Sickle cell disease and malaria morbidity: a tale with two tails

More than 230,000 children are born in Africa with sickle cell disease (SCD) each year: approximately 85% of all affected births worldwide. Although malaria is commonly viewed as a major problem for African patients with this condition, questions still remain about its relative importance as a cause of ill heath and death. In the absence of definitive studies investigating the contribution of malaria to morbidity and mortality in African children with SCD, policy makers will continue to lack the evidence on which to base appropriate management guidelines.     

Incidence of Sickle Cell Disease and Other Hemoglobin Variants in 10,095 Lebanese Neonates

Hemoglobinopathies are highly prevalent diseases and impose a public health burden. Early diagnosis and treatment can ameliorate the course of these diseases and improve survival. Despite purported high incidence of hemoglobinopathies in Lebanon, there are no nationwide screening programs. In this study, newborn screening utilizing high pressure liquid chromatography was executed in all public hospitals across Lebanon between 2010 and 2013. All newborns with an abnormal hemoglobin (Hb) were offered genetic counseling and all those with disease were enrolled in comprehensive hemoglobinopathy clinics. Among newborns, 2.1% were found to have an abnormal Hb variant with sickle Hb being the most common while 0.1% were found to have sickle cell disease (SCD). The majority of those with SCD had non-Lebanese origins. The most common causes of hospitalizations in infants with SCD were acute splenic sequestration and pain crises. No bacteremia or other life threatening infections were noted. At a median follow up 14 months (follow up range 7 to 34 months), all children with disease are alive and compliant with treatment. Systematic screening for SCD and other Hb variants was shown to be feasible, cost effective, and of accurate predictive value. This program was also clinically effective because it led to the identification of babies with disease and to providing them with free early multidisciplinary care. Conclusively, a newborn screening program should be implemented across Lebanon to detect hemoglobinopathies and initiate early therapeutic and preventive strategies and genetic counseling.     

Asthma is a risk factor for acute chest syndrome and cerebral vascular accidents in children with sickle cell disease

BACKGROUND: Asthma and sickle cell disease are common conditions that both may result in pulmonary complications. We hypothesized that children with sickle cell disease with concomitant asthma have an increased incidence of vaso-occlusive crises that are complicated by episodes of acute chest syndrome. METHODS: A 5-year retrospective chart analysis was performed investigating 48 children ages 3-18 years with asthma and sickle cell disease and 48 children with sickle cell disease alone. Children were matched for age, gender, and type of sickle cell defect. Hospital admissions were recorded for acute chest syndrome, cerebral vascular accident, vaso-occlusive pain crises, and blood transfusions (total, exchange and chronic). Mann-Whitney test and Chi square analysis were used to assess differences between the groups. RESULTS: Children with sickle cell disease and asthma had significantly more episodes of acute chest syndrome (p = 0.03) and cerebral vascular accidents (p = 0.05) compared to children with sickle cell disease without asthma. As expected, these children received more total blood transfusions (p = 0.01) and chronic transfusions (p = 0.04). Admissions for vasoocclusive pain crises and exchange transfusions were not statistically different between cases and controls. SS disease is more severe than SC disease. CONCLUSIONS: Children with concomitant asthma and sickle cell disease have increased episodes of acute chest syndrome, cerebral vascular accidents and the need for blood transfusions. Whether aggressive asthma therapy can reduce these complications in this subset of children is unknown and requires further studies.     

Gall stones in sickle cell disease in the United Kingdom.

The prevalence of gall stones was studied prospectively by abdominal ultrasound examination in 131 patients with sickle cell disease aged 10-65 years. Of 95 patients with homozygous sickle cell disease, 55 (58%) had gall stones or had had a cholecystectomy. Gall stones were present in four out of 24 (17%) patients with haemoglobin S + C disease and two out of 12 (17%) with haemoglobin S beta thalassaemia. The presence of gall stones was not related to sex, geographical origin, or haematological variables and was not associated with abnormal results of liver function tests. Symptoms typical of biliary colic were reported by 32 out of 47 adult patients with gall stones, and cholecystitis or cholestasis was diagnosed in 18. Cholecystectomy was performed in 29 patients with good relief of symptoms in most cases. Postoperative complications were common, occurring in 10 of the 28 patients who could be evaluated, but not generally serious; they were considerably lessened by a preoperative exchange transfusion that reduced the haemoglobin S concentration to below 40%. It is suggested that all patients with sickle cell disease should be screened for gall stones and that elective cholecystectomy should be performed in those with symptoms or complications.     

Hydroxycarbamide: Clinical aspects

Due to its oral route of administration and mild toxicity profile, as well as its potent laboratory and clinical effects, hydroxyurea (or hydroxycarbamide) has been the primary focus of fetal hemoglobin (HbF) induction strategies for the treatment of children with sickle cell anemia (SCA). When administered orally once a day, hydroxyurea treatment is very well tolerated with little short-term toxicity. Hydroxyurea has documented laboratory efficacy with increases in Hb and HbF; treatment also significantly reduces the number of painful episodes, acute chest syndrome, transfusions, and hospitalizations. Most young patients reach a maximum tolerated dose of hydroxyurea at 25–30 mg/kg/d, where they will achieve key laboratory thresholds (Hb ≥ 9 g/dL and HbF ≥ 20%) without excessive myelosuppression. Potential long-term toxicities continue to be of great concern and should be monitored in all patients with SCA who receive hydroxyurea therapy. To date, however, no increases in stroke, myelodysplasia, or carcinogenicity have been detected in SCA patient cohorts, with drug exposure now reaching 15 years for some treated children. Taken together, available evidence suggests that hydroxyurea represents an inexpensive and effective treatment option that should be offered to most, if not all, patients with SCA. As countries in Africa develop newborn screening programs to identify SCA, the widespread use of hydroxyurea may prove to be a useful treatment to help ameliorate the disease in resource-limited settings. Hydroxyurea is the only currently available disease-modifying therapy for SCA, and is emerging as a safe and effective treatment for all patients with SCA, in both developed and developing countries.     

Painful crises in sickle cell disease--patients' perspectives.

One hundred and two patients returned structured questionnaires sent to clinics for sickle cell disease in the United Kingdom in order to gain greater insight into the patients'' perception of painful crises. Most patients who suffer pain crises experience a prodromal stage that should be investigated further to find out if prophylaxis is possible. Cold, exertion, and tiredness were the most important precipitating factors. Despite the increase in the amount of knowledge about sickle cell disease in recent years, and though 29 out of 88 patients (30-40%) believed that medical services were improving, 33 out of 88 (30-40%) were still experiencing long delays in being treated in hospital. A third of patients do not seem to receive adequate pain relief.     

Bone marrow transplantation beyond treatment of aplasia and neoplasia.

Marrow transplantation has proved to be an important modality in the treatment of aplastic anemia, acute leukemia, and some other malignant diseases of hemopoietic cells. Much less attention has been paid to the role of marrow transplantation in the treatment of stem cell disorders such as sickle cell disease, chronic granulomatous disease, or Gaucher''s disease. Allogeneic transplantation is successful in these disorders, but carries a considerable risk to the recipient. Autologous transplantation becomes a reality when efficient gene transfer with sustained expression is developed. As methods are developed to harvest hemopoietic stem cells from the peripheral blood and to amplify these cells without causing them to differentiate, transplantation will become increasingly valuable in the treatment of stem cell disorders.     

Elevated Pulse Pressure is Associated with Hemolysis,Proteinuria and Chronic Kidney Disease in Sickle Cell Disease

A seeming paradox of sickle cell disease is that patients do not suffer from a high prevalence of systemic hypertension in spite of endothelial dysfunction, chronic inflammation and vasculopathy. However, some patients do develop systolic hypertension and increased pulse pressure, an increasingly recognized major cardiovascular risk factor in other populations. Hence, we hypothesized that pulse pressure, unlike other blood pressure parameters, is independently associated with markers of hemolytic anemia and cardiovascular risk in sickle cell disease. We analyzed the correlates of pulse pressure in patients (n  =  661) enrolled in a multicenter international sickle cell trial. Markers of hemolysis were analyzed as independent variables and as a previously validated hemolytic index that includes multiple variables. We found that pulse pressure, not systolic, diastolic or mean arterial pressure, independently correlated with high reticulocyte count (beta  =  2.37, p  =  0.02) and high hemolytic index (beta  =  1.53, p = 0.002) in patients with homozygous sickle cell disease in two multiple linear regression models which include the markers of hemolysis as independent variables or the hemolytic index, respectively. Pulse pressure was also independently associated with elevated serum creatinine (beta  =  3.21, p  =  0.02), and with proteinuria (beta  =  2.52, p  =  0.04). These results from the largest sickle cell disease cohort to date since the Cooperative Study of Sickle Cell Disease show that pulse pressure is independently associated with hemolysis, proteinuria and chronic kidney disease. We propose that high pulse pressure may be a risk factor for clinical complications of vascular dysfunction in sickle cell disease. Longitudinal and mechanistic studies should be conducted to confirm these hypotheses.     

Dactylitis in a child with sickle cell trait

Dactylitis commonly occurs in patients with homozygous hemoglobin S disease (sickle cell anemia), sickle cell-hemoglobin C disease or sickle cell-β-thalassemia. A case is reported of dactylitis associated with sickle cell trait, a very rare occurrence. It may be that in this patient the disorder was secondary to severe diarrhea and dehydration.     

The use of a free flap in homozygous sickle cell disease

This paper describes what is thought to be the first reported use of a free flap in a patient with homozygous sickle cell disease. The utilization of a free flap in homozygous sickle cell disease should be questioned because the obligate period of ischemia to which the flap must be subjected during the transfer from donor to recipient sites might lead to intravascular sickling in the flap and flap failure. Review of the literature suggests that by reducing the level of sickle hemoglobin to the range of 25 to 40 percent, the risk of failure of a free flap is not significantly increased in the homozygous sickle cell patient. Furthermore, there is good evidence to suggest that a well-vascularized muscle flap provides optimal coverage, reversing the pathophysiologic cycle of the sickle cell ulcer. Thus in cases of multiply recurrent sickle cell ulcers in areas devoid of a local well-vascularized muscle flap, a free muscle flap is indicated, may be the procedure of choice, and can be performed successfully. We report a patient with a 4-year history of multiple recurrent sickle cell ulcers of the left ankle treated with a gracilis free flap. This patient has been followed for 2 years and continues to be free of recurrent ulceration.     

Assessment of care of children with sickle cell disease: implications for neonatal screening programmes.

OBJECTIVE--To assess the quality of care provided by hospitals for young children with sickle cell disease. DESIGN--Retrospective survey. SETTING--Teaching hospital in London. PATIENTS--31 Children (mean age 4 years 4 months, range 4 months to 7 years 5 months) born with sickle cell disease between 1978 and 1985 identified from Hospital Activity Analysis data, an outpatient diagnostic register, and registers of the haematology department. Eight had been diagnosed on neonatal screening and at least four of these had not been followed up. MAIN OUTCOME MEASURES--Aspects of quality of outpatient care (blood testing, clinic attendance, and prophylactic drug treatment) and family care (adequate support and carers'' knowledge about the disease) as assessed by reviewing the notes and administering a semistructured questionnaire to the carers, in relation to a devised list of standards deemed necessary to ensure achievement of the aims of screening. RESULTS--There were 93 outpatient attendances during the previous 12 months, but 13 children had not attended at least every six months and four not at all for more than a year. Only eight children had had three of the blood tests considered to be necessary for good care; three had had none. Prophylactic treatment with penicillin and folic acid was erratic; three children with sickle cell anaemia were not receiving regular prophylactic penicillin. IMPLICATION--Diagnosis of sickle cell disease on neonatal screening must be linked with follow up to ensure optimal management.     

Pathophysiology and therapy for haemoglobinopathies. Part I: sickle cell disease

In sickle cell disease, a single base pair substitution in the gene encoding the beta-globin chain of the haemoglobin molecule gives rise to a surprisingly broad spectrum of pathophysiological and clinical manifestations. Inflammation, endothelial activation, red blood cell membrane abnormalities and altered availability of vasoactive factors characterise this disorder. Clinically, patients suffer from a host of seemingly unrelated maladies, from pain episodes to strokes, life-threatening infections and pulmonary hypertension. Deepened understanding of this complex disease now allows us to begin to turn away from simple supportive treatments, and move towards therapies aimed at specific pathophysiological targets. This article, the first of two reviews on the pathophysiology of haemoglobinopathies, discusses the molecular basis of sickle cell disease, and elaborates on the many factors that exacerbate or ameliorate the disease process. It then focuses on the promising targeted therapies currently in use or under investigation. An accompanying article on haemoglobinopathies (Part II) focuses on thalassaemias.     

Early deaths in Jamaican children with sickle cell disease.

In Jamaican children with homozygous sickle cell (SS) disease diagnosed at birth two-year survival was 87%, compared with 95% in children with sickle cell-haemoglobin C (CS) disease, and 99% in normal controls. Death among those with SS disease occurred most often between the ages of 6 and 12 months. Principal causes were acute splenic sequestration and pneumococcal infection. Neonatal diagnosis of haemoglobinopathies must be followed by close observation if mortality is to be reduced by early diagnosis and treatment of these complications.     

Acute admissions of patients with sickle cell disease who live in Britain.

All acute admissions of patients with sickle cell disease who lived in the London borough of Brent and attended this hospital were analysed for a period of one year. Sixty three of the 211 patients who were followed up by the haematology department required 161 acute admissions during the year. Most admissions (126) were for the 42 patients with homozygous sickle cell disease; 147 (91%) were for vaso-occlusive episodes, 142 of which were for painful crises, three for cerebrovascular accidents, and two for renal papillary necrosis. Preschool children with sickle cell disease were admitted predominantly with limb pain, whereas in schoolchildren and adults the incidence of trunk pain was higher. Twenty four of the 93 episodes of trunk pain culminated in an episode of severe visceral sequestration usually affecting the lungs, the liver, or the mesenteric circulation. Two patients died: an 18 month old baby with an acute splenic sequestration crisis and a 19 year old man with a severe girdle syndrome (sickling in the mesenteric circulation, liver, and lungs). Infective episodes were rare (11 episodes) but severe: one haemophilus meningitis, two salmonella infections, and three aplastic crises due to parvovirus infections. The average duration of the hospital stay was 7.4 days per admission. It is concluded that because sickle cell disease causes appreciable morbidity in older children, adolescents, and adults a systematic approach to management is needed to deal with acute episodes such as sequestration syndromes.     

What's new and what's true of what's new in dermatology

Within the past few years it has been noted that abnormal types of hemoglobin found in certain persons are associated with definite clinical disorders. At least four different varieties of sickle cell anemia are now recognized, three of them being heterozygous and one homozygous. When the gene for sickling is represented once, the person is asymptomatic and is said to have "sickle cell trait." However, when the sickle cell trait is present in combination with certain other hemoglobin abnormalities such as hemoglobin C or D or with thalassemia trait, symptomatic clinical disease results. The homozygous condition, in which two genes for hemoglobin C are present in the same person, has been observed in a few instances. A similar condition as regards hemoglobin D has not as yet been recognized.     

The health orientation scale: A measure of feelings about sickle cell trait

Abstract

The Health Orientation Scale (HOS), a written self‐report instrument, was developed to objectively appraise the psychological implications of identification as a sickle cell gene carrier (AS). The HOS uses the semantic differential technique and consists, of nine situations thought to be of importance in identification as a carrier. The instrument was completed by respondents during the various phases of the screening and counseling process. Discussion will focus on a comparison of carrier and noncarrier (AA) reactions to situations which involve the diagnoses of sickle cell trait (AS), sickle cell disease (SS), cancer, and hypertension along with a comparison of feelings before and after counseling. Results suggest that noncarriers have more negative feelings about sickle cell than carriers. Further, counseling, as it is currently practiced, does not contribute to any significant differences in feelings about sickle cell for either carriers or noncarriers. The attitudes and feelings of noncarriers toward sickle cell trait and disease suggest that carrier identification is a stigma.     

Candidate Sequence Variants and Fetal Hemoglobin in Children with Sickle Cell Disease Treated with Hydroxyurea

Background

Fetal hemoglobin level is a heritable complex trait that strongly correlates swith the clinical severity of sickle cell disease. Only few genetic loci have been identified as robustly associated with fetal hemoglobin in patients with sickle cell disease, primarily adults. The sole approved pharmacologic therapy for this disease is hydroxyurea, with effects largely attributable to induction of fetal hemoglobin.

Methodology/Principal Findings

In a multi-site observational analysis of children with sickle cell disease, candidate single nucleotide polymorphisms associated with baseline fetal hemoglobin levels in adult sickle cell disease were examined in children at baseline and induced by hydroxyurea therapy. For baseline levels, single marker analysis demonstrated significant association with BCL11A and the beta and epsilon globin loci (HBB and HBE, respectively), with an additive attributable variance from these loci of 23%. Among a subset of children on hydroxyurea, baseline fetal hemoglobin levels explained 33% of the variance in induced levels. The variant in HBE accounted for an additional 13% of the variance in induced levels, while variants in the HBB and BCL11A loci did not contribute beyond baseline levels.

Conclusions/Significance

These findings clarify the overlap between baseline and hydroxyurea-induced fetal hemoglobin levels in pediatric disease. Studies assessing influences of specific sequence variants in these and other genetic loci in larger populations and in unusual hydroxyurea responders are needed to further understand the maintenance and therapeutic induction of fetal hemoglobin in pediatric sickle cell disease.     

Regulation of iron absorption in hemoglobinopathies

Beta-thalassemia and sickle cell anemia (SCD) represent the most common hemoglobinopathies caused, respectively, by deficient production or alteration of the beta chain of hemoglobin (Hb). Patients affected by the most severe form of thalassemia suffer from profound anemia that requires chronic blood transfusions and chelation therapies to prevent iron overload. However, patients affected by beta-thalassemia intermedia, a milder form of the disease that does not require chronic blood transfusions, eventually also show elevated body iron content due to increased gastrointestinal iron absorption. Even SCD patients might require blood transfusions and iron chelation to prevent deleterious and painful vaso-occlusive crises and complications due to iron overload. Although definitive cures are presently available, such as bone marrow transplantation (BMT), or are in development, such as correction of the disease through hematopoietic stem cell beta-globin gene transfer, they are potentially hazardous procedures or too experimental to provide consistently safe and predictive clinical outcomes. Therefore, studies that aim to better understand the pathophysiology of the hemoglobinopathies might provide further insight and new drugs to dramatically improve the understanding and current treatment of these diseases. This review will describe how recent discoveries on iron metabolism and erythropoiesis could lead to new therapeutic strategies and better clinical care of these diseases, thereby yielding a much better quality of life for the patients.     

Improving the justice-based argument for conducting human gene editing research to cure sickle cell disease

In a recent article, Marilyn Baffoe-Bonnie offers three arguments that conducting CRISPR/Cas9 biotechnology research to cure sickle cell disease (SCD) would help address historical and current injustices in SCD research and care. I will grant that the first argument is sound, but show that the second and third arguments suffer from roughly the same defect, which is that they really argue for something else rather than for conducting CRISPR/Cas9 research to cure SCD. I conclude that a better justice-based argument would use only Baffoe-Bonnie’s first argument.     

Focus: Rare Disease: Pulmonary Alveolar Microlithiasis – A Review

Pulmonary Alveolar Microlithiasis (PAM) is a rare genetic disorder causing widespread deposition of calcium-phosphate crystals in the alveolar space. A hallmark of the disease is the discrepancy between perceived symptoms upon diagnosis compared with the extensive, sandstorm-like appearance of the microliths on chest X-ray or HRCT. Caused by a defective sodium-dependent phosphate transport protein due to loss-of-function variants of the SLC34A2 gene, PAM is an autosomal recessive transmitted disorder, and as such has a high correlation to consanguinity. The most common variants of the SLC34A2 gene are single nucleotide biallelic changes, but larger deletions are described. Initial suspicion of PAM on radiological examination should be followed by genetic testing to verify the diagnosis and identify the disease-causing variant. When not available, the diagnosis can be made by means of invasive techniques, such as transbronchial forceps or cryobiopsy, or a surgical lung biopsy. In families with a history of PAM, genetic counseling should be offered, as well as preimplantation/prenatal testing if necessary. As of writing this review, no definitive treatment exists, and PAM may in some cases progress to severe pulmonary disease with respiratory failure and potential death. Patients with PAM should be offered preventative and symptomatic treatments such as vaccinations and oxygen therapy when needed. In some cases, lung transplantation may be required.