have been developed for the treatment of this disorder. Hematopoietic cell transplantation offers curative potential, but it is associated with a 5-10% risk of dying. Patients who undergo allografting but develop stable donor-host hematopoietic chimerism appear to experience a significant clinical benefit. Our paper discusses the risks and benefits of hematopoietic cell transplantation in patients with sickle cell disease and summarizes the outcome of 147 patients who received allografts for sickle cell disease. We also review the development of new approaches to establish stable mixed chimerism after transplantation for sickle cell disease.
Abstract: Although the endocrine pancreas appears to play an important role in the pathophysiology of sickle cell disease, very little is known about the morphologic changes in this tissue. Our study was initiated to delineate the microscopic features of the endocrine pancreas in a large autopsy series of sickle cell hemoglobinopathies. From more than 650 cases archived at the Centralized Pathology Unit for Sickle Cell Disease (Mobile, AL), 224 autopsy cases were identified for review of clinical and gross autopsy findings and/or for microscopic studies, including histochemical stains (trichrome, reticulin, iron), and immunohistochemical stains (insulin, glucagon, somatostatin, and pancreatic polypeptide). The gross examinations were recorded as unremarkable in 65% of the autopsies. In childhood and adolescence (< or = 18 years), pancreas weights (50.76 +/- 5.16SE gm) were significantly greater (p < 0.0001) than age-matched controls (30.42 +/- 3.59SE gm). In adulthood, pancreas weights (108.34 +/- 5.29SE gm) were not significantly different from controls (110 gm). Microscopic findings included vascular congestion (48%), edema (65%), siderosis (31%), and nesidioblastosis (76%), which included islet cell dispersion (53%), hyperplasia (23%), and hypertrophy (25%). Analysis by age groups suggested that islet cell dispersion/hyperplasia persists unchanged, whereas diameters of compact islets tend to increase with age. These findings may be related to local tissue hypoxia and/or increased metabolic energy needs in sickle cell disease.
Abstract: OBJECTIVE: To determine whether children with homozygous sickle cell anemia (SCD) who have silent infarcts on magnetic resonance imaging (MRI) of the brain are at increased risk for overt stroke. METHODS: We selected patients with homozygous SCD who (1) enrolled in the Cooperative Study of Sickle Cell Disease (CSSCD) before age 6 months, (2) had at least 1 study-mandated brain MRI at age 6 years or older, and (3) had no overt stroke before a first MRI. MRI results and clinical and laboratory parameters were tested as predictors of stroke. RESULTS: Among 248 eligible patients, mean age at first MRI was 8.3 +/- 1.9 years, and mean follow-up after baseline MRI was 5.2 +/- 2.2 years. Five (8.1%) of 62 patients with silent infarct had strokes compared with 1 (0.5%) of 186 patients without prior silent infarct; incidence per 100 patient-years of follow-up was increased 14-fold (1.45 per 100 patient-years vs 0.11 per 100 patient-years, P =.006). Of several clinical and laboratory parameters examined, silent infarct was the strongest independent predictor of stroke (hazard ratio = 7.2, P =.027). CONCLUSIONS: Silent infarct identified at age 6 years or older is associated with increased stroke risk.
Abstract: The efficacy and side effects of hydroxyurea in young children with sickle cell disease are unknown. The authors followed-up eight young children (mean age 3.7 years) during therapy with hydroxyurea for an average of 137 weeks. Total and fetal hemoglobin levels rose with hydroxyurea therapy. Hospital admission rates and total hospital days decreased during hydroxyurea therapy. No unexpected toxicity occurred, and growth and development were unaffected. This pilot study suggests that hydroxyurea is safe and effective in young children with sickle cell disease.
Abstract: Erythrocyte transfusion can impair detection of sickle-cell disease, galactosemia, or biotinidase deficiency with newborn screening. We report on 4 infants with SCD in whom delayed diagnosis was associated with neonatal transfusion. In 2 cases, the initial newborn screening showed no hemoglobin S. In no case was the recommended screening >/=120 days from the last transfusion obtained. Two children had significant SCD-related morbidity before diagnosis.
Abstract: BACKGROUND: The acute chest syndrome is the leading cause of death among patients with sickle cell disease. Since its cause is largely unknown, therapy is supportive. Pilot studies with improved diagnostic techniques suggest that infection and fat embolism are underdiagnosed in patients with the syndrome. METHODS: In a 30-center study, we analyzed 671 episodes of the acute chest syndrome in 538 patients with sickle cell disease to determine the cause, outcome, and response to therapy. We evaluated a treatment protocol that included matched transfusions, bronchodilators, and bronchoscopy. Samples of blood and respiratory tract secretions were sent to central laboratories for antibody testing, culture, DNA testing, and histopathological analyses. RESULTS: Nearly half the patients were initially admitted for another reason, mainly pain. When the acute chest syndrome was diagnosed, patients had hypoxia, decreasing hemoglobin values, and progressive multilobar pneumonia. The mean length of hospitalization was 10.5 days. Thirteen percent of patients required mechanical ventilation, and 3 percent died. Patients who were 20 or more years of age had a more severe course than those who were younger. Neurologic events occurred in 11 percent of patients, among whom 46 percent had respiratory failure. Treatment with phenotypically matched transfusions improved oxygenation, with a 1 percent rate of alloimmunization. One fifth of the patients who were treated with bronchodilators had clinical improvement. Eighty-one percent of patients who required mechanical ventilation recovered. A specific cause of the acute chest syndrome was identified in 38 percent of all episodes and 70 percent of episodes with complete data. Among the specific causes were pulmonary fat embolism and 27 different infectious pathogens. Eighteen patients died, and the most common causes of death were pulmonary emboli and infectious bronchopneumonia. Infection was a contributing factor in 56 percent of the deaths. CONCLUSIONS: Among patients with sickle cell disease, the acute chest syndrome is commonly precipitated by fat embolism and infection, especially community-acquired pneumonia. Among older patients and those with neurologic symptoms, the syndrome often progresses to respiratory failure. Treatment with transfusions and bronchodilators improves oxygenation, and with aggressive treatment, most patients who have respiratory failure recover.
Abstract: This article outlines general strategies for outreaching to Southeast Asian immigrant and refugee communities with thalassemia education. Because of positive net migration and increased birthrates during the last 15 years, Asian Pacific Islanders are among the fastest growing populations in California. Dr. Fred Lorey of California Newborn Screening shows that 1 of 12 Southeast Asians is a carrier of hemoglobin E, demonstrating a particular need to outreach to these communities. The challenge of educating Southeast Asian populations include language barriers, differences in cultural and/or religious beliefs, geographic location, and unfamiliarity with and/ or mistrust of Western health care systems. In addition, outreach workers must consider the great diversity of ethnicity, language, literacy, and education levels, and degree of acculturation to the US within the Asian/Southeast Asian groups. It is crucial before embarking on any outreach campaign to understand the history and make-up of the target audience, including ethnic minorities and dialects, to translate written materials into appropriate languages or audio formats, and to have a group of trained interpreters for events. Additionally, a continuing education model for the outreach/medical staff is important to maintain robust understanding of these diverse communities. Specific strategies include using visual aids, medical professionals as authority figures, and bicultural high school and college students during presentations. Finally, establishing trust and maintaining a continued presence in communities are the most important aspects of a successful outreach campaign.
Abstract: Chronic transfusion therapy is being used more frequently to prevent and treat the complications of sickle cell disease. Previous studies have shown that the iron overload that results from such therapy in other patient populations is associated with significant morbidity and mortality. In this study we examined the extent of iron overload as well as the presence of liver injury and the predictive value of ferritin in estimating iron overload in children with sickle cell disease who receive chronic red blood cell transfusions. A poor correlation was observed between serum ferritin and the quantitative iron on liver biopsy (mean 13.68 +/- 6.64 mg/g dry weight; R = 0.350, P =.142). Quantitative iron was highly correlated with the months of transfusion (R = 0.795, P <.001), but serum ferritin at biopsy did not correlate with months of transfusion (R = 0.308, P =.200). Sixteen patients had abnormal biopsies showing mild to moderate changes on evaluation of inflammation or fibrosis. Liver iron was correlated with fibrosis score (R = 0.50, P =.042). No complications were associated with the liver biopsy. Our data suggest that, in patients with sickle cell disease, ferritin is a poor marker for accurately assessing iron overload and should not be used to direct long-term chelation therapy. Despite high levels of liver iron, the associated liver injury was not severe.
Abstract: Cerebral infarction occurs in one quarter of all children with sickle cell anemia (SCA). There is an increased risk of stroke in siblings with SCA, suggesting genetic factors may influence risk of stroke. The authors investigated whether HLA type was associated with risk of stroke in children with SCA. Fifty-three patients with SCA underwent complete HLA typing at both HLA class I (HLA-A, B) and HLA class II (HLA-DR, DQ, DP) loci. Of the 53 patients, 22 had magnetic resonance imagining (MRI)-documented evidence of cerebral infarction, and the remaining 31 patients had negative MRI scans. Comparison of the results of HLA typing between the SCA patients with a positive and those with a negative MRI documented that the 2 groups differed with respect to the class I HLA-B (P =.012), and the class II HLA-DRB1 (P =.0008) and DQB1 (P =.029). Susceptibility associations at the HLA-DRB1 locus included both DR3 alleles, where DRB1*0301 and *0302 were both associated with an increased risk of stroke. Protective associations were found in the DR2 group, where DRB1*1501 was protective for stroke. DQB1*0201, which is in linkage disequilibrium with DRB1*0301, was also associated with stroke. Similarly, DQB1*0602, in linkage disequilibrium with DRB1*1501, was protective. Specific HLA alleles may influence the risk of stroke in children with SCA. HLA typing may prove useful in identifying SCA patients at higher risk for stroke.
Abstract: Clinical, molecular, and genetic advances have revealed new pathophysiologic insights and treatments for the growing number of recognized hematologic and nonhematologic abnormalities in sickle cell disease. Treatment targets of cellular dehydration, sickle hemoglobin concentrations, endothelial dysfunction, and abnormal coagulation regulation have been validated as potential therapy. New uses for transfusion therapy hold the promise of decreased major symptoms of acute chest syndrome, stroke, and severe pain crises, but at the expense of increased risk for transfusion reactions, infections, and iron overload. Accumulated experience with autologous, chimeric, and stem cell bone marrow transplantation holds promise for a small percentage of patients with disease. Patient selection, suitable donors, and early mortality are still limiting factors. Genetic manipulation, which offers hope for ameliorating the disease in a larger percentage of patients, is progressing slowly. Combination and staged therapies will be developed and matched to the severity and progression of the patient's disease. Strategies for prevention of major organ damage to the brain, heart, lungs, and kidneys will be prospectively evaluated and refined.
Abstract: PURPOSE: To compare the results of standardized magnetic resonance imaging (MRI) of the brain and transcranial Doppler (TCD) ultrasonography of cerebral arteries in school-aged children with sickle cell disease to determine the correlation between these two different neurodiagnostic tests. PATIENTS AND METHODS: Data were analyzed from 78 children with sickle cell disease (mean age 11 yrs) who participated in both the Cooperative Study of Sickle Cell Disease (CSSCD) and the Stroke Prevention Trial in Sickle Cell Anemia (STOP). Patients who had experienced an overt stroke were excluded. MRI findings were classified as normal or "silent infarct." Results of TCD were classified as normal, conditional, or abnormal, based on the time-averaged maximum mean flow velocity in the proximal middle cerebral and distal internal carotid arteries. RESULTS: Of 61 patients who had a normal MRI examination, 11 (18%) had either conditional (5 patients) or abnormal (6 patients) TCD results. Among 17 patients in whom silent infarction was seen on MRI, only 5 (29%) had a conditional (1 patient) or abnormal (4 patients) TCD velocity. Thus, discordant results were seen in 23 patients: 12 in which the TCD result was normal and the MRI abnormal; 11 in which the TCD velocity was elevated and the MRI normal. CONCLUSIONS: Abnormal TCD and MRI examinations reveal different aspects of the pathophysiology of central nervous system (CNS) injury in sickle cell disease and are often discordant. Although TCD abnormality is predictive of overt stroke, the lack of concordance between TCD and MRI findings suggests a need to develop more sensitive and specific indicators of early CNS pathology, such as neuropsychometric testing and positron-emission tomography (PET) scans, and to obtain more information about microvascular pathologic processes that may affect CNS function.
Abstract: PURPOSE: Our objective was to evaluate L-arginine and nitric oxide metabolite (NOx) levels in children with sickle cell disease (SCD) at steady-state and during vaso-occlusive crisis (VOC). Because alterations in nitric oxide production may have an important role in the pathophysiology of SCD, our second aim was to determine if a relationship exists between these levels and vaso-occlusive crisis (VOC). PATIENTS AND METHODS: Plasma L-arginine and serum NOx levels were examined in 36 patients with SCD with 39 episodes of VOC and 10 children with SCD at steady-state. Daily levels were obtained in children requiring hospitalization. RESULTS: Steady-state L-arginine levels were normal in children with SCD. L-arginine levels were low, however, in children with VOC (37.4 +/- 2.7 vs. 53.6 +/- 4.6 micromol/L; P = 0.008) but returned to baseline during hospitalization. In contrast, NOx levels were normal at presentation but decreased during hospitalization for both patients with VOC and patients with acute chest syndrome (ACS) (21.1 +/- 2.0, 17.4 +/- 2.4, and 12.3 +/- 1.6 micromol/L, respectively; P < 0.05). In the patients with VOC who had ACS develop, L-arginine decreased to the lowest levels at the time of the ACS diagnosis, correlating with decreasing NOx levels. CONCLUSION: These data suggest that there may be a relationship between the L-arginine-nitric oxide pathway and vaso-occlusion in SCD. Low arginine levels during VOC could reflect a state of acute substrate depletion that results in a decrease in nitric oxide production.
Abstract: To determine the effects of L-arginine (L-Arg) supplementation on nitric oxide metabolite (NOx) production, oral L-Arg was given to normal controls, sickle cell disease (SCD) patients at steady state and SCD patients hospitalized with a vaso-occlusive crisis (VOC). L-Arg (0.1 g/kg) increased NOx formation by 18.8 +/- 68% in normal controls, whereas steady-state SCD patients demonstrated a paradoxical decrease in NOx of -16.7 +/- 4% (P = 0.004). In contrast, patients with VOC demonstrated a dramatic increase in NOx production by +77.7 +/- 103%, a response that was dose dependent. L-Arg appears to be the rate-limiting step in NOx production during VOC. Oral arginine may therefore benefit SCD patients by inducing an increase in NO production during VOC.
Abstract: The development of hemolytic alloantibodies and erythrocyte autoantibodies complicates transfusion therapy in thalassemia patients. The frequency, causes, and prevention of this phenomena among 64 transfused thalassemia patients (75% Asian) were evaluated. The effect of red blood cell (RBC) phenotypic differences between donors (mostly white) and Asian recipients on the frequency of alloimmunization was determined. Additional transfusion and patient immune factors were examined. 14 (22%) of 64 patients (75% Asian) became alloimmunized. A mismatched RBC phenotype between the white population, comprising the majority of the donor pool, and that of the Asian recipients, was found for K, c, S, and Fyb antigens, which accounts for 38% of the alloantibodies among Asian patients. Patients who had a splenectomy had a higher rate of alloimmunization than patients who did not have a splenectomy (36% vs 12.8%; P =.06). Erythrocyte autoantibodies, as determined by a positive Coombs test, developed in 25% or 16 of the 64 patients, thereby causing severe hemolytic anemia in 3 of 16 patients. Of these 16, 11 antibodies were typed immunoglobulin G [IgG], and 5 were typed IgM. Autoimmunization was associated with alloimmunization and with the absence of spleen (44% and 56%, respectively). Transfused RBCs had abnormal deformability profiles, more prominent in the patients without a spleen, which possibly stimulated antibody production. Transfusion of phenotypically matched blood for the Rh and Kell (leukodepleted in 92%) systems compared to blood phenotypically matched for the standard ABO-D system (leukodepleted in 60%) proved to be effective in preventing alloimmunization (2.8% vs 33%; P =.0005). Alloimmunization and autoimmunization are common, serious complications in Asian thalassemia patients, who are affected by donor-recipient RBC antigen mismatch and immunological factors.
Abstract: Acute chest syndrome (ACS) is the leading cause of death in sickle cell disease. Severe ACS often develops in the course of a vaso-occlusive crisis (VOC), but currently there are no predictors for its development. Secretory phospholipase A(2) (sPLA(2)), a potent inflammatory mediator, is elevated in ACS, and previous work suggests that sPLA(2) predicts impending ACS. We prospectively evaluated sPLA(2) concentration during 21 admissions for VOC; 6 of these patients went on to develop ACS. Elevation of sPLA(2) was detected all 6 patients 24 to 48 hours before ACS was clinically diagnosed. Adding the requirement for fever raised the specificity of sPLA(2) to 87% while retaining 100% sensitivity. These data indicate that sPLA(2) can be useful in alerting the clinician to patients with impending ACS. In addition, sPLA(2) may be useful for instituting early therapies to prevent or reduce the clinical morbidity of ACS.
Abstract: Fifty children who had symptomatic sickle cell disease received matched sibling marrow allografts between September 1991 and March 1999, with Kaplan-Meier probabilities of survival and event-free survival of 94% and 84%, respectively. Twenty-six patients (16 male, 10 female) had at least 2 years of follow-up after transplantation and were evaluated for late effects of transplantation and for its impact on sickle cell-related central nervous system (CNS) and pulmonary disease. Patients ranged between 3.3 and 14.0 (median, 9. 4) years of age and had a median follow-up of 57.9 (range 38-95) months after transplantation. Among 22 of 26 patients who had stable donor engraftment, complications related to sickle cell disease resolved, and none experienced further episodes of pain, stroke, or acute chest syndrome. All 10 engrafted patients with a prior history of stroke had stable or improved cerebral magnetic resonance imaging results. Pulmonary function tests were stable in 22 of the 26 patients, worse in two, and not studied in two. Seven of eight patients transplanted for recurrent acute chest syndrome had stable pulmonary function. Linear growth measured by median height standard deviation score improved from -0.7 before transplantation to -0.2 after transplantation. An adverse effect of busulfan conditioning on ovarian function was demonstrated in five of seven evaluable females who are currently at least 13 years of age. None of the four males tested had elevated serum gonadotropin levels. These data confirm that allogenic bone marrow transplantation establishes normal erythropoiesis and is associated with improved growth and stable CNS imaging and pulmonary function in most patients. (Blood. 2000;95:1918-1924)
Abstract: Only a few long-term survivors of homozygous alpha-thalassemia, a usually fatal condition, have been reported. The authors present a surviving infant with this disorder and discuss the complications, treatments, and implications of this genetic hemoglobinopathy. The child had no antenatal intervention and has been treated with regular transfusions. She has had normal growth and development and is currently 2.5-years-old. A literature review of survivors with Bart hemoglobinopathy reveals an intense perinatal course and a great prevalence of congenital urogenital and limb defects. Advances in antenatal diagnosis, intrauterine intervention, and postnatal treatments have resulted in extended survival of children with congenital defects that until recently were considered invariably fatal. Transfusion and chelation therapy and bone marrow transplantation provide long-term treatment and potential curative options.
Abstract: PURPOSE: To compare the rates of perioperative morbidity of patients with sickle cell anemia who were randomly assigned to 2 preoperative transfusion regimens and to identify predisposing factors for perioperative complications. PATIENTS AND METHODS: Investigators at 36 centers enrolled 118 patients who were scheduled to have elective surgery and agreed to randomization between 2 preoperative transfusion regimens. Forty-seven subjects were enrolled but not randomized, including 20 who were not transfused before surgery. Perioperative management was based on a prescribed care plan. RESULTS: Tonsillectomy and/or adenoidectomy (TA) were performed on 136 persons, and 29 had myringotomy as their primary procedure. There were no differences in the frequency of complications between the randomized groups. The serious, non-transfusion complication rates for randomized patients were 32% (34 of 107) for TA and 36% (4 of 11) for myringotomy. A history of pulmonary disease was a predictor of postoperative sickle cell-related events for patients undergoing TA surgery. CONCLUSIONS: The more intensive transfusion regimen did not result in fewer perioperative complications. The high frequency of complications emphasizes the need for anticipatory management of persons undergoing TA. A history of pulmonary disease identifies patients at increased risk for sickle cell-related events after TA surgery. Patients undergoing myringotomy have a low frequency of sickle cell-related events but a significant frequency of other serious perioperative complications.
Abstract: Nearly 25% of patients with sickle cell disease (SCD) experience central nervous system morbidity involving both large and small vessel disease. Optimal imaging methods for determining the extent of ischemia are not known. Positron emission tomography (PET) has the unique ability to show tissue function as well as structure. Reports concerning patients with non-SCD neurodegenerative disorders suggest PET may be useful in determining prognosis. We compared magnetic resonance imaging, magnetic resonance angiography, and neuropsychological testing with PET prospectively. Six patients with SCD and a history of stroke, aged 10 to 28, were enrolled. PET studies were performed on an ECAT HR 47 scanner (Siemens/CTI, Knoxville, TN) using 18-F-fluorodeoxyglucose as a tracer. PET interpretations were conducted in blinded fashion. MRI studies found two patients with only small vessel disease and four with both large and small vessel disease. In two of four subjects with large vessel disease, PET showed a corresponding metabolic abnormality and also identified an area of hypometabolism extending beyond the anatomical lesion as shown by MRI. PET did not demonstrate an abnormality corresponding with small vessel disease. Detailed neuropsychological testing demonstrated cognitive dysfunction in all cases. For some patients, PET may add sensitivity in detecting impaired metabolism in the area surrounding a major vessel infarct. However, the technique does not appear to be generally useful in characterizing small watershed or deep white matter infarcts. Larger studies, to include control subjects and carefully selected untransfused SCD patients, are needed. A combination of conventional imaging and neuropsychological testing remains the preferred evaluation for most SCD patients with neurologic symptoms.
Abstract: BACKGROUND: Silent infarcts have been reported in 17% of young patients with sickle cell disease and are associated with impaired performance on standardized psychometric tests. Risk factors for the development of these lesions have not been identified. METHODS: Investigators in the Cooperative Study of Sickle Cell Disease performed a brain magnetic resonance imaging scan on sickle cell anemia patients age 5.9 years and older who had been followed according to the protocols of the Cooperative Study since birth. Individuals with a known history of cerebrovascular accident were excluded from this analysis. Patients with and without silent infarctions were compared with regard to clinical and laboratory parameters. RESULTS: The study sample included 42 patients (18.3%) with silent infarcts. Patients who had silent infarcts were significantly more likely to have a clinical history of seizure and a lower painful event rate. Lower hemoglobin level, increased leukocyte count, elevated pocked red blood cell count, and SEN betaS globin gene haplotype were associated also with the presence of silent infarcts. There was no relationship between silent infarcts and platelet count, fetal hemoglobin level, reticulocyte percentage, serum aspartate aminotransferase level, total bilirubin concentration, blood pressure, growth parameters, or presence of alpha-thalassemia. A multivariate model for silent infarction identified the following as risk factors: low pain event rate, history of seizure, leukocyte count >/=11.8 x 10(9)/L, and the SEN betaS globin gene haplotype. CONCLUSIONS: Patients with risk factors for silent infarcts should be evaluated for cerebrovascular disease. If evidence of infarction is found, consideration must be given to therapeutic intervention. At present, the appropriate treatment has not been determined.
Abstract: Orthopedic disease affects the majority of sickle cell anemia patients of which aseptic necrosis of the hip is the most common, occurring in up to 50% of patients. We conducted a multicentered study to determine the perioperative complications among sickle cell patients assigned to different transfusion regimens prior to orthopedic procedures: 118 patients underwent 138 surgeries. The overall serious complication rate was 67%. The most common of these were excessive intraoperative blood loss, defined as in excess of 10% of blood volume. The next most common complication was sickle cell-related events (acute chest syndrome or vaso-occlusive crisis), which occurred in 17% of cases. While preoperative transfusion group assignment did not predict overall complication rates, higher risk procedures were associated with significantly higher rates of overall complications. Transfusion complications were experienced by 12% of the patients. Two patients died following surgery. Both deaths were associated with an acute pulmonary event. The 52 patients undergoing hip replacements experienced the highest rate of complications with excessive intraoperative blood loss occurring in the majority of patients. Sickle cell-related events occurred in 19% of patients, and surgical complications occurred after 15% of hip replacements and included postoperative hemorrhage, dislocated prosthesis, wound abscess, and rupture of the femoral prosthesis. There were twenty-two hip coring procedures. Acute chest syndrome occurred in 14% of the patients. Overall, decompression coring was a safer, shorter operation. A randomized prospective trial to determine the perioperative and long-term efficacy of core decompression for avascular necrosis of the hip in sickle cell disease is needed. In conclusion, this study demonstrates a high rate of perioperative complications despite compliance with sickle cell perioperative care guidelines. Pulmonary complications and transfusion reactions were common. This study supports the results previously published by the National Preoperative Transfusion in Sickle Cell Disease Group. These results stated that a conservative preoperative transfusion regimen to bring hemoglobin concentration to between 9 and 11 g/dl was as effective as an aggressive transfusion regimen in which the hemoglobin S level was lowered to 30%.
Abstract: The practice of transfusion for patients with sickle cell disease is changing. Diminished childhood mortality is resulting in greater patient longevity and a higher prevalence of chronic systemic complications. Many of these chronic complications, as well as several acute ones, are treatable with erythrocyte transfusion. Proactive or preventive uses for transfusion are being considered for selected patients. Immunologic phenomena, hemosiderosis, and risk for transmission of infectious agents are the three most noticeable risks associated with repetitive transfusion. Evolving work with alternative oxygen carriers and surface modification of erythrocytes is also promising and relevant for patients with sickle cell disease.
Abstract: Cerebrovascular accident (CVA) is a major complication of sickle cell disease during childhood. Long-term transfusion reduces the hemoglobin S level and generally prevents recurrent stroke, but it also results in progressive iron overload that requires regular chelation therapy. Erythrocytapheresis offers an alternative approach aimed at reducing the iron accumulation. We reviewed the results of erythrocytapheresis in eight sickle cell patients (mean age of 12.1 years) at high risk for a first or recurrent stroke. They were maintained at the standard pre-transfusion hemoglobin S (Hb S) level of 30%. Over an average of 9 months of erythrocytapheresis, none of the patients developed complications related to the procedure or to the increased blood use. Ferritin levels decreased by a mean of 26.5% in all patients. When evaluating the ferritin level in five patients, who remained on chelation therapy with deferoxamine (DFO), the level dropped by a mean of 32%. The levels remained stable in the three patients who were not on DFO. The procedure is safe and effective in reducing iron overload and can obviate the need for chelation therapy, even when the target Hb S is maintained at the standard 30% range.
Abstract: The use of the iron chelator, Deferoxamine (DFO), in pregnant thalassemia women with iron overload has been generally avoided due to fear of its potential teratogenicity. We describe a case of a pregnant thalassemia major patient with iron overload, who received DFO throughout her second and third trimesters and gave birth to a healthy infant, who had no findings of DFO toxicity at birth and at a later follow-up. Review of the literature discloses over 40 other cases in which DFO was given in various periods of gestation without evidence of teratogenic effect. Sufficient documentation exists, therefore, to suggest that DFO can be considered for use in cases of pregnant women who need iron chelation treatment.
Abstract: BACKGROUND: Previous studies indicate that resting energy expenditure is elevated in children with sickle cell anemia, possibly caused in part by hemolysis and increased erythropoietic activity. The purpose of the present investigation was to determine whether erythrocyte transfusion normalizes resting energy expenditure in sickle cell anemia. METHODS: Five adolescents with sickle cell anemia (12-16 years old; 4 boys, 1 girl) were studied before and 1 week after erythrocyte transfusion before elective surgery or at the initial transfusion for growth failure. Resting energy expenditure was measured by indirect calorimetry, and laboratory measures were determined by routine, validated methods. Data comparisons were by nonparametric analysis. RESULTS: After erythrocyte transfusion, total hemoglobin levels increased (difference (D) = 15 g/l; p < 0.05), whereas hemoglobin S (D = -0.36; p < 0.05) and reticulocyte count (D = -0.12; p < 0.05) decreased. Mean pretransfusion resting energy expenditure was elevated to 124% above predicted levels (p < 0.05) and increased further to 134% above prediction (p < 0.05 vs. pretransfusion levels). Plasma triiodothyronine (T3) levels increased (D = 0.17 nmol/l; p < 0.05), reverse T3 (rT3) levels tended to decline (D = -0.04 nmol/l; p = 0.14), and rT3/T3 decreased (D = -0.03; p < 0.05). Plasma insulin-like growth factor-I (IGF-I) levels were low-normal before transfusion and did not change, despite the change in resting energy expenditure. CONCLUSIONS: The results confirm that resting energy expenditure is elevated in patients with sickle cell anemia. However, resting energy expenditure further increased after transfusion, despite decreased erythropoietic activity. A posttransfusion decrease in rT3/T3 may contribute to the increased resting energy expenditure. That there was no change in IGF-I implies that the growth hormone-IGF system is not involved in posttransfusion regulation of resting energy expenditure. Therefore, our data are not consistent with the hypothesis that increased resting energy expenditure in sickle cell anemia is directly related to erythropoietic activity. The mechanisms by which resting energy expenditure increases after transfusion in sickle cell anemia require additional investigation.
Abstract: STUDY OBJECTIVE: To determine whether the use of empiric chest radiography (CXR) is of significant value in detecting clinically unsuspected acute chest syndrome (ACS) in febrile patients with sickle cell disease (SCD). METHODS: Patients with SCD presenting to the emergency department and hematology clinic with temperature greater than or equal to 38 degrees C were prospectively evaluated using a physician-completed questionnaire. The questionnaire included inquiries into the patient's physical signs and symptoms and the physician's clinical impression for the presence of ACS. The questionnaire was completed before obtaining CXR results in all patients. RESULTS: Seventy-three patients with SCD with 96 febrile events were evaluated over a 1-year period. Twenty-four percent (23/96) of the patients had CXR evidence of ACS. On the basis of the questionnaire data, 61% (14/23) of ACS cases were not clinically suspected by the evaluating physician before obtaining CXR. Comparing the patients with and without ACS revealed that, with the exception of splinting (4/23 [17%] versus 0/73 [0%]), no symptom or physical examination finding helped to identify which patients had ACS. Fifty-seven percent of patients with ACS had completely normal findings on physical examination. The presentation of patients with clinically detected versus clinically unsuspected ACS also did not differ significantly. Length of hospitalization, oxygen use, and need for transfusion were the same in both the unsuspected and detected ACS groups. Overall physician sensitivity for predicting ACS was only 39%, and diagnostic accuracy did not improve significantly with increasing levels of pediatric training. CONCLUSION: ACS is common in patients with SCD who present with fever and was grossly underestimated by evaluating physicians. History and physical examination appear to be of little value in defining which febrile patients require CXR. In view of the mortality and morbidity associated with ACS, empiric CXR should be considered when evaluating a febrile patient with SCD.
Abstract: Hydroxyurea (HU) and sodium phenylbutyrate (SPB) have been shown to increase fetal hemoglobin (Hb F) levels in patients with thalassemia intermedia. The reported effects of these agents in increasing total Hb, however, have been inconsistent and there have been no studies on the combination of these medications. We describe the clinical response, as determined by increases in total Hb and decreased transfusion needs, in five patients with thalassemia intermedia treated with HU alone or in combination with SPB. All of the patients responded with increased levels of Hb F, but the responses in total Hb varied. Of the five patients, two had a marked response in total Hb in excess of 3 g/dl, two responded modestly with an increase in total Hb of 1-2 g/dl, and one did not respond. Prolonged responses were achieved with low doses of HU (3-10 mg/kg/day) and higher doses were associated with mild reversible hematologic or hepatic toxicity and no further increases in Hb. Sodium phenylbutyrate was added to treatment with HU in two patients, but failed to produce an increase in total Hb despite increasing Hb F levels. Of the four patients who responded to HU with an increase in total Hb, all reported symptomatic improvement and three have not required further transfusions. We conclude that low-dose HU therapy in patients with thalassemia intermedia may increase total Hb levels sufficiently to eliminate the need for transfusions. We, therefore, recommend a trial of HU for thalassemia intermedia patients in whom chronic transfusion therapy is being contemplated.
Abstract: Previous studies have determined the short-term toxicity profile, laboratory changes, and clinical efficacy associated with hydroxyurea (HU) therapy in adults with sickle cell anemia. The safety and efficacy of this agent in pediatric patients with sickle cell anemia has not been determined. Children with sickle cell anemia, age 5 to 15 years, were eligible for this multicenter Phase I/II trial. HU was started at 15 mg/kg/d and escalated to 30 mg/kg/d unless the patient experienced laboratory toxicity. Patients were monitored by 2-week visits to assess compliance, toxicity, clinical adverse events, growth parameters, and laboratory efficacy associated with HU treatment. Eighty-four children were enrolled between December 1994 and March 1996. Sixty-eight children reached maximum tolerated dose (MTD) and 52 were treated at MTD for 1 year. Significant hematologic changes included increases in hemoglobin concentration, mean corpuscular volume, mean corpuscular hemoglobin, and fetal hemoglobin parameters, and decreases in white blood cell, neutrophil, platelet, and reticulocyte counts. Laboratory toxicities typically were mild, transient, and were reversible upon temporary discontinuation of HU. No life-threatening clinical adverse events occurred and no child experienced growth failure. This Phase I/II trial shows that HU therapy is safe for children with sickle cell anemia when treatment was directed by a pediatric hematologist. HU in children induces similar laboratory changes as in adults. Phase III trials to determine if HU can prevent chronic organ damage in children with sickle cell anemia are warranted.
Abstract: Sickle cell disease results in significant morbidity and mortality for those affected with this disease. Despite the fact that every case of sickle cell disease results from the same genetic mutation, there is considerable heterogeneity in the clinical course of the disease. Considerable knowledge has been gained regarding the complications of sickle cell disease including pain episodes, infections, stroke, and lung disease. Clarifying the clinical course of sickle cell disease has enabled us to develop therapies to decrease the morbidity of this disease and, with hope, will direct further investigations into novel treatment interventions.
Abstract: BACKGROUND: Blood transfusions prevent recurrent stroke in children with sickle cell anemia, but the value of transfusions in preventing a first stroke is unknown. We used transcranial Doppler ultrasonography to identify children with sickle cell anemia who were at high risk for stroke and then randomly assigned them to receive standard care or transfusions to prevent a first stroke. METHODS: To enter the study, children with sickle cell anemia and no history of stroke had to have undergone two transcranial Doppler studies that showed that the time-averaged mean blood-flow velocity in the internal carotid or middle cerebral artery was 200 cm per second or higher. The patients were randomly assigned to receive standard care or transfusions to reduce the hemoglobin S concentration to less than 30 percent of the total hemoglobin concentration. The incidence of stroke (cerebral infarction or intracranial hemorrhage) was compared between the two groups. RESULTS: A total of 130 children (mean [+/-SD] age, 8.3+/-3.3 years) were enrolled; 63 were randomly assigned to receive transfusions and 67 to receive standard care. At base line, the transfusion group had a slightly lower mean hemoglobin concentration (7.2 vs. 7.6 g per deciliter, P=0.001) and hematocrit (20.4 vs. 21.7 percent, P=0.002). Ten patients dropped out of the transfusion group, and two patients crossed over from the standard-care group to the transfusion group. There were 10 cerebral infarctions and 1 intracerebral hematoma in the standard-care group, as compared with 1 infarction in the transfusion group -- a 92 percent difference in the risk of stroke (P<0.001). This result led to the early termination of the trial. CONCLUSIONS: Transfusion greatly reduces the risk of a first stroke in children with sickle cell anemia who have abnormal results on transcranial Doppler ultrasonography.
Abstract: Acute chest syndrome (ACS) is the presence of a new pulmonary infiltrate in combination with fever or respiratory symptoms in a patient with sickle cell disease. ACS is the leading cause of death in sickle cell disease, and many patients suffer from multiple, severe episodes. Age has a striking effect on the clinical course and outcome of ACS, with children having milder disease that often is infectious. Adults often have severe disease, and pulmonary fat embolism is frequently a component of severe ACS. Rapid diagnosis and appropriate therapy including antibiotics for atypical infections, fluids, aerosolized beta agonists, and adequate pain control are necessary to reduce morbidity. Transfusion is indicated in hypoxic patients and can be used to prevent recurrent episodes. As the pathophysiology of ACS is further delineated, new treatment strategies will be investigated.
Abstract: Heterozygotes and homozygotes for HbE (beta 26, GAG-AAG, Glu-Lys) are microcytic, minimally anemic, and asymptomatic. The microcytosis is attributed to the beta thalassemic nature of the beta(E) gene, whereas the in vitro instability of HbE does nor contribute to the phenotype, However the compound heterozygote state HbE/beta thalassemia results in a variable, and often severe anemia, with the phenotype ranging from transfusion dependence to a complete lack of symptoms, This has been well documented in Thailand, but the basis of the interaction and the cause of the variability remains unexplained. We have studied 50 HbE/beta thalassemics from the UK and 16 from Oakland, CA and assessed the role of HbE instability. Time-course globin chain synthesis experiments have shown that instability is not an important factor in the steady state, but that at 41 degrees C newly synthesized Hb molecules are unstable, We have identified one family in which HbE interacts with pyrimidine 5' nucleotidase deficiency to cause severe anemia with Hb instability, The UK individuals, mostly of Bengali origin, have Hb's from 4.5-11 g/dl, The beta thalassemia mutation, alpha thalassemia and the Xmn 1 G gamma polymorphism do not explain this variability, but the relative and absolute amounts of HbF correlate significantly with total Hb. The Oakland individuals, mostly from Southeast Asia, show similar variation in Hb, which again is largely unexplained.
Abstract: Stroke occurs in 7-8% of children with Sickle Cell Disease (Hb SS) and is a major cause of morbidity. Rates of recurrence have been reduced from 46-90% to less than 10% through chronic blood transfusions. Prevention of first stroke, however, would be preferable because even one stroke can cause irreversible brain injury. Transcranial Doppler (TCD) ultrasound can detect arterial blood flow rates associated with subsequent stroke risk. By combining TCD screening and a potentially effective treatment, first stroke may be prevented. The Stroke Prevention Trial in Sickle Cell Anemia (STOP) is the first stroke prevention trial in Hb SS and the first randomized, controlled use of transfusion in Hb SS. This multi-center trial is designed to test whether reducing sickle hemoglobin to 30% or less with periodic blood transfusions will reduce first-time stroke by at least 70% compared to standard care. Primary endpoints will be clinically evident symptoms of cerebral infarction with consistent findings on Magnetic Resonance Imaging and Angiography (MRI/MRA) or symptomatic intracranial hemorrhage. Secondary endpoints will be asymptomatic brain lesions detected by MRI in brain areas not involved in primary endpoints. The design calls for a 6-month start-up interval, 18 months of TCD screening and randomization, and observation for stroke from entry through month 54. Key features of the trial are standardized TCD and MRI/MRA protocols interpreted blindly, and blinded adjudication of endpoints. The sample size (60 per treatment group) is based on prospective data relating TCD velocity to risk of stroke. A time-averaged mean velocity of > or = 200 cm/sec is associated with a 46% risk of cerebral infarction over 39 months. The sample size is sufficient to detect 70% reduction in the primary endpoint at 90% power. This trial will determine if transfusion is effective in the primary prevention of stroke. Secondary aims may further the understanding of the effects of transfusion on the brain and guide future research into cerebrovascular disease in Hb SS.
Abstract: Heterozygotes and homozygotes for HbE (beta 26, GAG-AAG, Glu-Lys) are microcytic, minimally anemic, and asymptomatic. The microcytosis is attributed to the beta thalassemic nature of the beta E gene, whereas the in vitro instability of HbE does not contribute to the phenotype. However, the compound heterozygote state HbE/beta thalassemia results in a variable, and often severe anemia, with the phenotype ranging from transfusion dependence to a complete lack of symptoms. This has been well documented in Thailand, but the basis of the interaction and the cause of the variability remains unexplained. We have studied 50 HbE/beta thalassemics from the UK and 16 from Oakland, CA and assessed the role of HbE instability. Time-course globin chain synthesis experiments have shown that instability is not an important factor in the steady state, but that at 41 degrees C newly synthesized Hb molecules are unstable. We have identified one family in which HbE interacts with pyrimidine 5' nucleotidase deficiency to cause severe anemia with Hb instability. The UK individuals, mostly of Bengali origin, have Hb's from 4.5-11 g/dl. The beta thalassemia mutation, alpha thalassemia and the Xmn 1 G gamma polymorphism do not explain this variability, but the relative and absolute amounts of HbF correlate significantly with total Hb. The Oakland individuals, mostly from Southeast Asia, show similar variation in Hb, which again is largely unexplained.
Abstract: Severe forms of epidermolysis bullosa result in a transfusion-dependent chronic anemia and are fatal. The cause of the anemia is unknown. We evaluated five children whose anemia failed to respond to oral iron but who became transfusion independent after treatment with intravenous iron and human recombinant erythropoietin.
Abstract: While surgery is commonly required for complications related to hemoglobin SC (HbSC) disease, little is known about the perioperative complications or the indications for preoperative transfusion in this group. We describe the patient characteristics, preoperative transfusion regimens, and outcome in 92 patients with HbSC and sickle-variants undergoing elective surgery. Thirty-eight percent of the patients were transfused preoperatively. Patients transfused were more likely to have been hospitalized in the year prior to the surgery and scheduled for abdominal procedures. Abdominal and ear, nose and throat procedures were the most common surgeries in our study. The overall complication rate was 18% and sickle cell-related complications occurred in 9% of patients. In patients undergoing intra-abdominal procedures, the incidence of sickle cell-related complications was significantly higher in those patients not transfused prior to their surgery (35 vs. 0%). There were two deaths. We recommend selective use of preoperative transfusion in patients with HbSC disease undergoing surgery. Transfusion appears to be beneficial in abdominal cases but is not necessary with minor procedures such as myringtomy.
Abstract: PURPOSE: Hydroxyurea therapy reduces clinical complications in sickle cell disease. While evaluating the clinical and laboratory responses to hydroxyurea in children with sickle cell disease, we concurrently objectively monitored, for the first time during such treatment, compliance with therapy. Because most deaths in affected children are related to infection, we also evaluated the impact of hydroxyurea on splenic function, estimated by the percentage of red cells containing endocytic vacuoles ("pitted" cells) over 1 year of therapy. PATIENTS AND METHODS: Seventeen children with a history of > or = 3 hospital admissions in the previous year, aged (mean +/- standard error of mean) 12.3 +/- 1.2 years, were treated with hydroxyurea. Clinical and laboratory assessments monitored efficacy and toxicity. Compliance was monitored using computerized pill bottles containing cap microprocessors which monitor the frequency of bottle openings. RESULTS: Over 18.5 +/- 2.1 months, compliance with hydroxyurea (as determined by percent of the prescribed drug actually taken) was 96 +/- 2%, resulting in increases in mean fetal hemoglobin from 7.7 +/- 1.6% to 16.7 +/- 1.8% (p < 0.005). In 11 patients who reached maximum tolerated doses, an increase to 18.8 +/- 2.5% (p = 0.0001) was observed. Pitted red cell counts did not change. Annual rates of vaso-occlusive crisis (p = 0.0105), acute chest syndrome (p = 0.0417), transfusions administered (p = 0.0168), and days in hospital (p = 0.0017) all decreased significantly. CONCLUSIONS: Hydroxyurea in children is associated with sustained excellent compliance and monitoring this compliance is uncomplicated. Splenic function in most hydroxyurea-treated children did not change over 1 year of therapy.
Abstract: The familial pattern of recurring pain and early death seen so often among those affected by sickle cell disease has been long recognized within African cultures, though its first clear description in Western medical literature did not appear until 1910 (1). Although most common in persons of African ancestry, the mutation giving rise to the sickle gene arose independently in several locations where malaria was prevalent (2), traveled with migrating populations, and is now widely distributed among regions and ethnic groups. Recognizing the qualitative abnormality of sickle hemoglobin as a prototype, Pauling & Castle established the notion of a molecular disease (3). Ironically, while the biochemistry and molecular biology of sickle cell disease has been intensively investigated, research into patient care has been limited in scope until recently. Prospective study of large patient groups diagnosed at birth is now providing insight into the disease's natural history and facilitating investigational treatments. Newborn diagnosis, combined with study of new drugs, cytokines, surgical procedures, and a more proactive utilization of transfusion is leading to greatly improved care and survival. Life expectancy is increasing (4) but adults are experiencing more complications of chronic organ dysfunction. A few patients have been cured by stem-cell transplantation, but difficult problems will continue to limit its application.
Abstract: BACKGROUND: There is increasing use of highly sensitive testing with polymerase chain reaction (PCR) to study white cell microchimerism after transfusion and transplantation. This study investigated possible artifactual sources of allogeneic sample contamination before PCR testing. STUDY DESIGN AND METHODS: Quantitative Y-chromosome PCR was used to study microchimerism among transfused patients with sickle cell disease (SCD) and thalassemia by using residual specimens from the clinical laboratory. High levels of circulating male white cells among transfused patients with SCD but not thalassemia led to concern over the artifactual origin of male cells. To investigate, paired specimens were collected from 26 female SCD patients: one specimen underwent processing only for PCR, while the other underwent testing in the clinical laboratory before PCR as a process control. All laboratory instruments were also assessed for their ability to impart male allogeneic cells to aliquots of female blood. RESULTS: Thirty-three (31%) of 107 SCD samples, but 0 of 20 thalassemia samples, gave a high-level PCR signal. One of 26 paired samples that was not exposed to clinical laboratory equipment had low-level PCR positivity while 10 of the 26 became strongly positive after testing on a blood cell analyzer and a reticulocyte analyzer. Sixteen of 32 female samples became positive after reticulocyte analysis, while none became positive after blood cell analysis. Samples from thalassemia patients tested PCR-negative because reticulocyte counts had not been performed. CONCLUSION: Allogeneic cell contamination is common with clinical laboratory equipment. These samples may not be suitable for microchimerism studies. In addition to method controls, process controls should be employed where appropriate.
Abstract: As thalassemia patients age, bone disease becomes a serious cause of morbidity. The frequency and type of bone disease is affected by the underlying type of thalassemia and its treatment. Problems include rickets, scoliosis, spinal deformities, nerve compression, fractures and severe osteoporosis. In early stages, patients may be asymptomatic but can present with back pain, a limp, dyspnea, neurological emergencies, or sudden fractures. The etiologies are often multifactorial, culminating with increased bone resorption and remodeling. They include hormonal deficiency, bone marrow expansion, nutritional deficiency, or desferal toxicity. Particular risk factors include older patients, low baseline hemoglobin, delayed puberty, hormonal failure, and high iron stores. Nutritional deficiencies may further compound the patient's risk for bone disease. Increasing evidence suggests that these complications and their associated long-term morbidity can be prevented if an annual screening is done, followed by long-term intervention. Patients treated with amino biphosphonates inhibit bone resorption and may demonstrate rapid healing. Intra-nasal calcitonin has also been successful in treating osteopenia. Early use of estrogen and testosterone appears to markedly lower the risk for selective patients. Both transfused and non-transfused patients should be educated about risk factors and early symptoms. All patients should be screened annually for bone disease. Once adolescence occurs, annual testing in selected cases should include bone density studies with X-ray absorptiometry.
Abstract: Even though there is recognized morbidity and death associated with bone marrow transplantation, this procedure has been performed successfully in a substantial number of patients with hemoglobinopathies. However, finding a suitable related donor is often difficult and the morbidity associated with the use of unrelated donors is high. Several reports indicate that fewer than 30% of patients with thalassemia major and fewer than 20% of patients with sickle cell anemia have histocompatible siblings. Human umbilical cord blood (UCB) contains hematopoietic stem cells capable of reconstituting bone marrow. To date, approximately 200 transplantations have been performed with UCBs. Early results suggest that, even with substantial human leukocyte antigen (HLA) incompatibility, a decrease in the incidence of graft-versus-host disease occurs with cord blood. The extent to which HLA incompatibility can be tolerated when cord blood is used has not been determined. These results raise the possibility that UCB obtained from unrelated donors could be used for transplantation in patients with hemoglobinopathies. This review summarizes current data on UCB stem cells used for transplantation in hematologic diseases. The review contains a discussion of the potential uses of UCB for patients with hemoglobinopathies and the value of programs designed to collect UCB from newborn infants with hemoglobinopathies, from siblings of patients with hemoglobinopathies, and from groups of ethnic minorities similar to those in which hemoglobinopathies are found.
Abstract: PURPOSE: To evaluate the consequences of prolonged prophylactic penicillin use on the rates of nasopharyngeal colonization with Streptococcus pneumoniae and the prevalence of resistant pneumococcal strains in children with sickle cell anemia. METHODS: Nasopharyngeal specimens were obtained from children with sickle cell anemia (Hb SS or Hb S beta degrees thalassemia) at 10 teaching hospitals throughout the United States. These patients were participating in a prospective, randomized, placebo-controlled trial in which they were prescribed prophylactic penicillin before their fifth birthday and were randomized to prophylactic penicillin or placebo after their fifth birthday (PROPS II). The specimens were cultured for S. pneumoniae, and isolates were analyzed for antimicrobial susceptibility to nine commonly prescribed antimicrobial agents. RESULTS: Of the 226 patients observed, an average of 8.4 specimens were collected per patient. From 1,896 individual culture specimens, 5.5% of the specimens were positive for S. pneumoniae; 27% of patients had at least one positive culture. Nine percent of the study patients had at least one isolate of penicillin intermediate or resistant pneumococci. There was no significant difference in the percent of positive cultures for S. pneumoniae in those patients given penicillin prophylaxis after 5 years of age (4.1%) compared with those patients given placebo after 5 years of age (6.4%). Likewise, there was no significant difference (p = 0.298) in the percent of patients with at least one positive culture for S. pneumoniae in the group given prophylactic penicillin after 5 years of age (21.8%) compared with the group given placebo after 5 years of age (28.3%). There was no difference between the penicillin and placebo groups in the proportion of patients with penicillin intermediate or resistant pneumococci, but there was a trend toward increased carriage of multiply drug-resistant pneumococci in children > 5 years of age receiving prophylactic penicillin compared to children > 5 years of age receiving placebo. The increased colonization rate with multiply drug-resistant organisms of children > 5 years of age receiving penicillin prophylaxis is not statistically significant. CONCLUSIONS: The potential for continued penicillin prophylaxis to contribute to the development of multiply resistant pneumococci should be considered before continuing penicillin prophylaxis in children with sickle cell anemia who are older than 5 years of age. Added to the published data from PROPS II, which demonstrated no apparent advantage to continue prophylaxis, the data support the conclusion that, for children with no history of invasive pneumococcal disease, consideration should be given to discontinue prophylactic penicillin after their fifth birthday.
Abstract: Hydroxyurea (HU) can increase fetal hemoglobin (HbF) in sickle cell anemia (HbSS). To identify determinants of the HbF response, we studied 150 HU-treated patients grouped by quartiles of change in HbF from baseline to 2 years. Half of the HU-assigned patients had long-term increments in HbF. In the top two quartiles, HbF increased to 18.1% and 8.8%. These patients had the highest baseline neutrophil and reticulocyte counts, and largest treatment-associated decrements in these counts. In the lower two quartiles, 2-year HbF levels (4.2% and 3.9%) and blood counts changed little from baseline. In the highest HbF response quartile, myelosuppression developed in less than 6 months, compliance was best. and final doses of HU were 15 to 22.5 mg/kg. All four quartiles had substantial increases of F cells in the first year. This was maintained for 2 years only in the top three quartiles. Leukocyte and reticulocyte counts decreased initially in all quartiles, but drifted back toward baseline levels in the lowest HbF response quartile, initial HbF level and phenotype of the F-cell production (FCP) focus were not associated with HbF response, but absence of a Central African Republic (CAR) haplotype was. Bone marrow ability to withstand HU treatment may be important for sustained HbF increases during HU treatment of HbSS. This is a US government work. There are no restrictions on its use.
Abstract: Sickle cell disease (SCD) is characterized by repeated vaso-occlusive events, which result in substantial morbidity. Abnormal adhesion of sickle red blood cells (RBC) to the vascular endothelium is postulated to play a role in the pathogenesis of vaso-occlusion. Two adhesion receptors, very late activation antigen-4 (VLA-4) and CD36, are found in unusually high numbers on sickle cell reticulocytes and do mediate adhesion of sickle RBC to endothelium. Hydroxyurea (HU) therapy results in fewer vaso-occlusive episodes, and we postulated that HU-related modulation of VLA-4 and CD36 receptors may contribute to its clinical benefit. Using flow cytometry, eight patients were followed from the onset of HU treatment through a mean treatment length of 200 +/- 49 days. Mean corpuscular volume and percent fetal hemoglobin (Hb F) increased from 87% +/- 6% to 98% +/- 9% and 6.6% +/- 3.9% to 12.7% +/- 5.6%, respectively. The percentage of reticulocytes expressing VLA-4 decreased from 29.0% +/- 5.9% to 14.9% +/- 2.3% (P = .0003). Two thirds of the total decrease in VLA-4 expression occurred after 10 weeks of HU and plateaued by 20 weeks. Changes in VLA-4 expression occurred before substantial increases in Hb F. The percentage of reticulocytes expressing CD36 decreased from 55.3% +/- 6.4% to 42.6% (P = .0046). Changes in adhesion receptor expression were not caused by a decrease in reticulocytosis with HU therapy. This report is the first to associate a decrease in adhesion receptor expression with a therapy known to reduce the clinical severity of SCD.
Abstract: Until recently, transfusion was the only effective therapy for children with sickle cell disease (SCD). Although transfusion can be used to prevent or treat many of the complications of SCD, it has often been used indiscriminantly and with considerable risk to the patient. Recent studies attempted to define those clinical situations in which transfusion is effective as well as to optimize its delivery while minimizing complications. Other therapies are emerging, and in the future many will likely play an important role in the treatment of children with SCD. These therapies include pharmacologic interventions, such as hydroxyurea; bone marrow and cord blood transplantation; and improvements in supportive and preventive care. The future for new therapies looks promising, but the appropriate role for many of these therapeutic interventions remains to be determined.
Abstract: Cholecystectomy is the most common surgical procedure performed in sickle cell anemia (SCA) patients. We investigated the effects of transfusion and surgical method on perioperative outcome. A total of 364 patients underwent cholecystectomy: group 1 (randomized to aggressive transfusion) 110 patients; group 2 (randomized to conservative transfusion) 120 patients; group 3 (nonrandomized nontransfusion) 37 patients; and group 4 (nonrandomized transfusion) 97 patients. Patients were similar except group 3 patients were more likely to be female, over 20 years old, smokers, and more healthy by American Society of Anesthesiologists (ASA) physical status score. Total complication rate was 39%: sickle cell events 19%; intraoperative or recovery room events 11%; transfusion complications 10%; postoperative surgical events 4%; and death 1%. Group 3 patients had the highest incidence of sickle cell events (32%). Open cholecystectomies were performed in 58% and laparoscopic in 42%. Laparoscopic patients were younger and more healthy by ASA score. Laparoscopic patients had longer anesthesia time (3.2 v 2.9 hours), but shorter hospitalization time (6.4 days v 9.8). Complications were similar between these two groups. We conclude that SCA patients undergoing cholecystectomy have a high perioperative morbidity, and the incidence of sickle cell events may be higher in patients not preoperatively transfused. We recommend a conservative preoperative transfusion regimen, and we encourage the use of the laparoscopic technique for SCA patients undergoing elective cholecystectomy.
Abstract: Children with sickle cell anemia provide the best opportunity to assess the efficacy of hydroxyurea (HU) in preventing complications and progressive organ damage. The possibility of treating infants with sickle cell disease (SCD) to inhibit the development of organ dysfunction may be the most important future use of HU. The possibility even exists that instituting HU in the neonate may stop the fetal-to-adult globin chain switch and thus markedly change the clinical phenotype of SCD. Recent data suggest HU may also be especially beneficial in children not only by increasing hemoglobin F (HbF), but also by altering the adhesive receptors expressed on red blood cells and vascular endothelium, further increasing the possibility that vasculopathy can be prevented. Six pediatric trials that included small numbers of severely ill patients have been reported recently. All patients received relatively standard HU doses. All studies reported a significant improvement in HbF and mean corpuscular volume and a mild to marked increase in hemoglobin. The clinical response to HU in children with SCD seems to be consistent. The National Institutes of Health pediatric multicenter trial should help answer the question of short-term HU toxicity; however, questions remain concerning long-term risks, such as carcinogenesis, gametogenesis, marrow toxicity, growth retardation, and chromosomal damage. Long-term studies are needed to answer these questions. The future treatment of most children with SCD with HU alone or in combination with other agents looks promising, and long-term trials are warranted.
Abstract: Acute chest syndrome (ACS) is an important cause of morbidity and mortality in sickle cell disease (SCD). Previous studies reported conflicting pictures of ACS making therapeutic interventions difficult. The Cooperative Study of Sickle Cell Disease prospectively followed 3,751 patients enrolled from birth to 66 years of age for ACS. Data on presenting signs and symptoms, laboratory findings, and hospital course were collected. There were 1,722 ACS episodes in 939 patients. Young children (age 2 to 4 years) presented with fever and cough, a negative physical exam, and rarely had pain. Adults were often afebrile and complained of shortness of breath, chills, and severe pain. Upper lobe disease was more common in children; multilobe and lower lobe disease affected adults more often. Severe hypoxia occurred in 18% of adults tested and could not be predicted by examination or laboratory findings. Bacteremia was documented in 3.5% of episodes, but was strongly influenced by age (14% of infants and 1.8% of patients > 10 years). ACS was most common in winter with children having the most striking increase. Transfusion was used less frequently, but earlier in children. Young children were hospitalized for 5.4 days versus 9 days for adults. Fifty percent of adults had a pain event in the 2 weeks preceding ACS and children were more likely to have febrile events. The death rate was four times higher in adults than in children. Fatal cases generally developed rapid pulmonary failure and one third were associated with bacteremia. Age has a striking effect on the clinical picture of ACS. In children, ACS was milder and more likely due to infection, whereas in adults ACS was severe, associated with pain and had a higher mortality rate.
Abstract: PURPOSE: Blood pressure in individuals who have sickle cell disease has been reported to be lower than published normal values. We determine whether and to what degree this is true, using data obtained as part of a large natural history study. PATIENTS AND METHODS: Blood pressure was measured annually for 3,317 subjects with sickle cell disease who were 2 years old or older. Values obtained were compared with those reported by the National Health and Nutrition Examination Survey I and II (NHANES I and II). They were further analyzed with respect to age, sex, height, weight, hematologic diagnosis, blood urea nitrogen and creatinine, stroke, and death. RESULTS: Blood pressure was significantly lower in subjects with sickle cell anemia than published norms for age, race, and sex, a difference that increased with age. It correlated with body mass index, hemoglobin, measures of renal function and age, but the strength of the correlation varied among age and sex subgroups. The risk for occlusive stroke increased with systolic but not diastolic pressure. Mortality was related to elevated blood pressure in males (P < 0.05) and to a lesser extent in females (P = 0.10). In subjects with hemoglobin SC disease, blood pressure also deviated from normal but to a lesser degree. CONCLUSION: Blood pressure is generally lower than normal in individuals with sickle cell anemia. Those with high values relative to this population had an increased risk of stroke and death. Blood pressure should be monitored but values obtained must be assessed relative to the lower values expected for patients with this disease. Those with blood pressure values above 140/90 mm Hg should be evaluated and considered for treatment.
Abstract: The management of patients with acute chest syndrome is changing as its etiology and pathophysiology are being defined. Current management should include aggressive evaluation and monitoring, and treatment should be tailored to each patient's clinical course. New therapies show promise in reducing morbidity of acute chest syndrome in the future.
Abstract: OBJECTIVES: (1) To determine serotype-specific IgG antibody responses to reimmunization with pneumococcal polysaccharide vaccine at age 5 years in children with sickle cell anemia and (2) to determine whether continued penicillin prophylaxis had any adverse effects on these responses. STUDY DESIGN: Children with sickle cell anemia, who had been treated with prophylactic penicillin for at least 2 years before their fifth birthday, were randomly selected at age 5 years to continue penicillin prophylaxis or to receive placebo treatment. These children had been immunized once or twice in early childhood with pneumococcal polysaccharide vaccine and were reimmunized at the time of randomization. RESULTS: Serotype-specific IgG antibody responses to reimmunization varied according to pneumococcal serotype but in general were mediocre or poor; the poorest response was to serotype 6B. The antibody responses were similar in subjects with continued penicillin prophylaxis or placebo treatment, and in subjects who received one or two pneumococcal vaccinations before reimmunization. The occurrence of pneumococcal bacteremia was associated with low IgG antibody concentrations to the infecting serotype. CONCLUSIONS: Reimmunization of children with sickle cell anemia who received pneumococcal polysaccharide vaccine at age 5 years induces limited production of serotype-specific IgG antibodies, regardless of previous pneumococcal vaccine history. Continued penicillin prophylaxis does not interfere with serotype-specific IgG antibody responses to reimmunization.
Abstract: PURPOSE: In this article we describe the success of a unique newborn screening program for sickle cell disease and other hemoglobinopathies. We will present and discuss 4 years of experience from the California Newborn Hemoglobinopathy Screening Program. METHODS: Several aspects that ensure the success of the program will be reviewed. These aspects include (a) the use of high-pressure liquid chromatography as the initial screening technique, (b) a confirmatory testing laboratory that incorporates DNA technology and innovative protein analysis using electrospray mass spectrometry, and (c) a complex follow-up strategy that employs regional nurses to track positive results and ensure timely enrollment of infants into treatment systems. RESULTS: Of these 2 million infants screened, 492 were diagnosed with some form of sickle cell disease; 290 (58.9%) were diagnosed with hemoglobin SS, 143 (29.0%) were diagnosed with hemoglobin SC, and 47 (9.5%) were diagnosed with S beta+thalassemia. CONCLUSION: The prevalence and ethnicity data presented here demonstrate the ineffectiveness of targeted screening and justify universal screening. Had targeted screening been performed in California during the past 4 years, 58 nonblack infants with sickle cell disease would have gone undiagnosed, and 6,921 nonblack infants with sickle cell trait would not have been identified.
Abstract: Acute chest syndrome (ACS) is associated with significant morbidity and is the leading cause of death in patients with sickle cell disease (SCD). Recent reports suggest that bone marrow fat embolism can be detected in many cases of severe ACS. Secretory phospholipase A2 (sPLA2) is an important inflammatory mediator and liberates free fatty acids, which are felt to be responsible for the acute lung injury of the fat embolism syndrome. We measured SPLA2 levels in 35 SCD patients during 20 admissions for ACS, 10 admissions for vaso-occlusive crisis, and during 12 clinic visits when patients were at the steady state. Eleven non-SCD patients with pneumonia were also evaluated. To determine if there was a relationship between sPLA2 and the severity of ACS we correlated SPLA2 levels with the clinical course of the patient. In comparison with normal controls (mean = 3.1 +/- 1.1 ng/mL), the non-SCD patients with pneumonia (mean = 68.6 +/- 82.9 ng/mL) and all three SCD patient groups had an elevation of SPLA2 (steady state mean = 10.0 +/- 8.4 ng/mL; vaso-occlusive crisis mean = 23.7 +/- 40.5 ng/mL; ACS mean = 336 +/- 209 ng/mL). In patients with ACS sPLA2 levels were 100-fold greater than normal control values, 35 times greater than values in SCD patients at baseline, and five times greater than non-SCD patients with pneumonia. The degree of SPLA2 elevation in ACS correlated with three different measures of clinical severity and, in patients followed sequentially, the rise in SPLA2 coincided with the onset of ACS. The dramatic elevation of SPLA2 in patients with ACS but not in patients with vaso-occlusive crisis or non-SCD patients with pneumonia and the correlation between levels of SPLA2 and clinical severity suggest a role for SPLA2 in the diagnosis and, perhaps, in the pathophysiology of patients with ACS.
Abstract: PURPOSE: To define the spectrum of abnormalities in sickle-cell disease, including infarction, atrophy, and hemorrhage, that are identified by brain MR imaging. METHODS: All MR studies included T1, T2, and intermediate pulse sequences. Images were interpreted without knowledge of the clinical history or neurologic examination findings. Brain MR imaging was performed in 312 children with sickle-cell disease. RESULTS: Seventy patients (22%) had infarction/ischemia and/or atrophy, infarction/ischemia was noted in 39 children (13%) who had no history of a stroke (the "silent" group). The prevalence rates for silent lesions were 17% for sickle-cell anemia and 3% for hemoglobin sickle-cell disease. For patients with sickle-cell anemia and a history of cerebrovascular accident, infarction/ischemia lesions typically involved both cortex and deep white matter, while silent lesions usually were confined to deep white matter. Within the age range studied, the prevalence of infarction/ischemia did not increase significantly with age, although older patients with lesions had more lesions than did younger patients with lesions. CONCLUSIONS: Brain MR imaging showed infarction/ischemia in the absence of a recognized cerebrovascular accident in 13% of patients. The prevalence of these lesions did not increase significantly between the ages of 6 and 14 years, suggesting that lesions are present by age 6. However, the increase in the average number of lesions per patient with age may indicate progressive brain injury.
Abstract: PURPOSE: Ototoxicity often limits the dose of desferrioxamine (DFO) tolerated by patients who are transfusion dependent. Current recommendations advise doses of < 50 mg/kg/day after early reports noted higher rates of oxotoxicity with increasing doses. There have been no follow-up studies to determine the effect of this recommendation on oxotoxicity and iron overload. METHODS: We followed 28 patients who were chronically chelated with serial audiograms over a 5-year period. Patients with and without oxotoxicity were compared with respect to age, disease, DFO dose, peak DFO dose, length of DFO therapy, ferritin, and therapeutic index. RESULTS: Eight of the 28 patients (29%) had an abnormal audiogram during threshold testing. Two patients had two separate episodes with hearing deficit. Nine of the 10 episodes were high-frequency losses, with seven being moderate and three mild. All deficits were rapidly reversible with DFO dose reduction. No significant differences were found between the affected and unaffected groups with respect to age, DFO dose or duration, ferritin, or therapeutic index. Numbers of affected patients were small, but patients with SCD differed from patients with thalassemia in that they developed ototoxicity earlier and with lower doses of DFO and lower therapeutic indexes. CONCLUSIONS: Despite DFO doses usually felt to be low risk for ototoxicity, we found a high rate of ototoxicity in our patients who we've chronically chelated. No variables were identified that reliably predicted ototoxicity. We stress the need for regular audiological exams and feel no dose of DFO is "safe" from the development of ototoxicity.
Abstract: Much of the morbidity associated with sickle cell anemia (SCA) is due to ongoing infarction resulting in organ dysfunction. Because the spleen is often the first organ damaged in this illness, there is a significant impairment of the immune system in these patients. Hydroxyurea (HU) has been shown to increase fetal hemoglobin (HbF) and decrease painful episodes in patients with this disease. It is unclear whether HU can prevent organ damage. We treated two SCA patients with HU for several years and found evidence of reversal of previously documented splenic dysfunction. Patient no. 1 was treated for 30 months with an increase in HbF to 30%. HU was stopped because of cytopenia. She developed left upper quadrant pain. A splenectomy was performed due to the possibility of splenic abscesses. A pathologic review found no evidence of infection and an enlarged spleen that showed active germinal centers. Patient no. 2 was treated for 24 months with HU before developing splenomegaly. His HbF levels were 25% to 30%, his pit counts averaged 2%, and his liver spleen scans showed uptake. These two cases show that chronic HU therapy may reverse splenic dysfunction in certain patients and suggest that this drug may have efficacy beyond the elimination of pain in SCA.
Abstract: While allogeneic marrow transplantation is curative therapy for patients with sickle cell anemia, only a small fraction of patients in the United States receive this treatment. We surveyed participants in our multicenter study of marrow transplantation for sickle cell anemia to determine reasons for not proceeding to transplantation. Among the 4848 patients less than 16 years of age with sickle cell anemia that were followed in 22 collaborating centers, 315 (6.5%) patients were reported to meet protocol entry criteria for transplantation, although there was wide variation among the institutions (0.9-36%). Among the 315 patients eligible for transplantation, 128 (41%) had human leukocyte antigen (HLA) typing performed, and of these 44 (14% of those meeting entry criteria) had an HLA-identical sibling. Common reasons for not proceeding with HLA typing in the remaining 187 patients included lack of a candidate sibling donor (76 patients, 24% of those meeting criteria) and lack of financial or psychosocial support (33, 10.5%). Parental refusal (30, 9.5%), physician refusal (13, 4%), history of medical noncompliance (2, < 1%), and other reasons (33, 10.5%) were less frequently cited. To date, 25 patients have been transplanted. Of the remaining 19 patients with HLA-matched donors, seven did not proceed to transplantation because of parental refusal, while the others anticipate a future transplantation (6), have experienced symptomatic improvement (4), or have relocated abroad (2). We conclude that the major barrier to marrow transplantation for sickle cell anemia is lack of an HLA-identical donor. But since only 6.5% of all children with sickle cell disease were considered eligible for transplantation, it is possible that other significant obstacles remain to be identified. For patients reported to meet eligibility criteria, parental refusal and limited financial or psychosocial support were infrequent barriers to transplantation.
Abstract: Sickle-cell disease (SCD) is the most common cause of avascular necrosis (AVN) of the hip in childhood. It results in significant physical impairment and chronic pain, and often progresses to require hip replacement. Conservative therapy is ineffective. We evaluated whether core decompression can arrest progression of AVN. We performed 13 coring procedures in 10 patients with SCD and AVN. Patients ranged from age 9-21 years at diagnosis (mean, median age, 15 years); five hips were stage I, six hips were stage II, and two hips were stage III. Mean follow-up on these patients was 3.7 years. Efficacy of the procedure was evaluated by clinical improvement in pain, radiographic progression, and need for further surgery. All 5 stage I patients had substantial improvement in pain, and only one showed X-ray progression. Five of the 6 (83%) stage II patients had improvement in pain, and 2 patients progressed on X-ray. Both stage III patients progressed on X-ray, but one was clinically improved. None of the 10 patients has required further surgery. Our results demonstrate that in early AVN, core decompression was beneficial for almost all patients, even with progression on X-ray. Core decompression should be considered in the management of SCD patients with early AVN.
Abstract: From 1978 to 1988, The Cooperative Study of Sickle Cell Disease observed 3,765 patients with a mean follow-up of 5.3 +/- 2.0 years. One thousand seventy-nine surgical procedures were conducted on 717 patients (77% sickle cell anemia [SS], 14% sickle hemoglobin C disease [SC], 5.7% S beta zero thalassemia, 3% S beta zero + thalassemia). Sixty-nine percent had a single procedure, 21% had two procedures, and the remaining 11% had more than two procedures during the study follow-up. The most frequent procedure was abdominal surgery for cholecystectomy or splenectomy (24% of all surgical procedures, N = 258). Of these, 93% received blood transfusion, and there was no association between preoperative hemoglobin A level and complication rates (except reduction in pain crisis). Overall mortality within 30 days of a surgical procedure was 1.1% (12 deaths after 1,079 surgical procedures). Three deaths were considered to be related to the surgical procedure and/or anesthesia (0.3%). No deaths were reported in patients younger than 14 years of age. Sickle cell diseases (SCD)-related complications after surgery were more frequent in SS patients who received regional compared with general anesthesia (adjusted for risk level of the surgical procedure, patient age, and preoperative transfusion status, P = .058). Non-SCD-related postoperative complications were higher in both SS and SC patients who received regional compared with those who received general anesthesia (P =.095). Perioperative transfusion was associated with a lower rate of SCD-related postoperative complications for SS patients undergoing low-risk procedures (P = .006, adjusted for age and type of anesthesia), with crude rated of 12.9% without transfusion compared with 4.8% with transfusion. In SC patients, preoperative transfusion was beneficial for all surgical risk levels (P = .009). Thus, surgical procedures can be performed safely in patients with SCD.
Abstract: OBJECTIVE: To evaluate the consequences of discontinuing penicillin prophylaxis at 5 years of age in children with sickle cell anemia who had received prophylactic penicillin for much of their lives. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Eighteen teaching hospitals throughout the United States. PATIENTS: Children with sickle cell anemia (hemoglobin SS or hemoglobin S beta 0-thalassemia) who had received prophylactic penicillin therapy for at least 2 years immediately before their fifth birthday and had received the 23-valent pneumococcal vaccine between 2 and 3 years of age and again at the time of randomization. Of 599 potential candidates, 400 were randomly selected and followed for an average of 3.2 years. INTERVENTIONS: After randomization, patients received the study medication twice daily--either penicillin V potassium, 250 mg, or an identical placebo tablet. Patients were either seen in the clinic or contacted every 3 months thereafter for an interval history and dispensing of the study drug. A physical examination was scheduled every 6 months. MAIN OUTCOME MEASURES: The primary end point was a comparison of the incidence of bacteremia or meningitis caused by Streptococcus pneumoniae in children continuing penicillin prophylaxis versus those receiving the placebo. RESULTS: Six children had a systemic infection caused by S. pneumoniae, four in the placebo group (2.0%; 95% confidence interval 0.5%, 5.0%) and two in the continued penicillin prophylaxis group (1.0%; 95% confidence interval 0.1%, 3.6%) with a relative risk of 0.5 (95% confidence interval 0.1, 2.7). All invasive isolates were either serotype 6(A or B) or serotype 23F. Four of the isolates were penicillin susceptible, and two (one from each treatment group) were penicillin and multiply antibiotic resistant. Adverse effects of the study drug were reported for three patients (nausea, vomiting, or both), one of whom was in the placebo group. CONCLUSION: Children with sickle cell anemia who have not had a prior severe pneumococcal infection or a splenectomy and are receiving comprehensive care may safely stop prophylactic penicillin therapy at 5 years of age. Parents must be aggressively counseled to seek medical attention for all febrile events in children with sickle cell anemia.
Abstract: Within the Cooperative Study of Sickle Cell Disease, 694 infants with confirmed sickle cell disease were enrolled at less than 6 months of age. Information about the nature and frequency of complications was collected prospectively over a 10-year period. Painful crises and acute chest syndrome were the most common sickle cell-related events in homozygous sickle cell anemia (SS), hemoglobin SC disease (SC), and S beta thalassemia patients (overall incidence in SS patients of 32.4 and 24.5 cases per 100 person-years, respectively). Bacteremia occurred most frequently in SS children under 4 years of age and in SC patients less than 2 years of age. The mortality rate was low in this cohort compared with that found in previous reports. Twenty children, all with Hb SS, died (1.1 deaths per 100 person-years among SS patients). Infection, most commonly with Streptococcus pneumoniae and Hemophilus influenzae, caused 11 deaths. Two children died of splenic sequestration, 1 of cerebrovascular accident, and 6 of unclear causes. Two patients underwent cholecystectomies, and 17 underwent splenectomies after one or more splenic sequestration crises. The experience of this cohort should reflect closely the true clinical course of those children with Hb SS and Hb SC disease who are observed in sickle cell centers in the United States.
Abstract: OBJECTIVE: To determine the effect of a transfusion program on risk of stroke recurrence in children with sickle cell disease. DESIGN: The clinical course and experience with transfusion therapy at eight centers were reviewed for subjects whose initial stroke occurred after January 1988. RESULTS: Sixty subjects were observed for 191.7 patient-years. Eight had a single recurrent stroke (two intracranial hemorrhages and six infarctions) for a prevalence of 13.3%, or one recurrence for each 24 patient-years of observation. Thirteen subjects had 15 transient neurologic events; two of these had subsequent strokes, but the overall risk was similar for those who did and those did not have transient events. Hemoglobin S levels were greater than the desired maximum of 30% at the time of 7 of 16 transient events and five of six recurrent infarctions. The stroke recurrence rate was similar to those in previous reports of children receiving long-term transfusion therapy but significantly less than that reported for children who did not receive transfusions (p < 0.001). CONCLUSIONS: We conclude that maintenance of hemoglobin S at a level less than 30% appears to be effective in reducing the rate of recurrent infarction but does not prevent transient neurologic events. Transient neurologic events are common but do not appear to be related to recurrent stroke.
Abstract: BACKGROUND. Preoperative transfusions are frequently given to prevent perioperative morbidity in patients with sickle cell anemia. There is no consensus, however, on the best regimen of transfusions for this purpose. METHODS. We conducted a multicenter study to compare the rates of perioperative complications among patients randomly assigned to receive either an aggressive transfusion regimen designed to decrease the hemoglobin S level to less than 30 percent (group 1) or a conservative regimen designed to increase the hemoglobin level to 10 g per deciliter (group 2). RESULTS. Patients undergoing a total of 604 operations were randomly assigned to group 1 or group 2. The severity of the disease, compliance with the protocol, and the types of operations were similar in the two groups. The preoperative hemoglobin level was 11 g per deciliter in group 1 and 10.6 g per deciliter in group 2. The preoperative value for hemoglobin S was 31 percent in group 1 and 59 percent in group 2. The most frequent operations were cholecystectomies (232), head and neck surgery (156), and orthopedic surgery (72). With the exception of transfusion-related complications, which occurred in 14 percent of the operations in group 1 and in 7 percent of those in group 2, the frequency of serious complications was similar in the two groups (31 percent in group 1 and 35 percent in group 2). The acute chest syndrome developed in 10 percent of both groups and resulted in two deaths in group 1. A history of pulmonary disease and a higher risk associated with surgery were significant predictors of the acute chest syndrome. CONCLUSIONS. A conservative transfusion regimen was as effective as an aggressive regimen in preventing perioperative complications in patients with sickle cell anemia, and the conservative approach resulted in only half as many transfusion-associated complications.
Abstract: Purpose: To determine who might qualify for allogeneic bone marrow transplantation (BMT), we reviewed the medical records of all 143 patients with sickle cell anemia under the age of 16 years who were registered at our center. Patients and Methods: A total of 135 records were complete and were used to estimate donor availability and disease severity. The mean number of siblings per patient was two, but this number decreased to 0.73 if half-siblings and siblings who had sickle cell anemia were excluded. Probability calculations indicated that a human leukocyte antigen (HLA)-matched sibling donor would be available for only 18% of patients with sickle cell disease. Results: With regard to clinical severity, if only stroke and chronic debilitating pain are considered criteria for bone marrow transplantation, only 16% of sickle cell patients would qualify, but with use of the broader criteria of the National Collaborative Study, 38% of patients would qualify. However, not all parents will consent to have bone marrow transplantation for their child, and only a minority of patients (18%) will have an HLA-matched sibling donor. Thus, as few as 1-2% of the total population of children with sickle cell anemia will ultimately qualify for marrow transplantation. Increasing the number who can undergo transplantation will require increasing the size of the donor pool. Conclusions: Search for other therapies not based on marrow transplantation should continue. For the majority of patients with sickle cell disease, these nontransplant treatments offer the best chance for enabling patients to achieve greater longevity and a better quality of life.
Abstract: The efficacy of a long-term transfusion regimen in preventing sickle cell disease complications is unknown. We examined 17 patients before, during, and after transfusion for cerebral vascular accident and vaso-occlusive crisis. Total hospitalization rate, as well as admissions for vaso-occlusive crisis, cases of acute chest syndrome, and bacterial infections decreased while patients were on a transfusion regimen.
Abstract: The etiology of most cases of acute chest syndrome (ACS) in sickle cell disease (SCD) is unknown. Although pulmonary fat embolism (PFE) is frequently found on autopsy, it is rarely considered in the differential diagnosis in pediatric patients. We conducted a study to determine if we could identify PFE in SCD patients with ACS, define the clinical and laboratory course of PFE, and determine if bronchoalveolar lavage is safe and useful in diagnosis of PFE. Twenty-seven SCD patients with ACS were evaluated and compared with 43 control patients. Serial tests (complete blood count, platelet count, nucleated red blood cells [NRBCs], chest x-ray, and oxygen saturations) were compared with steady-state results. Diagnosis of PFE was made by quantitative evaluation of pulmonary macrophages for intracellular fat. No serious complications from bronchoscopy were observed. In the SCD patients with ACS, 12 were PFE+ and 15 were PFE-. The clinical course of the two groups was quite different. All PFE+ patients experienced bone pain and 11 of 12 had chest pain. In contrast, only 6 of 15 of PFE- patients had bone or chest pain. Neurologic symptoms developed in 6 of 12 of the PFE+ group and in none of the PFE- group. Mean hospital days for PFE+ was 13 compared with 7 for PFE-. Laboratory studies in PFE+ showed a significant decrease in hemoglobin (-2 g, P < .05), platelet count (-293,000, P < .001), and an increase in NRBCs/100 white blood cells (+8.3, P < .001) compared with PFE-. These results indicate that when PFE is associated with ACS, it is characterized by a distinct clinical course, and that bronchial lavage is a safe and useful test in diagnosing PFE in patients with ACS.
Abstract: In screening for hemoglobinopathies, high-performance liquid chromatography (HPLC) achieves excellent sensitivity and specificity, while adding the very important quantitative element to the analysis. Due to the development of a rapid, automated HPLC system, California began screening 600,000 births per year in 1990 using this method. Based on confirmatory testing for 97% of the initial positive results resulting from 2.2 million screens, HPLC has proven to be clinically accurate. In conjunction with the availability of quantitative data, HPLC provides a complete screening system, eliminating the need for a second screening test, and accurately discriminating beta thalassemia compound conditions. The large degree of ethnic diversity and high birth rate in California have produced detailed and reliable birth prevalence rates for most conditions and ethnicities.
Abstract: PURPOSE: To determine who might qualify for allogeneic bone marrow transplantation (BMT), we reviewed the medical records of all 143 patients with sickle cell anemia under the age of 16 years who were registered at our center. PATIENTS AND METHODS: A total of 135 records were complete and were used to estimate donor availability and disease severity. The mean number of siblings per patient was two, but this number decreased to 0.73 if half-siblings and siblings who had sickle cell anemia were excluded. Probability calculations indicated that a human leukocyte antigen (HLA)-matched sibling donor would be available for only 18% of patients with sickle cell disease. RESULTS: With regard to clinical severity, if only stroke and chronic debilitating pain are considered criteria for bone marrow transplantation, only 16% of sickle cell patients would qualify, but with use of the broader criteria of the National Collaborative Study, 38% of patients would qualify. However, not all parents will consent to have bone marrow transplantation for their child, and only a minority of patients (18%) will have an HLA-matched sibling donor. Thus, as few as 1-2% of the total population of children with sickle cell anemia will ultimately qualify for marrow transplantation. Increasing the number who can undergo transplantation will require increasing the size of the donor pool. CONCLUSIONS: Search for other therapies not based on marrow transplantation should continue. For the majority of patients with sickle cell disease, these nontransplant treatments offer the best chance for enabling patients to achieve greater longevity and a better quality of life.
Abstract: The formation of the sickle cell hemoglobin polymer associated with deoxygenation of the sickle erythrocyte is a complex process. There are also many intracellular, extracellular, and erythrocyte membrane changes that are recognized to play important roles in the pathophysiology of this disease. The variability among these components accounts for the diversity observed in the phenotypic expression of sickle cell disease. This article reviews some of the recent developments in the understanding of the variables involved in the pathophysiology of sickle cell disease. Some of the new developments regarding clinical complications of sickle cell disease and their management are presented. New therapeutic options are reviewed. Finally, a discussion regarding transgenic models of sickle cell disease is presented.
Abstract: PURPOSE: Stimulating expression of the normal fetal globin genes is a preferred method of ameliorating sickle cell disease and beta-thalassemia for the majority of patients in North America who do not have appropriate bone marrow donors. PATIENTS AND METHODS: Due to increased survival of red blood cells that contain both hemoglobin S and hemoglobin F, as little as 4-8% fetal globin synthesis in the bone marrow can produce levels of hemoglobin F of approximately 20% in the peripheral circulation. Some success has been achieved in stimulating hemoglobin F using chemotherapeutic agents (such as hydroxyurea and 5-azacytidine) and growth factors (erythropoietin) that alter erythroid growth kinetics. However, there is reluctance to treat children with chemotherapeutic agents because of possible undesirable long-term side effects. RESULTS: Butyric acid and butyrate derivatives are generally safe compounds that stimulate the promoters of individual fetal and embryonic globin genes and thus provide a more specific therapy. An initial trial with the parent compound, given as arginine butyrate, has demonstrated rapid stimulation of fetal globin expression to levels that can ameliorate these conditions. Phase I trials of an oral butyrate derivative with a long plasma half-life have begun. CONCLUSIONS: These agents may provide a new and specific approach for ameliorating the clinical manifestations of sickle cell disease and beta-thalassemia.
Abstract: PURPOSE: To characterize the non-acute abnormalities seen at computed tomography (CT) in patients with sickle cell (SC) disease and a prior history of acute chest syndrome (ACS)-pneumonia. MATERIALS AND METHODS: Twenty-nine patients with SC disease who had experienced one to more than 10 (median, six) previous episodes of ACS-pneumonia were prospectively studied with thin-section CT of the thorax. Scans were graded for interstitial disease and assigned a disease index ranging from 0 to 3. Twenty-four patients underwent pulmonary function tests (PFTs) and measurement of their blood gasses. RESULTS: Twelve of the 29 patients (41%) had significant interstitial disease that was multifocal. A correlation was found between the disease index and number of episodes of ACS-pneumonia (P = .02) but not between the disease index and PFT results. CONCLUSION: Thin-section CT demonstrates significant multifocal interstitial lung abnormalities in 41% of selected patients with SC disease. The pattern is most consistent with scarring from episodes of infarction or infection.
Abstract: Hydroxyurea can increase fetal hemoglobin (HbF) and improve the clinical course of sickle cell disease (SCD) patients. However, several issues of hydroxyurea therapy remain unresolved, including differences in patients' drug clearance, predictability of drug response, reversibility of sickle cell disease-related organ damage by hydroxyurea, and the efficacy of elevated HbF. We treated two patients with hydroxyurea for periods of 1 to 4 years, monitoring clinical course and laboratory parameters at regular intervals. The first patient (patient A) had a history of chronic pain and extensive hospitalizations. The second patient (patient B) had a history of stroke and refused to continue with chronic transfusion therapy and chelation. Both patients showed a fivefold to tenfold increase in HbF (5% to 25%, 3% to 31%). However, patient A developed an acute chest syndrome, despite an HbF level of 20%. After red blood cell transfusions for hypoxia, the HbF level decreased to 5%. When hydroxyurea dosage was increased, pancytopenia developed and was not resolved until 2 months after hydroxyurea was discontinued; Patient B developed a cerebral hemorrhage on hydroxyurea; he died shortly thereafter. His HbF level was 21% before death. We noted an increase in HbF and a general improvement in the two patients. However, both experienced major SCD-related complications despite HbF levels over 20%. Our findings also suggest that the progressive vascular changes associated with SCD are unlikely to be dramatically affected by increased HbF levels. Because neither the efficacy nor the toxicity of hydroxyurea have been thoroughly investigated, physicians should be cautious in prescribing hydroxyurea for patients with SCD before completion of the National Clinical Trial.
Abstract: The influx of Southeast Asian immigrants into California over the past few years has resulted in a dramatic increase of Hb E disorders detected in newborn screening. Initial hemoglobin patterns of FE do not distinguish between homozygous EE, a benign state, and E/beta-thalassemia, a clinically significant disorder which is frequently transfusion-dependent. Since language and cultural customs frequently prevent parent testing which can rule out the thalassemic disorder, and diagnosis in the neonate is not possible by traditional red cell indices and is relatively expensive by DNA methodology, an alternate screening method is proposed. This study investigated the Hb F and Hb E relative percentages obtained in the newborn's high-performance liquid chromatography result, and found that the percentage of Hb E was markedly lower in neonates with Hb E/beta-thalassemia versus those which were homozygous EE. Likewise, the F/E ratios were different in the E/beta-thalassemia group versus the EE group. This analysis can at least minimize the number of DNA tests required, and with more E/beta-thalassemia case data, may prove to be a reliable substitute.
Abstract: Studies on baboons and preliminary observations in three patients with sickle cell anemia (SS) suggested that high doses of pulse administered recombinant human erythropoietin (rHuEPO) stimulate F-reticulocyte production. We now report on the administration of rHuEPO in a double-blind format to ascertain frequency of response and potential precipitation of side effects. Ten patients were enrolled, but one was discontinued due to the indication of a blood transfusion. Of the other nine, five received rHuEPO in escalating doses (from 400 to 1,500 U per kg twice daily [BID] per week), alternating with a placebo, in blinded fashion. The second group, consisting of four patients, followed an identical protocol (except starting dose was 1,000 U/Kg, BID per week) and were iron supplemented during treatment. The criterion of response was a transient doubling (as a minimum) of the steady-state F-reticulocyte level. We found that none of the five patients in the first group responded to rHuEPO, and two of them became iron deficient, as judged by a significant decrease in ferritin. Of the second group, four patients responded with F-reticulocyte increases. In three patients, open label administration of rHuEPO confirmed the effect. We observed seven painful episodes during this study, two during the EPO administration and five during the placebo arm. Three patients were phlebotomized because the hemoglobin level increased 1.5 g/dL more than steady-state levels. Of the six patients followed-up by percent dense cell determinations, one exhibited increased levels during periods of the treatment, whereas the other five showed no change. No anti-rHuEPO antibodies were detected. We conclude that rHuEPO can stimulate F-reticulocyte response in some patients with sickle cell anemia, without apparent negative clinical side effects. The state of iron stores may be critical. Whether higher doses of rHuEPO and/or a different regimen might induce sustained F cells and fetal hemoglobin increases remains to be determined.
Abstract: BACKGROUND. Fetal-globin (gamma-globin) chains inhibit the polymerization of hemoglobin S (sickle hemoglobin) and can functionally substitute for the beta-globin chains that are defective or absent in patients with the beta-thalassemias. Identifying safe mechanisms to stimulate fetal-hemoglobin production is therefore of great interest. Previous studies have shown that administering butyrate selectively stimulates the promoter of the human fetal-globin gene and leads to increases in gamma-globin--gene expression in the developing fetus, cultured cells, and animal models. METHODS. To determine whether butyrate can stimulate fetal-globin production in humans, we treated three patients (3 to 13 years old) with sickle cell anemia and three patients (7 to 27 years old) with beta-thalassemia syndromes with a short course of intravenous infusions of arginine butyrate. The drug was infused continuously for either two or three weeks; the initial dose was 500 mg per kilogram of body weight per day. Globin-chain ratios, proportions of reticulocytes producing hemoglobin F (F reticulocytes), and levels of gamma-globin messenger RNA (mRNA) were determined before and during treatment. RESULTS. In all six patients, fetal-globin synthesis increased by 6 to 45 percent above pretreatment levels (P < 0.01). The proportion of F reticulocytes increased about twofold, and the level of gamma-globin mRNA increased twofold to sixfold. The increase in gamma-globin synthesis led to improvement in the globin-chain ratios in the patients with thalassemia. The treatment of one patient was extended for seven weeks, and her hemoglobin level increased from 4.7 to 10.2 g per deciliter (2.9 to 6.3 mmol per liter). Side effects were minimal; one patient had a transient increase in serum aminotransferase concentrations. CONCLUSIONS. In patients with beta-hemoglobinopathies butyrate, a natural fatty acid, can significantly and rapidly increase fetal-globin production to levels that can ameliorate beta-globin disorders. Further trials of this class of compounds are warranted to determine long-term tolerance and efficacy in patients with sickle cell anemia or beta-thalassemia.
Abstract: OBJECTIVES: To facilitate the differential diagnosis of hemoglobin FE in newborn infants (homozygous hemoglobin E vs hemoglobin E-beta O-thalassemia). METHODS: The beta-globin gene in DNA from infants found to have hemoglobin FE in the California newborn screening program was amplified by the polymerase chain reaction, and the product was digested with Mnl I, which fails to cut the product when the hemoglobin E mutation is present. When both amplified alleles fail to be cut, homozygous EE is diagnosed. If only one allele is cut, a beta-globin allele without the E mutation is present (non-E), which is most likely a gene with a beta O-thalassemia mutation. RESULTS: Samples from 18 infants revealed an EE genotype, and from two samples a non-E/E genotype was determined. Clinical examination of these two patients confirmed a diagnosis of hemoglobin E-beta O-thalassemia. An independent clinical diagnosis agreed with DNA analysis for all 17 of the 20 infants for whom follow-up and family studies were available. The DNA results were obtained within a week, but the clinical diagnoses often could not be resolved unequivocally for months. CONCLUSIONS: The direct analysis of patient DNA samples for the hemoglobin E mutation allowed rapid and accurate diagnosis in this sample of infants with hemoglobin FE on the newborn screen. This rapid discriminatory test should reduce cost and simplify the diagnostic approach for these patients, which currently consists of expensive and lengthy follow-up until clinical data and family studies result in a diagnosis.
Abstract: BACKGROUND AND METHODS. Acute episodes of pain are the principal symptom of sickle cell disease, but little is known about the epidemiologic features of these episodes or risk factors for them, nor is it known whether patients with high rates of such episodes die prematurely. We prospectively studied the natural history of sickle cell disease in 3578 patients ranging from newborns to persons up to 66 years old who were followed at clinical centers across the United States. RESULTS. There were 12,290 episodes of pain in 18,356 patient-years. The average rate was 0.8 episode per patient-year in sickle cell anemia, 1.0 episode per patient-year in sickle beta 0-thalassemia, and 0.4 episode per patient-year in hemoglobin SC disease and sickle beta(+)-thalassemia. The rate varied widely within each of these four groups--e.g., 39 percent of patients with sickle cell anemia had no episodes of pain, and 1 percent had more than six episodes per year. The 5.2 percent of patients with 3 to 10 episodes per year had 32.9 percent of all episodes. Among patients with sickle cell anemia who were more than 20 years old, those with high rates of pain episodes tended to die earlier than those with low rates. High rates were associated with a high hematocrit and low fetal hemoglobin levels. alpha-Thalassemia had no effect on pain apart from its association with an increased hematocrit. CONCLUSIONS. The "pain rate" (episodes per year) is a measure of clinical severity and correlates with early death in patients with sickle cell anemia over the age of 20. Even when the fetal hemoglobin level is low, one can predict that small increments in the level may have an ameliorating effect on the pain rate and may ultimately improve survival. This outcome is particularly encouraging to investigators studying hydroxyurea and other treatments designed to increase the fetal hemoglobin level.
Abstract: Transfusion therapy for sickle cell anemia is limited by the development of antibodies to foreign red cells. To evaluate the frequency and risk factors associated with such alloimmunization, we determined the transfusion history, red-cell phenotype, and development of alloantibodies in 107 black patients with sickle cell anemia who received transfusions. We compared the results with those from similar studies in 51 black patients with sickle cell disease who had not received transfusions and in 19 nonblack patients who received transfusions for other forms of chronic anemia. We assessed the effect that racial differences might have on the frequency of alloimmunization by comparing the red-cell phenotypes of patients and blood-bank donors (n = 200, 90 percent white). Although they received transfusions less frequently, 30 percent of the patients with sickle cell anemia became alloimmunized, in contrast to 5 percent of the comparison-group patients with other forms of anemia (P less than 0.001). Of the 32 alloimmunized patients with sickle cell anemia, 17 had multiple antibodies and 14 had delayed transfusion reactions. Antibodies against the K, E, C, and Jkb antigens accounted for 82 percent of the alloantibodies. Comparison of red-cell phenotypes in the three study groups (the patients with sickle cell anemia, the patients with other forms of anemia, and the blood donors) revealed statistically significant differences between the patients with sickle cell anemia and the donors but not between the patients with other forms of anemia and the donors. These differences are most likely racial. We conclude that alloimmunization is a common, clinically serious problem in sickle cell anemia and that it is partly due to racial differences between the blood-donor and recipient populations.
Abstract: Because peroxidative damage to red cell membranes may contribute to the pathophysiology of sickle cell disease, deficiency of fat- and water-soluble antioxidants could be a determinant in the pathogenesis of this disease. We have previously reported a deficiency of vitamin E in sickle cell disease. The present study was undertaken to see if a deficiency in vitamin C might also be detected. Leukocyte vitamin C, which reflects total body vitamin C reserve, was measured by a modified 2,4-dinitrophenylhydrazine method. Sickle cell patients (N = 18) had lower leukocyte vitamin C levels (18.3 +/- 9.4 micrograms/10(8) cells) than normal controls (N = 12; 30.3 +/- 7.5 micrograms/10(8) cells; p less than 0.01). Furthermore, 50% of the patients had vitamin C levels below 15 micrograms/10(8) cells, a value consistent with vitamin C deficiency. A statistically significant correlation (r = -0.62 with 0.01 less than p less than or equal to 0.025) was found between leukocyte vitamin C levels and serum ferritin concentration. Because dietary vitamin C intake appeared to be adequate, increased vitamin C utilization may account for this deficiency. However, the mechanisms for this deficiency as well as its pathophysiologic consequences remain to be established.
Abstract: Electrophoretic techniques are used for hemoglobinopathy diagnosis. Confirmation of the hemoglobin variants is necessary. Currently, citrate agar electrophoresis is the most available, but high performance liquid chromatography is highly recommended in a reference laboratory. Thin layer isoelectric focusing is an excellent technique that can be easily adapted for large-scale newborn hemoglobinopathy screening. Although the initial instrument cost can be about twice as much as the cost for standard electrophoretic equipment, cost-effectiveness for newborn screening is considerable because repeat analysis for uninterpretable results is not necessary. Resolution of hemoglobins is much better with thin layer isoelectric focusing than for any of the other electrophoretic methods currently available, and thin layer isoelectric focusing is the best method to use to establish a definitive diagnosis using newborn blood samples. Cord blood samples may be contaminated with maternal blood, and evaluation of Hb A2 levels in such samples can serve as the method to detect contamination. Follow-up testing is required regardless of the method of blood collection.
Abstract: In order to maintain adequate circulating numbers of blood cells, the bone marrow must produce billions of cells each day and must be able to rapidly increase production by 10-20-fold in response to infection and hemorrhage. The existence of circulating factors that regulate this process has been suspected for over 100 years. Recently, the genes encoding these growth factors were cloned and their functions are now identified. Interleukin-3 (IL-3) acts on the most primitive hematopoietic stem cell, driving this self-renewing cell to produce progeny of all hematopoietic lineages. Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates the granulocyte-macrophage progenitor cell, as well as cells committed to the erythroid lineage, to differentiate. G-CSF and M-CSF stimulate the most differentiated myeloid progenitors to produce granulocytes and monocytes/macrophages, respectively. Erythropoietin stimulates the differentiation of late erythroid progenitors. In the lymphoid progenitor lineage, IL-2 stimulates T cell differentiation; IL-4 and IL-6 stimulate differentiation of B cells. The colony-stimulating factors also enhance function and cause activation of the mature cells whose production they induce. In clinical trials, these hormones have successfully ameliorated anemia in renal failure, chronic disease, and in prematurity. They have improved pancytopenias in aplastic anemia, myelodysplastic syndromes, and congenital cytopenias, and they have hastened recovery from chemotherapy and bone marrow transplantation.
Abstract: Hydrogen breath tests were performed in eight children with sickle cell disease (Hgb S-S), four of whom were growth retarded. Average base-line breath H2 values after an overnight fast were elevated (22.4 +/- 10.8 ppm; normal = 7.1 +/- 5.0). Breath H2 concentrations increased significantly above base line within 30-40 min after lactulose ingestion in the four growth-retarded children whereas a negligible rise was observed in the four with normal growth indices. Breath H2 production for each time interval in the first 120 min was greater in all Hgb S-S then in normal children (p less than 0.01 for each time interval measured before 60 min). The results indicate that children with sickle cell disease have intestinal abnormalities favoring excess production of H2 in the fasted state combined with early elevations in postlactulose breath H2 in those with growth retardation. The possible role of disordered gastrointestinal motility and/or anomalously distributed intestinal flora in growth retardation of children with Hgb S-S requires further investigation.
Abstract: Increasing the expression of the gamma globin genes is considered a useful therapeutic approach to the beta globin diseases. Because butyrate and alpha-amino-n-butyric acid (ABA) augment gamma globin expression in normal neonatal and adult erythroid progenitors, we investigated the effects of sodium butyrate and ABA on erythroid progenitors of patients with beta thalassemia and sickle cell anemia who might benefit from such an effect. Both substances increased fetal hemoglobin (Hb F) expression in Bfu-e from 7% to 30% above levels found in control cultures from the same subjects with sickle cell anemia. The fraction of cultured erythroblasts producing Hb F increased more than 20% with sodium butyrate treatment in 70% of cultures. In most cultures, this produced greater than 20% total Hb F and greater than 70% F cells, levels which have been considered beneficial in ameliorating clinical symptoms. Alpha: non-alpha (alpha-non-alpha) imbalance was decreased by 36% in erythroid progenitors of patients with beta thalassemia cultured in the presence of butyrate compared with control cultures from the same subjects. These data suggest that sodium butyrate may have therapeutic potential for increasing gamma globin expression in the beta globin diseases.
Abstract: Newborn screening for sickle cell disease has been recommended as a method of decreasing patient mortality. However, its effectiveness in accomplishing this has not been reliably measured. To help determine the effectiveness, 10 years of experience in newborn screening have been summarized. The effects of early patient enrollment in a comprehensive treatment program on long-term morbidity and mortality are reported. From 1975 to 1985, 84,663 newborns were screened regardless of race or ethnic background. Bart's hemoglobin was present in 5%, hemoglobin AS in 2.6%, and hemoglobin AC in 0.75%. Excluding Bart's, approximately 3.6% of all newborns were carriers for hemoglobinopathy. Sickle cell disease occurred in 1:951 births (58 hemoglobin SS, 25 hemoglobin FSC, three hemoglobin S-beta +-thalassemia, and three hemoglobin S-beta O-thalassemia). In addition, one in every 4,233 newborns had a clinically significant thalassemia syndrome (eight hemoglobin FE, ten hemoglobin F only, two hemoglobin H). Compared with other newborn screening programs in California, (congenital hypothyroidism, 1:3,849; phenylketonuria 1:22,474, galactosemia 1:74,103), hemoglobinopathies are the most prevalent congenital disease. Eighty-one newborns with sickle cell disease were followed for 7.2 years. Patients experienced 513 hospitalizations, including 13 episodes of sepsis with or without meningitis and ten acute sequestration crises. The overall mortality rate for patients with sickle cell anemia diagnosed in the newborn period was 1.8%. In comparison, the clinical course of 64 patients with sickle cell anemia diagnosed after 3 months of age and followed for an average of 9.4 years was analyzed. Five of these patients died. In two of these, sickle cell anemia was diagnosed at the time of the death.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: It is the purpose of this article to provide guidelines used in our sickle cell center for the treatment of several frequent medical complications that occur in children with sickle cell anemia.
Abstract: Children with sickle cell anemia have an increased susceptibility to bacterial infections, especially to those caused by Streptococcus pneumoniae. We therefore conducted a multicenter, randomized, double-blind, placebo-controlled clinical trial to test whether the regular, daily administration of oral penicillin would reduce the incidence of documented septicemia due to S.pneumoniae in children with sickle cell anemia who were under the age of three years at the time of entry. The children were randomly assigned to receive either 125 mg of penicillin V potassium (105 children) or placebo (110 children) twice daily. The trial was terminated 8 months early, after an average of 15 months of follow-up, when an 84 percent reduction in the incidence of infection was observed in the group treated with penicillin, as compared with the group given placebo (13 of 110 patients vs. 2 of 105; P = 0.0025), with no deaths from pneumococcal septicemia occurring in the penicillin group but three deaths from the infection occurring in the placebo group. On the basis of these results, we conclude that children should be screened in the neonatal period for sickle cell hemoglobinopathy and that those with sickle cell anemia should receive prophylactic therapy with oral penicillin by four months of age to decrease the morbidity and mortality associated with pneumococcal septicemia.
Abstract: The effect of increased nutritional intake was evaluated in 5 growth-retarded children with sickle-cell disease. Growth on recommended daily calorie and protein intakes had been inadequate in all 5. Fat absorption and intestinal mucosal morphology were normal in all 5. 2 children were given nutritional supplementation by nasogastric intubation, 1 received nightly oral formula supplements, and 2 were supplemented with zinc, iron, folate, and vitamin E only. Nutritional supplementation by the nasogastric route produced a rapid sustained increase in growth rate, associated with striking reductions in pain crises and infections which had previously necessitated many hospital admissions. Oral supplementation improved the clinical course but had no effect on growth rate. Mineral and vitamin supplements influenced neither the growth rate nor the clinical course. The observations indicate that nasogastric nutritional supplementation may accelerate growth and reduce the incidence and severity of complications in growth-retarded children with sickle-cell disease.
Abstract: An increase in hemoglobin concentration characterizes the normal compensatory response to chronic tissue hypoxia. We observed no such increase in 42 chronically hypoxic patients with cystic fibrosis, in whom the mean concentration was 12.6 gm/dl; one third of the patients were anemic. Compared with patients with cyanotic heart disease, patients with cystic fibrosis did not have a compensatory increase in P50 or 2,3-diphosphoglycerate. Despite anemia, erythropoietin levels in patients with cystic fibrosis were not significantly different from normal control values. The growth of colony-forming units-erythroid in patients with cystic fibrosis was similar to that in control subjects, and there was no inhibition of growth with the addition of autologous serum. Erythropoietin sensitivity, determined by measuring the CFUe dose response curve, was normal in both patients and controls. Results of iron studies were consistent with iron deficiency in the majority of patients. Impaired absorption of iron was observed in six of 13 iron-deficient patients with cystic fibrosis. An inverse correlation between erythrocyte sedimentation rate and peak serum iron was obtained during the iron absorption study. Eight patients who underwent a therapeutic trial of iron demonstrated a 1.8 gm/dl rise in hemoglobin concentration. Two patients with previously documented iron malabsorption responded to parenteral iron therapy after failure to respond to oral supplementation. These studies demonstrate that patients with cystic fibrosis not only have an impaired erythroid response to hypoxia, but are frequently anemic. Their inadequate erythroid response to hypoxia results in part from disturbances in erythropoietin regulation and iron availability.
Abstract: To determine whether the CFUE pool within human bone marrow is heterogeneous with respect to erythropoietin (Epo) requirements, we studied CFUE growth in vitro as a function of Epo exposure time. We controlled the Epo exposure time by overlaying plasma clot cultures containing 0.5 U/ml Epo with an antibody prepared against human Epo. All cultures were grown for seven days. Benzidine-positive colonies containing eight or more cells were counted as CFUE. Colonies containing eight cells required at least 24-50 h of Epo exposure, and those containing 16 cells required at least 70-90 h of Epo exposure. After 50 h, the number of CFUE progressively increased until it reached a maximum at seven days of Epo exposure. These results suggest that the CFUE pool within human bone marrow is heterogeneous with respect to Epo requirements.
Abstract: To investigate the cellular events that accompany erythroid hyperplasia, we studied several effects of erythropoietin (Epo) on marrow CFU-E in sickle cell anemia (SCA). We measured CFU-E number, CFU-E growth as a function both of Epo exposure time and of Epo concentration, and suppression of Epo-induced CFU-E formation by anti-Epo antiserum. With 0.5 U Epo/ml, the number of CFU-E was elevated in SCA (1,087 +/- 520) compared to normal (430 +/- 130). CFU-E were formed even when Epo was immediately neutralized by a 1/150 dilution of anti-Epo. After 40 hr of Epo exposure, only 2% of total CFU-E were expressed in normal marrow, whereas 12%-40% of CFU-E were expressed in SCA. Inhibition of CFU-E growth required at least 1/50 dilution of anti-Epo in SCA and a 1/300 dilution in normal marrow. In contrast to normal, a small number (5%-20%) of CFU-E were expressed in the absence of added Epo in SCA, and this pool required a 1/150 dilution of anti-Epo for inhibition. The Epo dose-response curve in SCA revealed a peak in colony formation around 0.1 U Epo/ml and 0.5 U Epo/ml, whereas only one peak at 0.5 U Epo/ml was seen in normals. These data strongly suggest that, in response to the demands of chronic erythroid hyperplasia in SCA, a pool of CFU-E is present characterized by increased in vitro sensitivity to Epo.
Abstract: Iron deficiency is a common problem in otherwise healthy children and in children with systemic disease. We have reviewed the pathophysiology, laboratory diagnosis, and systemic effects of iron deficiency. We have emphasized that routine screening procedures do not efficiently predict those otherwise healthy children who will demonstrate a therapeutic response to iron. Furthermore, in patients with certain systemic diseases the diagnosis of iron deficiency is complicated by the inflammatory process and the response to a therapeutic trial of oral iron is often blunted. Since the potential adverse effects of iron deficiency may be extensive, a therapeutic trial of iron is indicated to establish the diagnosis of iron deficiency if the index of suspicion is high and laboratory results are equivocal.
Abstract: We studied 47 patients with sickle-cell anemia to determine the effect of alpha-thalassemia on the severity of their hemolytic anemia. We diagnosed alpha-thalassemia objectively by using alpha-globin-gene mapping to detect alpha-globin-gene deletions, studying 25 subjects with the normal four alpha-globin-genes, 18 with three, and four with two. The mean hemoglobin, hematocrit, and absolute reticulocyte levels (+/- S.D.) were 7.9 +/- 0.9 g per deciliter (4.9 +/- 0.6 mmol per liter), 22.9 +/- 2.9 per cent, and 501,000 +/- 126,000 per cubic millimeter, respectively, in the non-thalassemic group; 9.8 +/- 1.6 g per deciliter (6.1 +/- 1.0 mmol per liter), 29.0 +/- 5.0 per cent, and 361,000 +/- 51,000 per cubic millimeter in the group with three alpha-globin genes; and 9.2 +/- 1.0 g per deciliter (5.7 +/- 0.6 mmol per liter), 27.5 +/- 3.0 per cent, and 100,000 +/- 15,000 per cubic millimeter in the group with two alpha-globin genes. Deletion of alpha-globin genes was also accompanied by a decreased mean corpuscular hemoglobin concentration (MCHC) in post-reticulocyte erythrocytes and by increased hemoglobin F levels. The decreased intraerythrocytic hemoglobin S concentration and elevated hemoglobin F levels associated with alpha-thalassemia appear to diminish the degree of hemolytic anemia found in sickle-cell disease.
Abstract: In summary, we propose the following scheme (Figure 5) to describe the role of peroxidation in the pathophysiology of SCA. Sickle erythrocytes are more susceptible to peroxidation than are normal erythrocytes. This increased susceptibility to peroxidation is, in part, due to decreased blood vitamin E levels and abnormal membrane phospholipid organization induced by sickling. The peroxidative damage of sickle erythrocytes may accelerate or contribute to loss of cell deformability and to chronic hemolysis. Peroxidative damage can produce abnormal cellular properties, such as potassium leak and reduced filterability, and contribute to formation of ISCs. Increased red cell rigidity can initiate episodes of capillary obstruction, leading to vasoocclusive painful crises and to tissue infarction. Liver dysfunction as well as increased production of bilirubin secondary to hemolysis could result in bile sludging and decreased secretion of bile salts into the intestinal lumen. Reduced bile salt secretion leads to partial fat and vitamin E malabsorption. Vitamin E deficiency enhances red cell susceptibility to peroxidation and promotes a vicious cycle in SCA. Although we have not studied factors that might initiate peroxidative damage, sickle hemoglobin and excess body iron should be considered as potential sources. Our studies suggest that vitamin E supplementation to sickle-cell patients could be of clinical benefit.
Abstract: We determined the prevalence and optimal methods for laboratory diagnosis of iron deficiency anemia in patients with sickle cell disease. Laboratory investigations of 38 nontransfused and 32 transfused patients included transferrin saturation, serum ferritin, mean corpuscular volume (MCV), and free erythrocyte protoporphyrin (FEP). Response to iron supplementation confirmed the diagnosis of iron deficiency anemia in 16% of the nontransfused patients. None of the transfused patients were iron deficient. All iron-deficient patients (mean age 2.4 yr) had a low MCV, serum ferritin less than 25 ng/ml, transferrin saturation less than 15%, and FEP less than 90 micrograms/dl RBC. Following therapy, all parameters improved and the hemoglobin concentration increased greater than 2 g/dl. A serum ferritin below 25 ng/ml was the most reliable screening test for iron deficiency. There were 13% false positive results with transferrin saturation, 3% with MCV, and 62% with FEP. FEP values correlated strongly with reticulocyte counts. The high FEP was in part due to protoporphyrin IX and not completely due to zinc protoporphyrin, which is elevated in iron deficiency. We conclude that iron deficiency anemia is a potential problem in young nontransfused sickle cell patients. Serum ferritin below 25 ng/ml and low MCV are the most useful screening tests.
Abstract: In order to study fetal haemoglobin production during acute erythroid expansion we did sequential measurements of Hb F-containing erythrocytes (F-cells) and of relevant haematological parameters in 10 subjects recovering from eyrthroid aplasia, iron deficiency anaemia or following phlebotomy. An increased production of F-cells was consistently observed during the acute marrow expansion, but there were significant differences in the maximum F-cell response among individuals. These differences could not be explained by differences in the degree of anaemia alone, nor could they be correlated with the level of peak reticulocytosis. Two patients who reached the highest F-cell numbers were probably carriers of heterocellular hereditary persistence of Hb F, suggesting that this gene may play a role in determining the magnitude of F-cell production in anaemic patients. It is speculated that the main reason for the consistently observed increase in F cell production during acute marrow expansion is the premature terminal differentiation of earlier erythroid precursos (burst forming units; BFUe). This proposition is in accord with observations in vitro which suggest that Hb F is expressed en eyrthroid clones derived from BFUne's. It is further proposed that differences in the degree of BFUe recruitment may underly the disparities in Hb F response among individuals subjected to similar anaemic stimuli.
Abstract: The pathophysiology, laboratory investigation, clinical manifestation, and treatment for the most common serious genetic disease in the United States have been discussed. It is unfortunate how uninformed the medical community is about this illness. Treatment for a chronic disease such as sickle cell disease requires that the physician be knowledgeable and compassionate. Although there is no cure, a great deal can be done to help patients cope with their illness. Recent advances in prevention of pneumococcal infection, proper use of transfusion therapy, and prenatal diagnosis are such examples.
Abstract: Most patients with chronic Heinz body anemia do not require treatment. Dietary folic acid supplementation is recommended when hemolysis is chronic and severe. During infection, patients should be observed carefully because of the possibility of aplastic or hemolytic crises. Individuals with hemoglobins with altered oxygen affinity or M-hemoglobins do not require treatment, and should be counseled about the benign nature of their condition. Unnecessary procedures to exclude cardiac or pulmonary disease should be avoided.
Abstract: The immune response to intravenously administered bacteriophage phiX 174 and subcutaneously administered tridecavalent pneumococcal polysaccharide vaccine was studied in 31 patients with anatomical or functional asplenia. Antibody responses to primary immunisation with phiX 174 were significantly decreased while clearance was normal. Secondary responses were quantitatively normal; however, production of antibody did not switch from IgM to IgG as seen in controls. All groups of asplenic patients accept those patients with Hodgkin's disease demonstrated significant seroconversions in response to pneumococcal polysaccharide antigens. One patient with Hodgkin's disease, treated with local irradiation only, demonstrated normal responses to pneumococcal capsular antigens. 10 of the 12 capsular antigens for which antibody was measured stimulated threefold increases in antibody in the 26 asplenic patients without Hodgkin's disease, which is similar to that observed in controls. Since the majority of cases of overwhelming postsplenectomy infection are caused by Streptococcus pneumoniae, all patients with either anatomical or functional asplenia should receive pneumococcal polysaccharide vaccine.
Abstract: The publication of this 18th Edition of Nelson Textbook of Pediatrics combines an important synthesis of clinical pediatrics with the rapid advances in genomics, diagnosis, imaging, and therapeutics. The 18th edition continues to represent the “state of the art†on the care of the normal and ill neonate, child, or adolescent by presenting both evidence-based medicine as well as astute clinical experiences from leading international authors.
The promise that translational medicine will improve the lives of all children is greater than ever. Knowledge of human development, behavior, and diseases from the molecular to sociologic levels is increasing at fantastic rates. This has led to greater understanding of health and illness in children as well as to substantial improvements in health quality for those who have access to health care. These exciting scientific advances also provide hope to effectively address new and emerging diseases threatening children and their families.
Unfortunately, many children throughout the world have not benefited from the significant advances in the prevention and treatment of health-related problems, primarily because of a lack of political will and misplaced priorities. Additionally, many children are at substantial risk from the adverse effects of poverty, war, and bioterrorism. In order for our increasing knowledge to benefit all children and youth, medical advances and good clinical practice must always be coupled with effective advocacy.
This new edition of Nelson Textbook of Pediatrics attempts to provide the essential information that practitioners, house staff, medical students, and other care providers involved in pediatric health care need to understand to effectively address the enormous range of biologic, psychologic, and social problems that our children and youth may face. Our goal is to be comprehensive, yet concise and reader friendly, embracing both the new advances in science as well as the time-honored art of pediatric practice.
The 18th Edition is substantially reorganized and revised from the previous edition. There are the additions of new diseases and new chapters, as well as substantial expansion or significant modification of others. In addition many more tables, photographs, imaging studies and illustrative figures, as well as up-to-date references have been added. Every subject has been scrutinized for updating and improvement in its exposition and usefulness to pediatric health care providers. Although, to an ill child and his or her family and physician, even the rarest disorder is of central importance, all health problems cannot possibly be covered with the same degree of detail in one general textbook of pediatrics. Thus, leading articles and subspecialty texts are referenced and should be consulted when more information is desired.
The outstanding value of the 18th Edition of the Textbook is due to its expert and authoritative contributors. We are all indebted to these dedicated authors for their hard work, knowledge, thoughtfulness, and good judgment. Our sincere appreciation also goes to Judy Fletcher and Jennifer Shreiner at Elsevier and to Carolyn Redman at the Pediatric Department of the Medical College of Wisconsin. We have all worked hard to produce an edition that will be helpful to those who provide care for children and youth and to those desiring to know more about children's health worldwide.
In this edition we have had informal assistance from many faculty and house staff of the departments of pediatrics at the Medical College of Wisconsin and Wayne State University School of Medicine. The help of these individuals and of the many practicing pediatricians from around the world who have taken the time to offer thoughtful feedback and suggestions is always greatly appreciated and helpful.
Abstract: Liver iron measurements using biosusceptometers have been validated on two LTC SQUID systems (New York and Hamburg) built in the 1980’s. Recently, two new instruments have been installed in Torino, Italy (2001) and Oakland, California (2003). The design of the Oakland system is similar to those in Hamburg and Torino. Improvements were made to adjust for significant environmental noise, moreover, an active electronic noise cancellation, a computer controlled water coupling reference system using a pressure feedback and a faster data acquisition system using software lockin amplifiers have been implemented. All 3 systems (Hamburg, Torino, Oakland) are using the same standardized operational protocol. Presented here are the data collected from 276 patients measured with the SQUID biosusceptometer at Oakland since installation. The results from 149 patients with beta-thalassemia (b-Thal, age: 2-66 y), 76 patients with sickle-cell disease (SCD, age: 5-55 y), 35 patients with various rare diseases (RD, age: 2-80 y), and 16 patients with hereditary hemochromatosis (HHC, age: 6-74 y) are reported. The liver iron concentration in the different groups are 222 - 7570 (b-Thal), 518 - 7918 (SCD), 511 - 6234 (RD), 258 - 2041 (HHC) μg/g-liver. The long-term reproducibility (12 months) in a patient on constant treatment regimen demonstrated a mean liver iron of 1141 ± 133 μg/g-liver. The new SQUID Ferritometer® located on the US West coast will give more patients access to this non-invasive liver iron assessment.
Abstract: BACKGROUND: Risks factors, clinical parameters and mortality associated with Doppler-defined-pulmonary xD;hypertension (DdPH) in thalassemia are poorly defined. This report summarizes the prevalence of elevated tricuspid xD;regurgitant jet velocity (TRV) indicating risk for pulmonary hypertension (PH) in patients screened by Doppler xD;echocardiography in the Thalassemia Clinical Research Network (TCRN). xD;PATIENTS AND METHODS: The TCRN is an NIH-sponsored network of major thalassemia centers in the US, Canada xD;and London, UK. This analysis is part of the Thalassemia Longitudinal Cohort (TLC), which comprises 428 patients at xD;16 centers. Results from 303 patients (71%) who were assessed by echo at least once are reported. Prospective data xD;on serial echos are available in a subset of this cohort. Risk factors and mortality associated with an abnormal TRV xD;are described. Multivariable effects of predictors significant in univariate analysis were modeled using logistic xD;regression for elevated TRV. xD;RESULTS: A measurable TRV was detectable in 148/325 (46%) of patients. Average age of the cohort with a xD;detectable TRV was 25.9 years (range 5-56). Half were female and 97% were transfusion dependent. Mean TRV was xD;2.3±0.4m/s (range 0.2-3.5m/s). An abnormal TRV≥2.5m/s was identified in 49/148 (33%) of assessable patients, xD;16% (8/49) of whom had a TRV≥3.0m/s suggesting significant risk of PH. Older age was strongly associated with xD;DdPH (r=0.38,p<0.0001), however 16% of children <18 years screened had a TRV≥2.5 m/s. A history of xD;splenectomy (odds ratio:5.3;[2.1-13.5]), hepatitis-C (OR:2.7;[1.12-6.64], smoking in the past year (OR:4.4; xD;[1.38-14]), high WBC (OR:1.1;[1.03-1.2] or cardiac MRI-LVEF% (OR:1.1;[1.01-1.18] was associated with high TRV, xD;using logistical regression modeling. After adjusting for other variables, smoking and MRI-LVEF% remained xD;independently associated with TRV. The prevalence of DdPH rises steadily with age in splenectomized patients, and xD;with time after splenectomy (Figures 1&2). Serial echos in 72 patients found variations in TRV status over time:19% xD;progressed to a TRV≥2.5 m/s, while 48% with DdPH demonstrated a normalized TRV on repeat examination. Only xD;one death occurred in a TLC patient with DdPH with a mean follow-up for mortality of 3 8±11 months (range:17-96 xD;months). No patients with an elevated TRV were on therapy for PH. xD;CONCLUSIONS: Elevated TRV is noted in 1/3 of transfusion-dependent thalassemia patients with measurable TRV, xD;and affects both children and adults. Age, splenectomy, smoking and history of hepatitis-C are risk factors with xD;splenectomy surfacing as an important risk factor over time. TRV measures are variable over time in this population. xD;Mortality was low. Long-term longitudinal studies are needed.
Abstract: Introduction: The erythrocyte redox environment contributes to increased hemolysis and decreased nitric oxide(NO) xD;bioavailability in pulmonary hypertension(PH) of sickle cell disease(SCD). Glutathione(GSH) is the principal thiol xD;redox buffer in erythrocytes and its depletion has been linked to hemolysis. Glutamine plays an additional xD;anti-oxidant role through preservation of the intracellular nicotinamide adenine dinucleotide(NAD) levels, required for xD;reducing GSSG back to GSH. Altered GSH and glutamine metabolism will promote hemolysis and contribute to xD;altered redox homeostasis. Erythrocyte glutamine depletion and low levels of the obligate NO substrate L-arginine are xD;associated with PH in SCD. Low arginine bioavailability is also associated with increased mortality risk. Targeting xD;these deficiencies in SCD has generated interest, however, little information on the pharmacokinetics (pK) is xD;currently available. Methods:We performed pK studies to determine the metabolic fate of glutamine xD;supplementation on plasma and erythrocyte amino acids in patients with SCD. Patients fasting for > 8 hours received xD;L-glutamine (10 grams). Blood was analyzed at baseline, 30/60/90 minutes and after 2/3/4/8hrs. A standardized xD;diet was administered to all participants at 3 established time-points (after 2/5/7hrs). A subset of patients also had xD;pK studies performed without study drug to follow normal diurnal fluctuations in amino acids. Results:We report xD;data on 5 patients with SCD, three of whom performed pK studies both with and without glutamine supplementation. xD;Average age was 50.6±5.6 years, 60% were female, 40% SS, 60% SC, and 4 had Doppler-defined PH (mean xD;TRV=3.4±0.8m/s, range 2.9-4.6m/s) while one patient had a TRV=2.25m/s and no history of PH. Plasma glutamine xD;levels more than doubled after oral glutamine supplementation, compared to minimal fluctuations with diet (Fig1A). xD;Plasma glutamine concentration peaked within 30-minutes of ingestion (p=0.01) before decreasing to a plateau by xD;2-hours that remained higher than baseline by 8 hours. Oral glutamine also increased plasma arginine concentration, xD;which peaked by 4-hrs (p=0.03) and remained elevated through 8-hrs (Fig1B). Erythrocyte glutamine levels began xD;to increase by 8-hours, (Fig1C), while erythrocyte arginine concentration peaked at 4-hours. Anecdotally, the xD;greatest improvement in intracellular erythrocyte arginine bioavailability occurred in our patient with severe PH and a xD;TRV=4.6 (Fig1D). Conclusions:Oral glutamine supplementation acutely improves glutamine and arginine xD;bioavailability in both plasma and erythrocytes. The clinical implications of these observations remain to be xD;determined, however this represents a promising novel therapy for hemoglobinopathies. Phase II studies of xD;glutamine supplementation targeting PH patients with SCD or thalassemia are ongoing at Children’s Hospital & xD;Research Center Oakland.
Abstract: DISSEMINATED JUVENILE XANTHOGRANULOMA CULMINATING IN BONE MARROW FAILURE AND DEATH xD;Authors: J. Chu, MD, H. Guo, R. Raphael, J. Torkildson, E. Vichinsky, C. Hastings xD;Theme: Leukemia/Lymphoma/Histiocyte Disorders xD;Primary Institution: Children's Hospital & Research Center Oakland xD;Institution City: Oakland xD;Institution State: California xD;Year: 2011 xD;Background: Juvenile xanthogranuloma (JXG), the most common form of non-Langerhans cell histiocytoses, is generally known to be a benign, cutaneous and spontaneously resolving disorder seen within the first two years of life. However, numerous cases describing JXG with extracutaneous lesions; presenting later in life even into adulthood; and malignant JXG requiring chemotherapy, have been reported. xD; xD;Objectives: To give information on potential treatment options for rare malignant JXG. xD; xD;Design: We present a rare, fatal case of malignant JXG with fulminant bone marrow necrosis in a previously healthy three-year old. xD; xD;Results: Previously healthy three year old boy presented with persistent and worsening respiratory distress and stridor following hospitalization for pneumonia and asthma. Biopsy of cutaneous papular fleshed-colored nodules and diffuse inflammatory lesions on bronchoscopy confirmed JXG. He underwent a tracheostomy and gastric tube placement due to involvement of the trachea and esophagus. Due to aggressive disease, he was started on VP/prednisone but when he failed to respond, cladribine was initiated with a noted rapid clinical remission. Afterwards, our patient developed a rapidly deteriorating course with multi-organ involvement with impressive bone marrow necrosis following an uncomplicated tonsillectomy and adenoidectomy. He developed fever, respiratory symptoms and pancytopenia several days after surgery. A full body magnetic resonance image showed widespread, diffuse bone marrow necrosis with biopsies most suggestive of disseminated JXG. He was restarted on etoposide, cyclosporine and dexamethasone with some initial response, but then developed status epilepticus and apnea five weeks later. Cladribine was reinitiated with improvement, but he expired 1.5 months after his seizure. Cause of death was determined to be multi-organ failure from JXG and actinobacter infection. xD; xD;Conclusion: Our patient appeared to undergo malignant transformation of JXG. Possible triggers in our patient include prolonged infection, surgery, chemotherapy, immune system dysfunction or cytogenic transformation. Since symptomatic JXG is uncommon, its treatment utilizes protocols for Langerhan cell histiocytosis or hemophagocytic lymphohistiocytosis. Our case study shows potential for cladribine as an effective chemotherapeutic agent against malignant JXG. Cladribine should be considered in a multi-drug regimen for patients with rapidly progressive systemic malignant JXG.
Abstract: Background: Long-term efficacy and safety of the iron chelator deferasirox in SCD patients has been previously reported (Vichinsky et al. BJH 2011). Hydroxyurea (HU), a common treatment for SCD, is associated with adverse events (AEs) such as bone marrow depression. However, long-term data for iron chelation and concomitant HU are limited. This study provides further efficacy and safety data for deferasirox including PK and safety data + HU. xD;Methods: SCD patients aged ≥2 yrs and iron overload from blood transfusions were enrolled and randomized 2:1 to deferasirox (DFX; 20 mg/kg/day) or deferoxamine (DFO; 175 mg/kg/week [wk]) for 24 wks (24-wk DFX or DFO cohort). DFO patients then crossed over to DFX; all patients received DFX up to Wk 52. Patients entered a 52-wk extension receiving DFX (DFX up to 2 yrs cohort). PK sampling was carried out pre- and 2 hrs post-dose in patients on DFX at Wk 12. Plasma concentrations of DFX and iron-complex Fe-[DFX]2 were determined using a validated LC-MS/MS method. Dose adjustments were implemented for changes in patient weight, serum ferritin, serum creatinine, liver function tests and rash. Primary objective was DFX safety compared with DFO during 24 wks. Secondary objectives included DFX safety and efficacy for up to 2 yrs and DFX safety in patients with concomitant HU. xD;Results: xD;24-weeks, DFX (n=135) vs DFO (n=68). xD;Patients were severely iron overloaded at baseline (BL); 37% had serum ferritin ≥4000 ng/mL (median 3385 ng/mL). In the DFX and DFO cohorts, respectively, 93 and 78% of patients completed 24 wks of treatment. AEs leading to discontinuation were reported by 0 and 1 (1.8%) patient in the DFX and DFO cohorts, respectively. Investigator-assessed drug-related AEs were reported in 27 and 29% of patients in the DFX vs DFO cohort, respectively; most common (>5%) were gastrointestinal (DFX vs DFO cohort: diarrhea 10.4 vs 3.6%; nausea 5.2 vs 3.6%). Serious AEs (any causality) were reported in 30 and 36% of patients in the DFX vs DFO cohort, respectively. One death occurred in the DFX cohort, not considered drug-related (patient had past history of multi-organ failure). At the 3-6 month timepoint, median change from BL in serum ferritin was -196 (range -4029 to 10,168) and -400 (range -10,001 to 3908) ng/mL for DFX (n=130) and DFO (n=58) cohorts, respectively. xD;
Abstract: Background: Individuals with sickle cell disease (SCD) face a number of barriers as they attempt to access timely and appropriate health care. We previously reported that adult and pediatric patients with SCD differed significantly on some barriers reported, with adults citing more barriers related to insurance and provider knowledge and attitudes. Patients’ emotional status, including worry, frustration and anger, were also reported barriers to accessing health care. However, there has been limited research formally assessing mental health symptoms as potential barriers to accessing health care. Objective: To investigate the relation between mental health symptoms, quality of life and reported barriers to accessing healthcare. We hypothesized that 1) mental health symptoms would be predictive of reported barriers, for adults with SCD compared with children, and 2) quality of life would be inversely related to the number of reported barriers, for adults and children. Methods: 112 patients with SCD were enrolled in a cross sectional study. Pediatric patients and their parents, and adults with SCD completed screening measures of depression (Patient Health Questionnaire-9 or Children’s Depression Inventory) and anxiety (Generalized Anxiety Disorder- 7 or Multidimensional Anxiety Scale for Children-10) and were categorized with no, mild, moderate or severe symptoms. They also completed quality of life measures (SF 36v2® or PedsQL®) and a validated checklist of barriers to accessing healthcare for SCD. Results: Participants were 35 children (M age 9.5, 1- 17 years) and their parents and 77 adults (M age 31.2, 18 - 68 years); 53% were female; 71% were diagnosed with SCD-SS. Sixty one percent of adults reported moderate to severe depressive symptoms, compared with 4% of children (p < .001). Thirty-six percent of adults reported moderate to severe symptoms of anxiety, compared with 12% of children (p < .05). Adults reported significantly worse quality of life in the Physical (M =53.0, SD =23.7) and Mental Health (M =49.4, SD =23.2) domains compared with children (Physical M =65.6, SD =21.4, p < .05 and Mental Health M =66.0, SD =17.9, p < .01). In regression analyses, we found that, with gender and hemoglobin type controlled for, depression was predictive of the number of barriers faced for adult (R2 = .27, β = 3.57 ± .88, n = 74) but not pediatric patients (R2 = .26, β = 5.68 ± 2.54, n = 26). Anxiety was predictive of the number of barriers faced for adults (R2 = .28, β = 3.99 ± .94, n = 75) but not pediatric patients (R2 = .13, β = 2.13 ± 1.96, n = 26). Greater number of barriers faced was predictive of worse quality of life in the Mental Health domain for both adults and pediatrics, controlling for gender and hemoglobin type (R2 = .19, β = -.98 ± .26, n = 73 for adults and R2 = .28, β = -1.06 ± .36, n = 33 for pediatrics. In the Physical domain, greater number of barriers faced was predictive of worse quality of life adults but not pediatrics, controlling for gender and hemoglobin type (R2 = .19, β = -.98 ± .26, n = 73 for adults and R2 = .28, β = -1.06 ± .36, n = 33 for pediatrics). Conclusion: Adults with SCD reported a higher prevalence of moderate to severe symptoms of depression and anxiety, compared with children with SCD and the general African American population. Their quality of life was more impaired compared with the children. Mental health symptoms were predictive of difficulties with accessing health care for adult more so than pediatric patients. There is an urgent need to address barriers to health care for patients with SCD and to improve mental health services available to adults in particular.
Abstract: Background: Moyamoya disease is a progressive cerebrovascular complication of sickle cell anemia characterized by collateral arterial formation in response to progressive stenosis of the large intracranial arteries. Despite chronic transfusions, moyamoya is associated with a high risk of stroke recurrence. Encephaloduroarteriosynangiosis (EDAS) is a surgical technique used to reestablish or augment cerebral perfusion in patients with moyamoya disease. However, evidence for its efficacy in SCA patients is limited. We initiated a prospective study to determine whether EDAS is safe and increases blood flow to ischemic areas of brain in SCA patients with moyamoya. xD;Methods: xD;SCA patients who had complete or partial obstruction of the dICA with progression to moyamoya disease were eligible for EDAS. Progressive cognitive decline, dystonia and persistent seizures were also factors influencing eligibility. xD;Seven SCA patients (age: median , range 4-23yrs; sex: 5F/2M ) with moyamoya disease underwent encephaloduroarteriosynangiosis (EDAS) procedures between 3/2007 and 9/2010. All 7 patients were regularly transfused for a history of stroke or MRA-documented ICA stenosis. Complete or partial obstruction of the dICA with moyamoya changes was detected on MRA scans and confirmed by cerebral angiography. Bilateral (n = 2) or unilateral (n = 5) encephaloduroarteriosynangiosis procedures in which the superficial temporal artery is transplanted through a small craniotomy with dural and arachnoid opening and sutured to the pia were performed. Perfusion MR-weighted imaging was performed pre- and post-operatively to evaluate changes in relative cerebral blood volume and time to peak enhancement. xD;Results: xD;All patients have remained free of neurovascular complications and have had no new ischemic changes on MRI with an average follow-up of 26 months. All patients subjectively reported improvement in overall well-being. A decrease in the frequency of headaches (n=1), resolution of seizures (n=2) and improved gait (n=1) were also observed. Collateral anastomoses between external and internal carotid arteries were established by MRA in all patients. All 4 patients who had pre and post-procedure MRA perfusion imaging showed a reduction in the delay of time to peak enhancement in the affected territory after EDAS. xD;Conclusion: xD;Our results indicate that EDAS is a safe and effective surgical procedure to re-establish blood flow to ischemic brain tissue in patients with SCA who develop moyamoya disease. MRA perfusion imaging may be a useful tool to evaluate improved perfusion status after EDAS. Further examination of neuropsychologic correlates, such as executive function, with EDAS procedures in these patients is presently underway. xD;
Abstract: ntroduction: The baseline characteristics and therapeutic management of sickle cell disease (SCD) can be quite variable depending on disease severity. This report describes baseline assessments and therapies of 420 patients in an ongoing registry designed to study current treatment patterns, natural history, and outcomes in patients with SCD. xD;Methods: This registry trial involving 57 US hematology centers had a sequential recruitment target of 600 patients with SCD subdivided into 3 age groups (2−<12 yr, 12−<18 yr, ≥18 yr). Patients ≥2 years of age with HbSS, HbS/β-thalassemia, or HbSC were eligible. Follow-up visits were every 6 months for a maximum of 5 years. Assessments included demographics, SCD history, Karnofsky Performance Status, medical history, types of crises, frequency of crises and hospitalization, treatment history, transfusion practices and use of iron chelation. Differences between pediatric (<18 yrs) and adult (≥18 yrs) patients were examined. (ClinicalTrials.gov identifier, NCT01220115). xD;Results: Enrollment: 420 patients (254 <18 yrs, 166 ≥18 yrs) completed the initial baseline visit. Baseline characteristics and medical history are shown in the Table and Figure. xD;Conclusions: xD;These data indicate differences in baseline characteristics and treatment patterns between adult and pediatric patients with SCD in this registry. Karnofsky performance status was worse, and serum ferritin levels were higher in adult versus pediatric patients. The percentage of patients having regular transfusions was higher in pediatric patients, while adult patients had higher rates of intermittent transfusions. As expected, the lifetime chelation exposure was more frequent in adult patients. Hospitalizations and use of hydroxyurea were also greater in pediatric patients. In terms of medical history related to SCDs, pediatric patients had higher frequencies of asthma, abnormal TCDs, dactylitis and splenic sequestration, while adults had more frequent evidence of avascular necrosis, gall bladder disease, leg ulcers and pulmonary hypertension. Pain was the most common crisis type in both cohorts, although this accounted for a greater relative proportion of crises in the adult cohort. The relative proportion of ACS events was lower in the adult versus pediatric patients; all other crisis types occurred in similar relative proportions in both cohorts. This ongoing registry will provide information about disease patterns, current treatment practices, and outcomes, thus contributing to a better understanding of the appropriate therapeutic management of patients with SCD.
Abstract: Deferasirox has been approved for the treatment of transfusional hemosiderosis in xD;patients aged ≥ 2 years. It is to be taken on an empty stomach and dispersed in water, xD;apple juice or orange juice ≥ 30 minutes before food.1 xD;• This mode of administration has been particularly challenging for younger patients. xD;• Two pharmacokinetic studies provided data on bioavailability of a single dose of xD;deferasirox when dispersed in different liquids or with different food combinations.2,3 xD;These studies demonstrated that: xD;–– Relative bioavailability is increased when administered with or before meal xD;–– Fat content of the meal positively influences bioavailability; however, total exposure is xD;not influenced by the fat content when administered 30 minutes before a meal. xD;• These additional options may increase the palatability of deferasirox and may ultimately xD;improve complianc
Abstract: Beta thalassemia major requires life-long chelation for survival. New oral (po) chelating agents are available for use with the assumption that they improve patients' health-related quality of life (HRQoL) over previously available continuous subcutaneous (sc) chelation. xD;We did a secondary analysis of a North American multicentre study designed to validate the TranQol, a new disease-specific HRQoL measure in children and adults with thalassemia. The HUI 3 was included as a well-standardized reference that can be administered to both adults and children. Mean HRQoL scores were compared using a 2-tailed independent samples t-test. xD;79 participants were enrolled in the validation study (51 adults and 28 children), with 21 of the children and all of the adults being able to self complete the questionnaires. The mean age was 22 years (2 to 51) with 38% male. The mean self-completed TranQol (0 to 100) were 66.6 (SD 16.4) and HUI 3 scores (0 to 1) for the group and 0.76 (SD 0.27) respectively. 2 patients were not receiving a chelator, 14 used Desferal (DFO) sc alone, 8 used DFO and L1 po, 17 used DFO and Exjade and 31 used Exjade po alone. We were unable to find a difference in TranQol and HUI scores between the treatment groups (none 73, 0.93; DFO 66, 0.79; DFO + L1 64, 0.66; DFO + Exjade 66, 0.78; Exjade 68, 0.76; p = 0.95, 0.73 respectively). A sub analysis of the pediatric age group showed a significant difference in TranQol scores between the sc (DFO and DFO + Exjade) and po (Exjade) treatment groups (72 vs. 83, p = 0.034; Figure1), which was not seen with the adult patients (62 vs. 62, p = 0.997; Figure 2). xD;In a cross-sectional study of patients with thalassemia, we were unable to find a difference in HRQoL scores between po and sc chelation. On sub analysis the TranQol scores in the pediatric age group were significant higher for patients receiving only po chelation.
Abstract: Abstract 2057 BackgroundIron chelators in current use (parenteral deferoxamine, oral deferasirox and deferiprone) are individually efficacious in many patients with transfusion dependent anemias, but each has liabilities relating to safety, ease of administration, patient acceptance, or narrow therapeutic index. The oral chelator FBS0701 is a polyether derivative of the siderophore-related compound, desazadesferrithiocin, a tri-dentate chelator with high affinity binding and selectivity for Fe(III). Animal studies of FBS0701 demonstrated a 4-fold higher no-observable-adverse-effect level in pre-clinical studies compared to deferasirox suggesting a favorable clinical safety profile with respect to nephrotoxicity. Single dose safety and pharmacokinetic studies in both healthy volunteers and iron overloaded patients have established preliminary data to guide further clinical trials. ObjectivesTo assess multiple-dose pharmacokinetics, safety, and tolerability of FBS0701 in patients with congenital transfusion-dependent anemias. MethodsThis was a multicenter, open-label, dose-escalating, multiple dose study of four dose levels (3, 8, 16 and 32 mg/kg/d) of FBS0701. Sixteen patients with documented transfusional iron overload over the age of seventeen were studied. Each dose cohort consisted of 4 patients. After a washout period, patients were dosed daily for seven days. Patients were clinically evaluated on Days 3, 6, 7, 8, 9, 10 and 15 and then weekly thereafter for three weeks. Assessments included physical exam, clinical pathology and ECG. A standard pharmacokinetic protocol of plasma sampling was performed throughout Day 7 and continuing to Day 10. Urine was collected in three intervals over the 24 hour period following the last dose. Each dose level was separated by a minimum of three weeks to assess safety before escalating to the next dose level. ResultsFBS0701 was well tolerated in all dose cohorts. There were no serious adverse events related to the drug. With the exception of a change in urine color that was regarded as without clinical significance, adverse events did not show dose-dependency in frequency or severity. Pharmacokinetic parameters derived from plasma and urine drug levels are shown in the table below. There was no evidence of accumulation after 7 days of dosing. Dose- dependent pharmacokinetics were observed as predicted. View this table: T1500400T1 AUC0-24: area under the plasma concentration versus time, zero time point to 24 hours; Cmax: time to maximum observed plasma concentration; tmax: time to maximum plasma concentration; kel: terminal elimination rate constant; t[1/2]: half-life calculated by the equation t[1/2] = 0.693/kel; CL/F: the apparent total plasma clearance of drug after oral administration; Vz/F: the apparent volume of distribution during terminal phase after oral administration; Ue: amount of drug excreted into urine; Fe: the fraction of orally administered drug excreted unchanged in urine; CLr: renal clearance ConclusionsFBS0701, a novel tridentate iron chelator, was well tolerated for 7 days at doses up to 32 mg/kg, the high end of the predicted therapeutic dose range. The compound is of interest because in preclinical animal studies there was no evidence of gastrointestinal toxicity and FBS0701 was less able to cause renal toxicity than deferasirox. The pharmacokinetic parameters suggest good dose proportionality and support once-daily dosing that might provide 24 hour protection from non-transferrin bound iron based on the gradual terminal-phase elimination. FBS0701 warrants Phase 2 safety and efficacy studies in transfusional iron overloaded patients. DisclosuresRienhoff: Ferrokin, Inc.: Employment, Equity Ownership. Viprakasit: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ferrokin, Inc.: Research Funding. Tay: Ferrokin, Inc.: Research Funding. Harmatz: Ferrokin, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Vichinsky: Novartis: Research Fun ing. Chirnomas: Novartis: Research Funding. Kwiatkowski: Ferrokin, Inc.: Research Funding. Tapper: Ferrokin, Inc.: Employment. Porter: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Neufeld: Novartis, Inc: Research Funding; Ferrokin, Inc: Research Funding.
Abstract: Abstract 2077 IntroductionPulmonary arterial hypertension (PAH) has been accepted to be a clinical entity associated with hemoglobinopthies, mostly reported in sickle disease and thalassemia intermedia (TI). Anecdotal cases of PAH in other chronic hemolytic disorders have been reported; many of which have been associated with a prior splenectomy. The pathogenesis of PAH in the non sickle-cell RBC hemolytic disorders has not been well defined and the large variability in its frequency and severity are not clear. We aimed to characterize biomarkers in thalassemia and in other RBC disorders and evaluate the specific role of splenectomy (spleen.) in these diseases. Patients and MethodA total of 106 patients were analyzed: Forty two were regularly transfused thalassemia major (TM), 34 had TI (16 with Hb E/beta thalassemia, 11 with beta thalassemia, and 7 with hemoglobin H-Constant Spring (Hb H-CS); 18 with hereditary spherocytosis (HS) or pyruvate kinase (PK) deficiency, 2 with an unstable Hb (Hb Koln), and 10 with a history of splenectomy for non-RBC related reasons (trauma or chronic ITP). PAH was determined by using a Doppler echocardiogram showing a tricuspid regurgitation jet velocity (TRV) of >2.5m/s. Markers of platelet activation (P- selectin, soluble CD40 (sCD40L); abnormal exposure of Phosphatidyl Serine (PS) on RBCs, thrombin generation (thrombin-anti-thrombin, TAT); increased ventricular pressure strain (brain natriuretic peptide (BNP); plasma free Hb, LDH and NOx, and endothelin-1, soluble vascular cell adhesion molecule (sVCAM) were analyzed. ResultNineteen (56%) of the TI patients (15 with beta-TI and 4 with Hb H-CS) had abnormally elevated TRV (Mean 3.0{+/-}0.5). The 2 patients with Hb Koln had increased TRV. There were no PAH cases detected among patients with membrane or RBC enzyme deficiencies, neither was there an increased TRV in patients who had been splenectomized without a RBC disorder. There were also no cases of increased TRV in the transfused TM cohort. Patients with TI, in addition to a prior splenectomy and increased hemolysis had increased platelet activation, abnormal RBC PS exposure and anemia. TI patients also had an increase in ET-1 levels, a potent vasoconstrictor. The 2 patients with Hb Koln had increased thrombin generation in addition to hemolysis and absence of spleen. View this table: TU1500400TU1 View this table: TU2500400TU2 ConclusionsPAH was not detected in splenectomized patients with only a mild chronic hemolytic disorder or in those without a RBC disorder. In addition to the absence of spleen, a higher rate of hemolysis, resulting in NO scavenging and increase in ET-1 and the involvement of platelet activation or thrombin generation are likely required for the development of dysregulation of the pulmonary vascular function. PAH is rare in TI patients which have not undergone splenectomy; absence of spleen likely enhances the effects of thrombocytosis and platelet activation. Our data indicates that PAH is common in patients with Hb H-CS, mostly splenectomized, and should be screened for. In addition our data shows that blood transfusions reduce the elements of anemia, hemolysis and coagulation activation and prevent the development of PAH in splenectomized and non-splenectomized patients. DisclosuresNo relevant conflicts of interest to declare.
Abstract: Abstract 254 Clinical experience and research with sickle cell patients and those with other genetic diseases suggests that the period of "transition," in which patients move from pediatric care to adult-centered clinical care, is a period of high health services utilization. Young adult patients may not have learned to effectively manage disease symptoms and may not be connected to a "medical home" or have established a relationship with a primary care physician or adult hematologist. Further, these patients may not have insurance coverage previously provided by parents or by public pediatric insurance programs. As part of a collaborative agreement through the Centers for Disease Control and Prevention (CDC) and the National Heart, Lung & Blood Institute (NHLBI), California and five other states are conducting epidemiologic surveillance to determine the prevalence of hemoglobinopathies as well as health services utilization. Such data are essential to inform allocation of resources to meet the medical and social service needs of patients. Within the state, this project is a collaborative effort among the CA Dept. of Public Health Genetic Disease Screening Program, Children's Hospital Los Angeles and Children's Hospital & Research Center Oakland. Using administrative data obtained as a part of this effort, we describe emergency room (ER) utilization patterns among young adults with sickle cell disease. The CA Office of Statewide Health Planning and Development has collected data on ER utilization for the years 2005 - 2008. Using ICD 9 codes beginning with 282.6 to identify sickle cell-related ER visits during those years, we report usage patterns by patient age, gender, and payer type. To calculate risk of repeat ER visits, we used a negative binomial regression model (with 1 visit as the baseline for analysis, rather than 0 visits, due to the limitations of the data set). The following means and counts are adjusted to account for this shift. Analyses were conducted using SAS 9.1. The mean number of ER visits among sickle cell patients in the data set was 3.36 per year and 54% of visits were made by women, but gender differences in average visits per year per patient (3.18 female, 3.60 male) were not statistically significant. Medi-Cal (Medicaid) was the primary payer for 47% of visits during this time frame, and patients with Medi-Cal averaged nearly one additional visit per year (3.82 visits) compared to patients with other forms of payment (3.04 visits). Among patients seen at any time during the four years and controlling for gender and payer type, we found a 78% increase (IRR 1.78, 95% CI 1.59, 2.00) in risk of visiting the ER a second or subsequent time in a given year among the 20 to 30 year old group compared to all other age groups, a four fold increase (IRR 4.22, 95% CI 3.61, 4.93) in risk of a second or subsequent visit in a year compared to the group aged 10 to 20 years, and a 30% increase (IRR 1.34, 95% CI 1.16, 1.55) compared to the group 30 to 40 years of age. Average number of visits in the transition age group was 4.53 per year, compared to 1.93 per year in the 10 to 20y group and 3.56 in the 30 to 40y age group. The number of individuals visiting the ER per year was higher in this age group compared to the two adjoining age groups (520 individuals on average per year for 20 - 30y, vs. 311 per year for 10 - 20y and 355 for 30 to 40y). The increase in visits per year of age can be seen (Figure 1) to begin at age 18 or 19 and continue to approximately age 30. The proportion of patients with no insurance coverage increased from 8% in the 10 to 20y age category to 19% of patients in the 20 to 30y age category, and remains high for the subsequent age categories (11 to 17%). The transition period from pediatric care to adult care in California sickle cell patients is marked by a dramatic increase in emergency room visits (both more patients visiting and more visits per patient) compared to other age groups. ERs are also visited significantly more often by uninsured sickle cell patients in this age grou than other age groups. Patients in this age group would likely benefit from access to a medical home model of care. F1"> WIDTH=200 HEIGHT=131 SRC="/small/bld0011000220018.gif" ALT="Figure 1"> View larger version (126K): F1779613F1 Figure 1. Mean Annual Number of Visits by Age of Patient among Those Seen in ER with SCD-related ICD 9 Codes, California, 2005-2008 DisclosuresCoates: Novartis: Research Funding, Speakers Bureau.
Abstract: Abstract 845 BackgroundTransfusion therapy can effectively treat many complications associated with sickle cell disease (SCD), but iron overload will develop without iron chelation therapy. Despite long-term transfusion requirements, long-term data for iron chelation in SCD are limited. The oral iron chelator, deferasirox, effectively reduced iron burden in SCD patients aged [≥]2 years during 1 year of treatment (Vichinsky et al. Br J Haematol 2007). This 5-year follow-up is the first report of long-term deferasirox treatment in SCD patients. MethodsEligible patients that completed the 1-year core study (randomized to deferasirox [deferasirox cohort] or deferoxamine [crossover cohort]) entered the 4- year extension. All received deferasirox while continuing their regular transfusion regimen. Deferasirox dose in the extension was initially based on serum ferritin (SF) trends in the core study (deferasirox cohort) or transfusion requirements (crossover cohort). Dose adjustments were based on monthly SF and safety assessments (investigator-reported adverse events [AEs] and centrally processed lab parameters). Growth and sexual development (Tanner staging) were assessed annually. ResultsOf the patients in the deferasirox (n=132) and crossover (n=53) cohorts that received '1 deferasirox dose during the core or extension, 43 (33%) and 19 (36%) patients, respectively, completed the extension. Reasons for discontinuation included withdrawal of consent (n=44, 23.8%), loss to follow-up (n=17, 9.2%) and AEs (n=14, 7.6%). Three deaths occurred, all in the extension (intraventricular hemorrhage, n=2; intracranial bleed post liver transplantation, n=1); none considered by investigators to be deferasirox-related. Mean dose during the study was 18.7 {+/-} 6.5 and 21.2 {+/-} 5.3 mg/kg/day in the deferasirox and crossover cohorts, respectively. Investigator-assessed drug-related AEs ([≥]5% overall) included nausea (14.6%), diarrhea (10.8%), increased blood creatinine (5.9%) and vomiting (5.4%). Generally, these AEs were manageable and transient, and decreased in frequency over time. Serious AEs were reported in 70.8% of patients overall and were mostly related to the underlying disease. Serious investigator-assessed drug-related AEs were reported in 8 patients (6.1%) in the deferasirox cohort and 1 patient (1.9%) in the crossover cohort. In the deferasirox and crossover cohorts respectively, 9 (6.8%) patients and 1 (1.9%) patient had 2 consecutive serum creatinine level increases >33% above baseline and >upper limit of normal (ULN). Median creatinine clearance remained stable within normal range throughout the study. One patient from each cohort had alanine aminotransferase (ALT) >10 x ULN on 2 consecutive visits; both had ALT values [≤]ULN at the start of deferasirox treatment. In 37 patients with data available before and after dose increases to [≥]30 mg/kg/day, no clinically relevant differences were observed in AE profile or laboratory parameters before and after dose increase. Deferasirox had no adverse effect on pediatric growth and adolescent sexual development. Overall, median SF levels in patients who received deferasirox treatment for [≥]4 years decreased significantly from 3410 to 3108 ng/mL at end of study (median absolute change, -591 ng/mL, P=0.027; n=67). Decreases in SF were more pronounced when mean deferasirox dose increased to >20 mg/kg/day (Figure 1). In the deferasirox cohort, the median absolute change in SF levels from start of deferasirox to end-of-study was greater in patients aged [≥]16 than 2-<16 years (-476 vs -156 ng/mL) reflecting low 1st-year deferasirox doses and conservative dose escalation in pediatric patients. F1"> WIDTH=147 HEIGHT=200 SRC="/small/bld0011000250007.gif" ALT="Figure 1"> View larger version (112K): F17801057F1 ConclusionsThis is the first study to report that deferasirox can significantly decrease SF levels over the long-term in SCD patients without evidence of renal toxicity. Treatment for up to 5 years was associated with a clinically manageable safety profile, ithout progressive decreases in median creatinine clearance, which remained within normal range. The modest, but statistically significant, decrease in SF is most likely due to under-dosing in the first 2 years and variability in SF related to disease factors. Patients titrated to an appropriate dose had a clinically relevant decrease in SF, highlighting the need to adjust dose, usually to >20 mg/kg/day, to achieve negative iron balance. DisclosuresVichinsky: Novartis: Consultancy, Research Funding, Speakers Bureau; Apotex: Consultancy, Research Funding; Hemaquest: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bernaudin: Novartis: Investigator for SCD deferasirox (Exjade). Forni: Novartis: Research Funding. Gardner: Novartis: Research Funding. Hassell: Novartis: Research Funding. Heeney: Novartis: Research Funding. Kutlar: Novartis: Research Funding. Lane: Novartis: Research Funding. Mathias: Novartis: Research Funding. Porter: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Tebbi: Novartis: Speakers Bureau. Wilson: Novartis: Honoraria, Research Funding, Speakers Bureau. Griffel: Novartis: Employment. Deng: Novartis: Employment. Giannone: Novartis: Employment. Coates: Novartis: Research Funding, Speakers Bureau.
Abstract: Abstract 2078 Ineffective erythropoiesis, the hallmark of {beta}-thalassemia, is a result of the myriad deleterious effects of globin chain imbalance. A major translational research goal in thalassemia is to restore {alpha}/non-{alpha} globin chain balance by inducing expression of {gamma}-globin synthesis from the intact {gamma}-globin gene (HBG). Repression of HBG in adult erythroid cells involves DNA methylation and other epigenetic changes; one possibly useful strategy to re-induce HBG expression is to deplete DNA methyl-transferase 1 (DNMT1) in hematopoietic cells using the cytosine analogue decitabine. A dose and schedule of decitabine intended to deplete DNMT1 without causing significant cytotoxicity was examined in a pilot safety study in {beta}-thalassemia intermedia, a condition which, despite a lack of requirement for monthly transfusions, is often associated with significant long-term clinical complications. Six patients ([≥]18 years of age) with {beta}-thalassemia intermedia were enrolled on study to receive decitabine 0.2 mg/kg subcutaneous 2x/week on consecutive days each week for 12 weeks followed by 12 weeks of follow-up. One patient withdrew from study because of fatigue requiring transfusion after week 2. Of the five evaluable patients, two patients received 24 of the 24 planned doses of drug, one patient received 21 of 24 planned doses, and two patients received 16 of 24 planned doses. Doses were missed because of treatment-associated increases in platelet count to >1000 x 109/L which according to protocol, required interruption of therapy. The primary outcome, an increase in total hemoglobin (Hb) of [≥]1.5 g/dL above that determined at baseline, was achieved in two of five evaluable patients. In the group overall, Hb increased from a baseline of (mean {+/-} SEM) 7.88 {+/-} 0.88 g/dL to a peak of 9.04 {+/-} 0.77 g/dL (P = 0.004); peak values in Hb were observed from the 6th to 12th week of treatment. Absolute fetal Hb increased from a baseline of (mean {+/-} SEM) 3.34 {+/-} 0.97 g/dL to a peak of 4.39 {+/-} 1.15 g/dL (P = 0.021); peak values in fetal Hb were observed in the 4th to 12th week of treatment. Reflecting decreased hemolysis and more effective erythropoiesis, indirect bilirubin declined from (mean {+/-} SEM) 3.2 {+/-} 1.0 mg/dL to a nadir of 2.2{+/-} 0.8 mg/dL, while reduction in serum LDH from (mean {+/-} SEM) 479.4 {+/-} 125.8 U/L to 362.8 {+/-} 100.4 U/L was not significant (P =0.083). Platelet counts increased from a baseline of (mean {+/-} SEM) 585.2 {+/-} 90.6 (x109/L) to a peak of 940.2 {+/-} 184.3 (x109/L) (P = 0.007); peak platelet values were observed between the 6th to 12th weeks of treatment. These increases triggered interruption of therapy in three of the five evaluable patients. In the only patient not previously splenectomized, minimal change in platelet count was observed (baseline, 233 x109/L; peak, 296 x109/L). No clinical events were associated with the increased platelet counts. Changes in neutrophil count, from (mean {+/-} SEM) 6.51 {+/-} 1.20 (x109/L) to 3.36 {+/-} 0.63 (x109/L) were not significant (P = 0.069). The lowest neutrophil counts were observed between the 4th and 10th week of treatment. Two quantitative in vitro assays for mutagenicity, specifically enumeration of illegitimate VDJ recombination events and micronuclei within early reticulocytes, were performed at baseline, midpoint, and study exit. No significant changes were identified between baseline and 24-week values from either laboratory assay. In this first clinical study of decitabine in patients with {beta}-thalassemia, drug dose was aimed at induction of DNMT1 depletion; the frequent but intermittent schedule of administration was intended to modify differentiation without causing prolonged cytostasis resulting in cytopenia. Consistent with a non-cytotoxic/cytostatic, differentiation-altering mechanism of action, the dose-limiting toxicity observed was not thrombocytopenia or neutropenia, but asymptomatic increases in platelet count. In conclusion, decitabine therapy was well-tolerated in thalassemia intermedia. Significant mean and individual increases in total and fetal hemoglobin concentrations observed in this study may direct the selection of patients in extended trials, to explore the potential of chromatin-relaxing therapy for {beta}-thalassemia. DisclosuresOff Label Use: FDA approved decitabine for use in MDS, therefore, its use in thalassemia is off-label. Furthermore, the dose, schedule and route of administration used is also not on the label. Decitabine was used in a study to augment production of fetal hemoglobin in an NIH sponsored trial.
Abstract: Abstract 1636 IntroductionThe erythrocyte redox environment may contribute to increased hemolysis and decreased nitric oxide (NO) bioavailability in pulmonary hypertension (PH) of sickle cell disease (SCD). Glutathione (GSH) is the principal thiol redox buffer in erythrocytes and its depletion has been linked to hemolysis. Glutamine plays an additional anti-oxidant role through preservation of the intracellular nicotinamide adenine dinucleotide (NAD) levels, required for reducing GSSG back to GSH. Altered GSH and glutamine metabolism will promote hemolysis and contribute to altered redox homeostasis. Glutamine depletion and low levels of the obligate NO substrate L-arginine are associated with pulmonary hypertension (PH) in SCD. Low arginine bioavailability is also associated with increased mortality risk. Pilot data of L-glutamine therapy has been associated with improved vasculopathy and increased NAD redox potential in SCD. Targeting these deficiencies in SCD has generated interest, however, little information on the pharmacokinetics (pK) is currently available. MethodsWe performed pK studies to determine the metabolic fate of glutamine supplementation on plasma and erythrocyte amino acids in patients with SCD. Patients fasting for > 8 hours received 10 grams of L-glutamine powder mixed with Gatorade. Blood was analyzed at baseline, 30, 60, 90, 2hr, 3hr, 4hr and 8hrs after ingesting study drug. A standardized diet was administered to all participants at 3 established time-points (after 2hr, 5hr and 7 hrs). A subset of patients also had pK studies performed without study drug to follow normal diurnal fluctuations in amino acids. ResultsWe report data on 5 patients with SCD, three of whom performed pK studies both with and without glutamine supplementation. Average age was 50.6 {+/-}5.6 years, 60% were female, 40% SS, 60% SC, and 4 had PH (mean TRV=3.4{+/-}0.8m/s, range 3.0-4.6m/s) while one patient had a TRV=2.25 and no history of PH. Diurnal variations in many amino acids were observed. However plasma glutamine levels more than doubled after oral glutamine supplementation, compared to minimal fluctuations with diet. Plasma glutamine concentration peaked within 30 minutes of ingestion (p=0.01) before decreasing to a plateau by 2 hours that remained higher than baseline by 8 hours. Oral glutamine also increased plasma arginine concentration, which peaked by 4 hrs (p=0.03) and remained elevated through 8 hrs (FigB). Global arginine bioavailability (plasma arginine/(ornithine+ citrulline) also increased (0.67{+/-} 0.2 to 1.83{+/-}0.6, p=0.02). Erythrocyte glutamine levels began to increase by 8 hours, (Fig 1C), while erythrocyte arginine concentration peaked at 4 hours. Anecdotally, the greatest improvement in intracellular arginine bioavailability occurred in our patient with severe PH and a TRV=4.6 (Fig 1D). The erythrocyte glutamine/glutamate ratio peaked at 1-2 hrs, as did the erythrocyte glutathione concentration, although these trends did not reach statistical significance. F1"> WIDTH=200 HEIGHT=136 SRC="/small/bld0011000270030.gif" ALT="Figure 1"> View larger version (49K): F1780629F1 ConclusionsOral glutamine supplementation (10 gm) acutely improves glutamine and arginine bioavailability in both plasma and erythrocytes. The clinical implications of these observations remain to be determined, however this represents a promising novel therapy for hemoglobinopathies. Phase II studies of glutamine supplementation targeting PH patients with SCD or thalassemia are ongoing at Children's Hospital & Research Center Oakland. DisclosuresOff Label Use: L-glutamine - an amino acid that may improve arginine bioavailability. IND held by C. Morris.
Notes: Morris, Claudia R. Ansari, Michael Lavrisha, Lisa Sweeters, Nancy Kuypers, Frans A. Vichinsky, Elliott P. xD;6th Int Conf on Biol, Chemistry, and Therapeutic Applications of Nitric Oxide/2nd Int Conf NO and Cancer/10th Annual Meeting of the Nitric-Oxide-Soc-Japan xD;JUN 14-18, 2010 xD;Kyoto, JAPAN xD;Nitr Oxide Soc Japan xD;S
Abstract: Abstract 3221 BackgroundMost adult sickle cell anemia patients have received transfusion therapy. However, prospective studies evaluating the efficacy of transfusions in preventing sickle cell-related complications are lacking. The Phase II Neuropsychological Adult Sickle Cell Anemia Study is a randomized trial of chronic transfusion vs. standard of care in patients with abnormal neurocognitive function in order to determine the safety and benefits of transfusion therapy on neurocognitive function. A secondary goal of the study is to evaluate the benefit of chronic transfusion on the frequency and severity of acute sickle cell events; this is a preliminary report of this specific aim. MethodsEligibility required normal neurological exam, WAIS III PIQ score [≤] 90, hemoglobin [≤] 9 g/dL, hemoglobin SS electrophoresis, and age between 21 and 55 years. Patients were randomly assigned to receive either standard care or transfusions. The transfusion goal was to maintain a hemoglobin of 2 g/dL rise over baseline with matched red cells for D, C/c, E/e, and Kell antigens. The protocol required simple transfusions at approximately 4 week intervals. Chelation therapy was not part of the study design. Patients underwent serial clinical and laboratory evaluations with central analysis of all clinical and transfusion events and complications. Laboratory testing of subjects in the transfusion arm included quantitative hemoglobin S/A, hemoglobin concentration, ferritin levels, and red cell antibody screening; a full hematology/chemistry panel was performed for all subjects at baseline, the study mid-point, and at the end of the study. ResultsThere were 20 patients in the transfusion arm (TX arm) with a mean age of 29 years vs. 16 patients in the standard care arm (SC arm) with a mean age of 30.5 years. The baseline data in the TX arm was similar to the SC arm: hemoglobin 7.8 vs. 8.0 g/dL; hematocrit 22.6% vs. 23.1%; hemoglobin F 10.5% vs. 12.5%. Thirty-five percent of patients randomized to the TX arm had a history of acute chest syndrome (ACS) vs. 31% in the SC arm; 30% of patients in the TX arm were on hydroxyurea compared to 50% in the SC arm. The TX arm patients have received an average of 5.6 transfusions (2 units per transfusion) with only one subject requiring an acute transfusion (5%); in contrast, 4 SC arm patients (25%) were transfused for acute events for a total of 7 units (average 1.8 per patient). The transfusion therapy improved the average hematologic status of patients: hemoglobin S% decreased from 85% to 32% (p=0.0003); hemoglobin and hematocrit increased from 7.6 to 9.4 g/dL (p=0.0052) and 22% to 28%, (p=0.007), respectively. Bilirubin declined from 3.6 to 2.4 mg/dL (p=0.042). In contrast, only bilirubin showed a significant decrease in the SC arm. In the TX arm, serum ferritin rose an average of 1318 to 2368 (p=.001); there was no change in liver function. There were no clinical transfusion reactions in the 120 study transfusions (360 units); however, one patient on routine screening reported a transient anti-D antibody without clinical or laboratory changes. Clinical ResultsAdverse events were higher in the SC arm. Total number of adverse events in the TX arm were 23 (1.2 per person) vs. 66 in (4.1 per person) in the SC arm. There were 5 hospitalizations in the TX arm and 21 in the SC care arm, with a median number of hospitalized days per hospitalization of 5.0 and 6.0 respectively. The total number of serious events was 6 in the TX arm (0.3 per person) vs. 23 in the SC arm (1.4 per person). The total number of vaso-occlusive events in the TX arm were 14 (0.7 per person) vs. 57 (3.6 per person) in the SC arm. Acute pulmonary events occurred in 25% (4 patients) of the SC arm vs. none in the TX arm. ConclusionsThis is preliminary data from the first prospective randomized study of the safety and efficacy of transfusion therapy in adults with SCD. We demonstrate the safety of transfusion therapy. Compared to standard therapy, transfusions improve or stabilize critical laboratory markers, decrease seriou sickle cell anemia-related adverse events, and decrease in hospitalizations. Increase in ferritin is an expected outcome in transfused patients since chelation was not a part of this transfusion protocol. On completion of the study, the potential benefits of transfusion therapy on sickle cell disease morbidity including neurocognitive function will be reported. DisclosuresField: Novartis Pharm: Honoraria.
Abstract: Abstract 264 Background:Approximately half of sickle cell anemia (SCA) patients will develop aseptic necrosis (AVN) of the hips, with the majority of cases progressing to total collapse of the femoral head. Total hip arthroplasty (THR) in patients with SCA has been associated with high rates of perioperative complications and eventual failure of the prosthesis. Previous studies have suggested that hip coring decompression (HCD) is effective in decreasing pain and slowing the progression of AVN. In the most recent study of HCD in SCA, the mean surgical time was 1.1 hours and anesthesia time 2.1 hours; associated blood loss was 56cc. The length of hospital stay (LOS) was 5 days with a mean of 3 days postoperatively. We report a surgical approach designed to decrease surgical time while at the same time improving perfusion to the effected tissue with repeated small bone fenestrations. Patients and Methods:From 11/1/2009 to 7/1/2010, 8 patients (10 hips) with SCA underwent HCD for femoral AVN: 3 females and 5 males with an average age of 31.3 years (median 25.5, range 11 to 50). 5 patients had SS and 3 SC disease. Seven hips were diagnosed as Ficat stage II and 3 as stage III. Physical exams and pain assessments were performed before surgery and at follow-up by the same orthopedic surgeon. The clinical protocol includes a two day hospital stay: admission the day before surgery with overnight hydration at 1.5x maintenance fluids, postoperative management of pain and hydration, and discharge after PT evaluation and instruction. Patients are fully ambulatory at discharge and given exercise instructions by physical therapists. Description of Procedure and Physical Therapy Plan: Under anesthesia, patients are placed in a lateral position on a bean-bag and bony prominences are well padded; an axillary roll is used. The hip, thigh, and mid part of the leg are sterilely prepared and draped, allowing rotation of the leg. The fluoroscopic C-Arm is placed underneath the bed, so that a true AP of affected hip is obtained. The fluoroscopic image determines the starting point for the initial 0.5 cm incision with a 15-blade. The drill (with a 5.0 bit) is then advanced to the proximal lateral cortex of the femur, distal to the greater trochanter. Under radiographic guidance, drill position is confirmed and advanced to the affected area of the femoral head. The drill is then withdrawn to the cortex (but within the cortical window) and advanced in different directions to achieve 3 adequate core channels. Prior to applying dressings, a six-inch long 18-gauge needle on a 10 cc syringe, containing 0.25% Marcaine with epinephrine is placed into the affected hip joint, under fluoroscopic guidance, and a small volume of the anesthetic is injected for relief of postoperative pain and pain associated with synovitis. Results:The average surgical and anesthesia time in minutes were: 15.9 {+/-} 6.6 and 53.4 {+/-} 18.1 respectively; mean blood loss was less than 10 cc. Three procedures were performed under conscious sedation without tracheal intubation. Two procedures were performed during an admission for acute pain; the remaining 8 were scheduled surgical admissions. The average LOS for the scheduled procedures was 5 days (3.5 days postoperative). No complications were reported in the immediate or 6-week postoperative periods. In this series of 10 hips, all patients were fully weight bearing and ambulatory at discharge. Prior to surgery, all 10 hips were rated as a 10 on a 10-point pain scale. At the 6 week follow-up exam, 8/10 hips were rated as pain free, one hip was rated as a 1/10 and one hip remained a 10/10. The two patients undergoing surgery during acute pain episode involving the affected hip received immediate relief and were able to be discharged early. Conclusion:The modified HCD technique utilizing small, repeated fenestrations is safe and is associated with reduced operative times, reduced anesthesia time, and negligible blood loss compared to previous studies of HCD for femoral AVN in SCA. Preliminary data indicates it is effect ve in decreasing the pain associate with AVN. We plan to follow these and future patients for 5 years with serial radiographs and evaluations utilizing the validated, reliable Children's Hospital Oakland Hip Evaluation Scale. DisclosuresNo relevant conflicts of interest to declare.
Abstract: Abstract 5155 IntroductionDeferasirox (Exjade(R), Novartis Pharmaceuticals) is an oral iron chelator indicated for the treatment of transfusional iron overload. The recommended mode of administration is to be taken on an empty stomach in water, apple juice or orange juice [≥]30 minutes before food. However, there have been post-marketing reports of discontinuation or reduced compliance of deferasirox secondary to palatability and gastrointestinal adverse events. Registration trials with deferasirox did not evaluate different food combinations in an attempt to maintain predictable plasma levels. Early single dose studies suggested that the bioavailability of deferasirox is increased when administered with or before meals, and is positively influenced by fat content, but is not affected by degree of dispersion nor type of liquid. Long-term pharmacokinetic and tolerability studies involving a food effect have not been conducted to date, and the ability of alternate methods of administration to improve patient compliance with iron chelation therapy is unknown. MethodThis is an ongoing single-arm, open-label, multi-center study designed to evaluate the palatability, safety, tolerability and pharmacokinetics of deferasirox when administered with food, dispersed in any liquid of choice, or crushed and added to food. The patient population includes patients with transfusional hemosiderosis (minimum entry serum ferritin [≥]500 {micro} g/L) aged >2 years with thalassemia major, sickle cell disease (SCD), low or intermediate (INT-1) risk MDS or other anemias, who are on, starting, or resuming treatment with deferasirox. The study began with a 1-month run-in phase with deferasirox dosed according to prescribing information, then a 3-month assessment phase where subjects could choose each week from 5 general administration options including with or without meals, in the morning or evening, crushed and added to a soft food, or mixed in a liquid of choice. Subject diaries are used to record the meal and method of administration at the end of each week. Palatability is assessed with a modified facial hedonic scale, with additional directed questions capturing gastrointestinal side effects. This is a data analysis of the run-in phase. ResultTarget enrollment has been met with 65 patients. Baseline data on the first 58 subjects include 8 in the 2 to <10 years of age group (median 7.5 years; range 3-9); 42 in the 10 to <60 years of age group (median 18.5 years; range 10-48); and 8 in the [≥]60 years of age group (median 74 years; range71-83). Underlying hematologic diagnoses included SCD (41%), thalassemia major (29%), MDS (12%) and other anemias (17%). Sixty-nine percent of subjects were receiving deferasirox prior to entering the study. The median baseline serum ferritin level was 2405 {micro} g/L (range 560-8660) and was distributed as shown in Table 1. The most frequent adverse events were diarrhea (19%) and nausea (9%) (Table 2), which were more common in MDS (P=0.23 and P<0.01, respectively). View this table: T1780602T1T1 Table 1. Summary of age and baseline serum ferritin by underlying hematological condition View this table: T2780610T2T2 Table 2. Most frequent treatment-emergent AEs for run in phase ConclusionThis ongoing trial (NCT00845871) is evaluating whether alternative modes of administration improve palatability and tolerability while maintaining safety. Preliminary data from the assessment phase (deferasirox taken with meals, different liquids, or crushed and added to food) will be presented at the meeting. DisclosuresGoldberg: Novartis Oncology: Consultancy, Honoraria, Research Funding, Speakers Bureau. Off Label Use: Exjade, iron chelation therapy, off-label method of administration. Giardina: Novartis: Research Funding. Parkhurst Cain: Novartis: Research Funding. Chirnomas: Novartis: Research Funding. Esposito: Novartis: Employment. Paley: Novartis: Employment. Vichinsky: Novartis: Consultancy, Research Funding, Speakers Bureau; Hemaquest: Consultancy, Membership on an entity's Board of Directors o advisory committees; Apotex: Consultancy, Research Funding.
Abstract: Abstract 256 BackgroundPain is not a symptom generally associated with thalassemia. However, healthcare providers have anecdotally noted increasing patient reports of chronic pain over the last decade creating an impetus for the TCRN to conduct this prospective, observational assessment of pain in patients with thalassemia over the age of 12. Study goals include assessment of pain prevalence, severity and sites and whether these factors are impacted by age, gender or diagnosis. MethodsPain was assessed quarterly using the Brief Pain Inventory (BPI). Two hundred fifty-one thalassemia patients ranging in age from 12 to 71 (average age of 28.75) receiving care at one of 12 thalassemia centers across the US and Canada participated in the study. Fifty-four percent of participants were female. Diagnoses included: Beta Thalassemia (80%), E Beta thalassemia (11%), Hemoglobin H and H Constant Spring (6%) and other thalassemia conditions (3%). Eighty percent of participants were chronically transfused, 6% intermittently transfused and 14% had never been transfused. This report reviews baseline findings. ResultsAt study entry, 64% of the 251 participants reported experiencing pain over the last four weeks, of whom 21% reported pain on a daily basis. In comparison, 26% of the American public, 20 years and older, reported pain over a one month period according to National Center for Health Statistics data, 2006. Ordinal regression analysis of participant ratings of worst, least, and average pain over the last seven days demonstrated significant (p<0.001) correlation of increased age with increased pain across all categories irrespective of diagnosis, transfusion status or gender. Similarly, ordinal regression analysis revealed that pain increased with participant age and significantly correlated (p<0.001) with a negative impact of pain on patient's affect and activity as measured by the BPI interference scales. Eighty-two percent of those reporting pain indicated lower back as a site of pain. In logistic regression models, lower back (p=0.046), arm (p=0.047) and hip (p=0.009) pain significantly increased with age. The number of bodily pain sites (p=0.033) also increased with age which was determined using linear regression. Among patients reporting pain in the last seven days, 77% reported having pain for one year or longer and 26% reported pain for 5 or more years. Participants reporting pain in the last 7 days identified the following reasons for their pain: thalassemia (60%), low hemoglobin (55%), bone pain (37%) and muscle spasm (30%). Participants indicated multiple methods of managing pain including: blood transfusion (54%), rest (51%) massage (46%) and heat (39%). Medications were the most frequently cited pain intervention (72 % of participants) with the most common mediations taken being NSAIDs (71%), followed by acetaminophen (48%), short acting narcotics (24%) and long acting narcotics (11%). Twenty-five percent of participants reported they received no pain relief from medications or non-pharmaceutical treatments, and only 4% reported they received complete pain relief with treatment. Half the population reported they gained about 50% relief from pain with treatments. ConclusionsThese data show that pain is a significant issue for patients with thalassemia and as patient's age pain increases. Pain assessment should be conducted on a regular basis for all patients with thalassemia since neither transfusion status nor diagnosis are a reliable indicator of pain status. The study also indicates that chronic pain (pain lasting greater than one year) is an issue for thalassemia patients and underscores the need for further study of pain in this population. Analysis of pain follow up data collected at 3 month intervals post baseline is being conducted to assess whether severity levels vary over time. DisclosuresCoates: Novartis: Research Funding, Speakers Bureau. Neufeld: Novartis, Inc: Research Funding; Ferrokin, Inc: Research Funding.
Abstract: Abstract 4269 Therapeutic regimens that combine two iron chelators may enhance chelation efficiency by improving access to different tissue iron stores and control of the toxic labile iron pool. The combination of two chelators can reduce toxicity through averting the need for high doses of a single drug, but it is essential to establish the safety such regimens. We therefore explored the combined use of deferasirox (DSX) and deferoxamine (DFO) in patients with transfusion-dependent thalassemia who had failed standard chelation therapy with single drug. Patients were eligible if the liver iron concentration (LIC) >15 mg/g dry liver-weight or if iron-induced end organ injury was present. Subjects were monitored for hepatic and renal toxicity, visual or auditory changes, and the development of new complications from iron overload. The ability of the combined therapy to control systemic iron burden (serum ferritin and LIC) and myocardial iron overload (MRI T2*) was evaluated. We also measured changes in plasma levels of non-transferrin bound iron (NTBI) and labile plasma iron (LPI). Fifteen subjects were enrolled in 3 groups: adults with LIC <15 mg/g dry liver-weight (group A), adults with LIC >15 mg/g (group B), and children 8-18 years with LIC >5 mg/g (group C). The duration of therapy was 52 weeks. DSX (20-30 mg/Kg) was administered daily and DFO (35-50 mg/Kg/infusion) was infused on 3-7 days/week (as 8-12 hour infusion) based upon the degree of iron overload present at baseline. At the initiation of the study, the mean daily dose of DFO was 16, 33, and 17 mg/Kg/day and mean DSX dose was 21, 25 and 22 mg/Kg/day for groups A, B and C, respectively. At the conclusion of the trial, the median LIC declined by 48% from 10.8 mg/g (3.9-34.8 mg/g) to 5.7 mg/g (1.0-24.0 mg/g, p=0.003). The median ferritin fell by 43% from 2030 ng/mL (1000-5230 ng/mL) to 1150 ng/mL (421-5260 ng/mL, p=0.008). Myocardial iron in the 3 subjects who had T2* <20 msec at study entry (range 6.5-19.5 msec at week 0) showed an average improvement of +2.43 msec following treatment (range 8.8-21.3 msec at week 52, p=0.027). All 3 subjects with left ventricular ejection fraction below 60% at baseline (47.5-58.1%) showed improvement at end of study (60.6-64.4%). There was progressive decline in median plasma NTBI level during the study from 3.26 {micro}M (1.79-5.79 {micro}M) at baseline to 2.38 {micro}M (1.59-3.08 {micro}M) at 12 months (p=0.008). DSX produced immediate and significant decline in plasma NTBI when administered during infusion of DFO. The median plasma NTBI measured on DFO alone was 2.46 {micro}M (0.92-5.90 {micro}M), which decreased to 1.96 {micro}M (0-3.50 {micro}M) following administration of the dose of DSX (p<0.001). A sustained control of the LPI fraction was also demonstrated throughout the study period. At baseline the median LPI was 0.87 {micro}M (0-2.43 {micro}M) which decreased to 0.05 {micro}M (0-1.20 {micro}M) during the study period (p=0.004). No significant toxicity or unusual adverse events were observed with combined chelation therapy in this group of high-risk patients with thalassemia. Elevation of serum creatinine or ALT was not observed in any subject. One subject from group B died at 9 weeks from start of trial from sepsis. One subject interrupted DSX therapy because of abdominal pain. In all other cases the treatment was well tolerated and no dose adjustment or suspension of therapy was required on account of toxicity. Protocol-mandated modification of treatment (temporary cessation of DSX or DFO) occurred in three subjects owing to a marked fall in serum ferritin and LIC. These results suggest that simultaneous administration DSX and DFO is well tolerated and has low potential for toxicity. Combined chelation therapy appears to be effective in rapidly reducing systemic iron burden, lowering myocardial iron, and controlling plasma NTBI and LPI in patients at risk of developing end-organ damage. DisclosuresHarmatz: Ferrokin: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novart s: Research Funding. Porter: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Vichinsky: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.
Abstract: Abstract 4260 BackgroundAlpha thalassemia disorders are rapidly increasing in North America. This has resulted in proposals for universal newborn screening (NBS) for hemoglobin H disease. However, the institution of routine newborn screening and construction of guidelines for early intervention requires longitudinal clinical data before setting national goals. Since 1995, California has performed universal screening for alpha thalassemia disorders. The longitudinal follow up of data from patients with hemoglobin H disorders diagnosed in the asymptomatic period provides essential information needed for formulating public health policy. MethodsHemoglobin H disorders were diagnosed by high performance liquid chromatography with multiplex GAP-PCR assay to determine deletional hemoglobin H disease (deletion of 3 {alpha} globin genes, HbH) and the non-deletional hemoglobin H Constant Spring ({alpha}0 thalassemia with Constant Spring mutation, HCS). Longitudinal clinical data for all patients from the Northern California Thalassemia Center were analyzed. Ethnicity, growth data, clinic visits, hospitalizations, complications including splenectomy, transfusion, and iron overload were monitored. Quantitative liver iron concentration was determined by ferritometer. Results86 patients predominantly diagnosed through NBS were longitudinally followed. Out of these, 60 (70%) had HbH, 23 (27%) had HCS and 3 (3%) had other forms of hemoglobin H disease. The parental ethnicity in HbH was 79% Asian, 6% Hispanic, and 15% African-American (in one or both parents). All patients with HCS were of Asian ethnicity. Longitudinal data for hemoglobin revealed that anemia was more severe in HCS at all ages (p<0.001). Mean hemoglobin in HbH increased from 8.8 g/dL (6.9-10.6 g/dL) at 6 months to 9.4 g/dL (7.9-11.5 g/dL) at 5 years (p<0.001). However, mean hemoglobin in HCS remained unchanged from 7.4 g/dL (5.8-9.9 g/dL) at 6 months to 7.2 g/dL (3.8-8.7 g/dL) at 5 years (p=ns). There was no hemoglobin value <6.7 g/dL in 237 patient-years of observation of 60 patients with HbH. Compared to HbH, red blood cells in HCS had higher mean corpuscular hemoglobin (18.6 versus 16.6 pg, p<0.001) and mean corpuscular volume (65.2 versus 54.0 fL, p<0.001). The mean absolute reticulocyte count was 88.2 x103/{micro}L in HbH versus 235.1 x103/{micro}L in HCS (p<0.001), while the mean serum bilirubin was 0.56 mg/dL and 2.60 mg/dL, respectively (p<0.001). Clinical severity and complications were markedly worse in HCS in contrast with HbH. Growth was delayed in HCS with mean weight-for-age Z-score -0.91 compared with -0.06 in HbH (p<0.001). The mean height-for-age Z-score was also lower in HCS (-1.29) compared with HbH (-0.43, p<0.001). The striking susceptibility to acute worsening of anemia with infections requiring urgent blood transfusion was observed in HCS, but not in HbH. The probability of receiving one or more blood transfusion by 20 years was 3% in HbH and 82% in HCS (p<0.001). Transfusions in HCS were required for 13% infants and median transfusion-free survival was 6 years. Splenectomy improved hemoglobin by 2.9 g/dL (0.4 to 4.0 g/dL, p=0.012) and reduced transfusions in HCS. Iron overload, measured by serum ferritin and liver iron concentration, developed during the first decade in HCS and increased during follow up. Median ferritin in HCS between 12 -17 years was 330 ng/mL (66-1420 ng/mL). Serum ferritin in HbH did not increase between 0-18 years (median 40 ng/mL, range 5-182 ng/mL), but older patients showed strong positive correlation between age and ferritin (p<0.001). In patients with HbH or HCS undergoing ferritometer examination, the degree of serum ferritin elevation underestimated the liver iron concentration. ConclusionsOur data support the utility of a universal NBS program, particularly in areas where {alpha}CS mutation is prevalent, since young infants with HCS can develop life-threatening anemia. HCS is a serious disease that needs close follow-up by a specialty thalassemia center to plan for emergency and elective transfusions, measure ron overload, monitor growth failure and evaluate the need for splenectomy. In contrast, HbH is asymptomatic during infancy and childhood; its complications are age-dependent, and monitoring for hemosiderosis and growth failure is more important in older children. In summary, HCS should be recognized as a thalassemia syndrome distinct from HbH with a different screening and treatment approach. DisclosuresNo relevant conflicts of interest to declare.
Abstract: Abstract 4260 BackgroundAlpha thalassemia disorders are rapidly increasing in North America. This has resulted in proposals for universal newborn screening (NBS) for hemoglobin H disease. However, the institution of routine newborn screening and construction of guidelines for early intervention requires longitudinal clinical data before setting national goals. Since 1995, California has performed universal screening for alpha thalassemia disorders. The longitudinal follow up of data from patients with hemoglobin H disorders diagnosed in the asymptomatic period provides essential information needed for formulating public health policy. MethodsHemoglobin H disorders were diagnosed by high performance liquid chromatography with multiplex GAP-PCR assay to determine deletional hemoglobin H disease (deletion of 3 {alpha} globin genes, HbH) and the non-deletional hemoglobin H Constant Spring ({alpha}0 thalassemia with Constant Spring mutation, HCS). Longitudinal clinical data for all patients from the Northern California Thalassemia Center were analyzed. Ethnicity, growth data, clinic visits, hospitalizations, complications including splenectomy, transfusion, and iron overload were monitored. Quantitative liver iron concentration was determined by ferritometer. Results86 patients predominantly diagnosed through NBS were longitudinally followed. Out of these, 60 (70%) had HbH, 23 (27%) had HCS and 3 (3%) had other forms of hemoglobin H disease. The parental ethnicity in HbH was 79% Asian, 6% Hispanic, and 15% African-American (in one or both parents). All patients with HCS were of Asian ethnicity. Longitudinal data for hemoglobin revealed that anemia was more severe in HCS at all ages (p<0.001). Mean hemoglobin in HbH increased from 8.8 g/dL (6.9-10.6 g/dL) at 6 months to 9.4 g/dL (7.9-11.5 g/dL) at 5 years (p<0.001). However, mean hemoglobin in HCS remained unchanged from 7.4 g/dL (5.8-9.9 g/dL) at 6 months to 7.2 g/dL (3.8-8.7 g/dL) at 5 years (p=ns). There was no hemoglobin value <6.7 g/dL in 237 patient-years of observation of 60 patients with HbH. Compared to HbH, red blood cells in HCS had higher mean corpuscular hemoglobin (18.6 versus 16.6 pg, p<0.001) and mean corpuscular volume (65.2 versus 54.0 fL, p<0.001). The mean absolute reticulocyte count was 88.2 x103/{micro}L in HbH versus 235.1 x103/{micro}L in HCS (p<0.001), while the mean serum bilirubin was 0.56 mg/dL and 2.60 mg/dL, respectively (p<0.001). Clinical severity and complications were markedly worse in HCS in contrast with HbH. Growth was delayed in HCS with mean weight-for-age Z-score -0.91 compared with -0.06 in HbH (p<0.001). The mean height-for-age Z-score was also lower in HCS (-1.29) compared with HbH (-0.43, p<0.001). The striking susceptibility to acute worsening of anemia with infections requiring urgent blood transfusion was observed in HCS, but not in HbH. The probability of receiving one or more blood transfusion by 20 years was 3% in HbH and 82% in HCS (p<0.001). Transfusions in HCS were required for 13% infants and median transfusion-free survival was 6 years. Splenectomy improved hemoglobin by 2.9 g/dL (0.4 to 4.0 g/dL, p=0.012) and reduced transfusions in HCS. Iron overload, measured by serum ferritin and liver iron concentration, developed during the first decade in HCS and increased during follow up. Median ferritin in HCS between 12 -17 years was 330 ng/mL (66-1420 ng/mL). Serum ferritin in HbH did not increase between 0-18 years (median 40 ng/mL, range 5-182 ng/mL), but older patients showed strong positive correlation between age and ferritin (p<0.001). In patients with HbH or HCS undergoing ferritometer examination, the degree of serum ferritin elevation underestimated the liver iron concentration. ConclusionsOur data support the utility of a universal NBS program, particularly in areas where {alpha}CS mutation is prevalent, since young infants with HCS can develop life-threatening anemia. HCS is a serious disease that needs close follow-up by a specialty thalassemia center to plan for emergency and elective transfusions, measure ron overload, monitor growth failure and evaluate the need for splenectomy. In contrast, HbH is asymptomatic during infancy and childhood; its complications are age-dependent, and monitoring for hemosiderosis and growth failure is more important in older children. In summary, HCS should be recognized as a thalassemia syndrome distinct from HbH with a different screening and treatment approach. DisclosuresNo relevant conflicts of interest to declare.
Abstract: Abstract 943 Definitive therapies to reduce the underlying pathology in sickle cell syndromes are still needed, particularly non-cytotoxic therapeutics which could be used either alone or in combination with hydroxyurea. Increased fetal hemoglobin (HbF) levels correlate with reduction in organ damage and improved patient survival. An oral, promoter-targeted fetal globin gene stimulant, HQK-1001, which also prolongs erythroid survival and proliferation, has demonstrated favorable pharmacokinetic (PK) and safety profiles in normal volunteers in a Phase 1 clinical trial. Accordingly, a randomized, blinded dose-ranging Phase 1/2 trial was performed in 24 adult patients with sickle cell disease (including HbSS or S/{beta} thalassemia). The study therapeutic was administered once daily for two 6-week cycles of daily therapy with a 2 week treatment break between the two cycles. Three dose levels (10, 20, 30 mg/kg/dose) were studied sequentially, with 4 placebo treated subjects. 21 patients were evaluable. Five patients received active drug at the lower two dose levels; 7 patients received active study drug at the 30 mg/kg dose level. HQK-1001 was well-tolerated with no significant drug-related adverse events. Increases in HbF levels were observed at all dose levels with the highest effects observed at 30 mg/kg, where 5 of 7 treated patients responded with a mean peak increase of 2.6% HbF (absolute 0.2 g/dl, p=0.04) above baseline. HbF increased both in patients who did, and who did not, take concomitant hydroxyurea. A mean peak increase in total hemoglobin of 1.3 g/dL (range 0.9 to 2.4) above baseline was also observed in these HQK-1001-treated patients. F-reticulocytes and F-cells increased by 20-33% and 6-18%, respectively, in the 5 responders at the 30 mg/kg dose level. LDH declined in 4 of 5 responding subjects receiving 30 mg/kg doses. Fetal globin mRNA increased by 4- to 9-fold over baseline throughout the study period in treated patients and was still increasing at the end of the dosing period, implying that HbF expression had not yet peaked. Other fetal globin inducing agents, such as hydroxyurea require 6-9 months of treatment for optimal effects on HbF to be achieved. Therefore, the findings of HbF induction and rises in total Hgb in 70% of subjects with short treatment duration in the current study indicate that longer trials of HQK-1001 are warranted to evaluate potential therapeutic effects on HbF expression and anemia more definitively in sickle cell disease. DisclosuresKutlar: HemaQuest Pharmaceuticals, Inc: Research Funding. Vichinsky: HemaQuest Pharmaceuticals, Inc: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Neumayr: Novartis : Honoraria, one time honoraium 10/09; NIH: Research Funding. Labotka: HemaQuest Pharmaceuticals, Inc: Research Funding. Keefer: HemaQuest Pharmaceuticals, Inc: Research Funding. Shen: HemaQuest Pharmaceuticals, Inc: Research Funding. Boosalis: HemaQuest Pharmaceuticals, Inc: Equity Ownership, Research Funding. Thomson: HemaQuest Pharmaceuticals: Employment, Equity Ownership. Bobbitt: HemaQuest Pharmaceuticals, Inc: Employment, Equity Ownership, Patents & Royalties. Wallis: HemaQuest Pharmaceuticals: Consultancy, Equity Ownership. Johnson: HemaQuest Pharmaceuticals: Employment, Equity Ownership. Berenson: HemaQuest Pharmaceuticals, Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Perrine: HemaQuest Pharmaceuticals, Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.
