Sickle-cell disease

New Sickle Cell Test Can Transform Screening

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Sickle cell disease is common throughout much of sub-Saharan Africa. It affects up to 3% of births in some areas and is associated with very high mortality.

Many cases go undiagnosed in regions where there are few resources, because standard methods for diagnosing the disease require sophisticated equipment and reliable electricity.

A new test that costs less than $2, requires only a small drop of blood, and can be performed in about 10 minutes could dramatically change the dynamics of sickle cell diagnosis in Africa, say researchers who developed the product.

“HemoTypeSC is an accurate, inexpensive, and rapid tool that can enable sickle cell disease screening programs across Africa and India,” explained study author Erik Serrao, PhD, director of business and product development at Silver Lake Research Corporation in Azusa, California, the manufacturer of the test. “It is easy to use with no reported issues with protocol or reading results.”

Serrao was talking here at the American Society of Hematology (ASH) 2018.

In a study he presented, HemoTypeSC correctly identified 998 of 1000 phenotypes, for an overall accuracy of 99.8%, in a cohort of 1000 young children. It is also suitable for routine newborn screening, he commented, citing a smaller study that involved about 60 babies.

Sickle Cell Disease Undiagnosed in Africa

Sickle cell disease accounts for 20% of annual childhood deaths in Uganda, which was one of the first countries in Africa to be surveyed to determine the prevalence of this disease.

Prophylactic intervention programs, which include treatment with hydroxyurea, antibiotics, and immunizations, have been implemented in developed regions of the world and have been shown to drastically reduce deaths from sickle cell disease.

These measures could also be used in sub-Saharan Africa in a cost-effective manner, but the problem in these regions is that the disease is often undiagnosed. Whereas in the United States, for example, newborns are screened for sickle cell disease, such screening has not been widely implemented in Uganda or elsewhere in Africa. “Most people with sickle cell are identified only after they come to the hospital with life-threatening symptoms,” Serrao said.

The current gold-standard diagnostic methods are sophisticated, requiring laboratory equipment and highly trained personnel to run the tests. Up-front investment and maintenance are needed, a large volume of blood is required, the cost per test is unaffordable to most, and the blood specimens and results must be shipped away from and then returned to the point of care.

In contrast, HemoTypeSC is an inexpensive lateral-flow immunoassay that uses monoclonal antibodies to detect hemoglobins (Hbs) A, S, and C in only a 1.5-μL droplet of whole blood. In this study, Serrao and colleagues conducted a field validation of the test’s accuracy in a cohort of 1000 children living in southeastern Uganda. The goal was to provide evidence to support use of the test in widespread newborn screening programs in the region. The accuracy of HemoTypeSC was compared to that of Hb electrophoresis, which served as a reference.

The majority of children (84.5%) were aged 5 years or younger; 19.7% were aged 1 month to 1 year, and 24.9% were aged from 1 to 2 years.

In the initial analysis, HemoTypeSC correctly identified 998 of 1000 phenotypes, for an overall accuracy of 99.8%. These included 720 of 720 specimens (100%) that were correctly identified as HbAA, 182 of 182 specimens (100%) correctly identified as HbAS, and 96 of 98 (98%) correctly identified as HbSS.

The two discordant samples were both identified as HbSS by electrophoresis but as HbAS by HemoTypeSC.

When the two patients were retested, however, it was disclosed that they had already been diagnosed with sickle cell disease and had recently undergone transfusion. Therefore, the children had both normal and sickle hemoglobin in their blood at the time of testing, and so the diagnosis with use of HemoTypeSC was in fact correct.

When a secondary analysis was conducted, the two discordant specimens were included as true positive specimens for HbSS and true negative specimens for HbAS. It was thus determined that HemoTypeSC correctly identified 1000 of 1000 phenotypes across all patients screened, for overall sensitivity, specificity, positive predictive value, and negative predictive value of 100%.

Serrao noted that one limitation of the study was that the test was not used for newborn screening, but a recent study in this setting showed that the HemoTypeSC test was 100% accurate.

Sickle cell screening programs can be cost-effective in Africa, Serrao said. He predicted that it “will actually save significant amounts of money for governments.

“Early screening plus treatment and counseling can save millions of lives over the coming decades,” he added.

Commenting on the new test at an ASH press briefing in which the study was highlighted, moderator Mark Crowther, MD, from McMaster University, Hamilton, Ontario, Canada, commented that the test would also be useful in the developed world. As an example, he said it could be performed on the spot for a patient who was admitted into the emergency department at 2 AM. Currently, testing would take at least a day and could be conducted only when laboratories were open.

HemoTypeSC is approved for sale in Europe, and the company hopes that the test will be approved across Africa and in India within the coming year.

The study was funded by Silver Lake Research Corporation, manufacturer of the test. Serrao is an employee of Silver Lake Research and no other disclosures were reported.

Calcified Spleen and Gallstones

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A 35-year-old man presented to the gastroenterology clinic for treatment of chronic hepatitis C virus (HCV) infection. He had a type of sickle cell disease, hemoglobin Sβ thalassemia, with recurrent, episodic abdominal pain that had been present since childhood. A complete blood count showed microcytic anemia. The total bilirubin level was 8.5 mg per deciliter (145 μmol per liter; reference range, 0.3 to 1.2 mg per deciliter [5.1 to 20.5 μmol per liter]) and the indirect bilirubin level was 6.2 mg per deciliter (106 μmol per liter; reference range, 0.1 to 1.0 mg per deciliter [1.7 to 17.1 μmol per liter]). A peripheral-blood smear showed microcytic and hypochromic red cells, target cells, nucleated red cells, and sickle cells. An abdominal radiograph, which was obtained during a previous presentation for abdominal pain, showed a radiopaque gallstone (Panel A, arrowhead) and a calcified spleen (Panel A, arrow). A computed tomographic scan of the abdomen, obtained without the administration of contrast material, showed multiple gallstones and a calcified splenic pulp and capsule (Panel B). Pigment gallstones may occur as a result of hemolysis. Bilirubin stones, which are normally radiolucent, can be radiopaque when bilirubin binds with calcium. This patient completed treatment for chronic HCV infection, and he was vaccinated against encapsulated organisms. He has continued to do well on follow-up visits.

CRISPR Gene Editing Has Been Used to Cure Mice of Sickle Cell Disease

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IN BRIEF
  • The results are promising and could lead to a treatment for this disease that afflicts about 100,000 Americans.
  • While human tests are still a ways off, CRISPR could one day be used to effectively treat a number of ailments, from high cholesterol to HIV.

CORRECTING A MUTATION

Gene editing shows promise as a new treatment for sickle cell disease, according to a study published in the online journal Science Translational Medicine.

Experts from the University of California, Berkeley, UCSF Benioff Children’s Hospital Oakland Research Institute (CHORI), and the University of Utah School of Medicine have found success in correcting the blood cell mutation in tests of the blood of both mice and human sickle cell patients using CRISPR-Cas9, a genome “scissor” that can cut out and edit a DNA sequence.

After CRISPR was used to correct the mutated hematopoietic stem cells — precursor cells that mature into the hook-shaped hemoglobin characteristic of sickle cell disease, the corrected blood stem cells produced healthy hemoglobin. Following reintroduction into the mice, the genetically engineered stem cells remained in circulation for at least four months — a significant indication that any potential therapy would be lasting.

 The tests of blood from afflicted humans showed that the proportion of corrected stem cells was high enough to produce substantial benefit for the patients, so the researchers are hoping to one day be able to reinfuse the human patients with the edited strain of cells as it could alleviate symptoms of sickle cell disease, including anemia and pain caused by vessel blockages.

While the results are promising and could lead to a treatment for this disease that afflicts about 100,000 Americans, the researchers emphasize that future testing on mice and safety analyses would need to be conducted before human trials could begin.

A CRISPR’D FUTURE

“Sickle cell disease is just one of many blood disorders caused by a single mutation in the genome,” said Jacob Corn, senior author on the study. “It’s very possible that other researchers and clinicians could use this type of gene editing to explore ways to cure a large number of diseases.”

Indeed, developments in gene-editing  technology within such fields as medicine, agriculture, and biology are taking us further into what some are calling “the age of CRISPR.”

It’s already being researched as a treatment for many other ailments and disorders— β-thalassemia, severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, even HIV — so this one type of technology could end up being something of a panacea for what ails us, as long as what ails us is genetic.

CRISPR Gene Editing Has Repaired a Blood-Borne Disease

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IN BRIEF
  • Researchers from Stanford have used the CRISPR-Cas9 gene editing technique to fix the gene defects that cause sickle cell disease.
  • Approximately 70,000 – 100,000 individuals in the United States have sickle cell disease and 3 million have sickle cell trait.

GENE THERAPY

Gene editing remains a widely controversial topic due to the large potential for both benefit and “accidents.” Despite this, scientists are still hard at work developing gene edits that can solve a wide variety of diseases.

A new study may have found the key to solving a painful, and potentially fatal, genetic defect. Researchers from Stanford used the CRISPR-Cas9 gene editing technique to fix the gene defects that cause sickle cell disease.

Sickle cell disease is actually a group of related diseases that cause the formation of hemoglobin S, or sickle-shaped hemoglobin. That shape results in red blood cells becoming tangled in each other. Enough tangling, and blood vessels could be blocked, causing pain and even death.

To correct the issue, one has to repair the genes that code for abnormal hemoglobin. Using CRISPR, the researchers were able to do this. They took hematopoietic stem cells from patients that have the disease and edited them to repair their genome.

After, the repaired stem cells are concentrated and injected to healthy mice. Once there, the stem cells find their way into bone marrow and start producing more of their healthy variants. Sixteen weeks after injection, the researchers found healthy red blood cells thriving in the bone marrow.

ONE OF MANY

This is just one of the increasing number of diseases that have met their match thanks to CRISPR. The gene editing technique is composed of an enzyme that can splice DNA sequences and guide RNA that take them to the specific sequences that need splicing.

“There’s already a lot of active research going on using the CRISPR technology to fix diseases like Duchenne muscular dystrophy or cystic fibrosis or Huntington’s disease,” says Jennifer Doudna, a pioneer of the technology, to CNBC.

But even if ways to cure using CRISPR are abound, researchers are treading lightly on implementation, since editing genes is risky and can have disastrous consequences. Ultimately, we will need to have a serious debate on how to go about the changing the very blueprint of our bodies.

Sickle Cell Treatment Guideline Released

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Hydroxyurea and long-term, periodic blood transfusions should be used more often to treat patients with sickle cell disease (SCD), according to an expert panel.

In an article published in the September 10 issue of JAMA, the panel contends that both therapies are currently underused.

Cochairs Barbara P. Yawn, MD, MSPH, from the Olmsted Medical Center, Department of Research and Education, Rochester, Minnesota, and George R. Buchanan, MD, from the University of Texas Southwestern Medical Center in Dallas, led the panel in drafting a new guideline at the request of the National Heart, Lung, and Blood Institute.

The 12-member panel included experts in adult and pediatric hematology, family medicine, internal medicine, psychiatry, transfusion medicine, emergency nursing, and obstetrics and gynecology. They developed the guideline to support and expand the number of healthcare practitioners treating patients with SCD.

The relatively rare genetic disorder affects about 100,000 people in the United States, most of whom are black. People with SCD carry 2 copies of a mutated gene that makes sickle-shaped instead of disk-shaped hemoglobin. The sickle-shaped hemoglobin can slow blood flow and damage organs and can often cause severe body pain.

Hydroxyurea

The panel members write that hydroxyurea, a ribonucleotide reductase inhibitor, has been used since the 1970s to treat patients with myeloproliferative cancers, and since the 1980s, it has been used to treat patients with SCD. The drug is used to increase fetal hemoglobin levels. Short-term hydroxyurea therapy can result in a substantial reduction in the frequency of painful episodes and acute chest syndrome. Long-term therapy can result in reduced mortality.

“Hydroxyurea treatment of children beginning as early as 9 months of age yields improvements in laboratory parameters such as total hemoglobin and fetal hemoglobin levels and decreased numbers of sickle cell–related acute clinical events such as pain and [acute chest syndrome],” the panel writes. “The panel recommends that hydroxyurea therapy be offered in children beginning at 9 months of age, including those who are asymptomatic.”

Blood Transfusions

The benefits of long-term transfusions vary, they write, but are generally associated with reduced risk for stroke in children. Possible complications include hyperviscosity and iron overload.

“Decisions to administer blood transfusions in persons with SCD must be based on risk-benefit assessments and are often made in consultation with a hematologist, transfusion medicine specialist, or SCD expert,” the panel writes.

Overall

The guideline includes recommendations for health maintenance, including a strong recommendation for the administration of daily oral prophylactic penicillin up to the age of 5 years. The guideline also addresses acute and chronic complications including acute chest syndrome and pain. “Sickle cell pain often becomes chronic, resulting in poorer quality of life. Early and aggressive treatment of acute sickle cell pain may reduce the development of chronic pain,” the panel writes.

The panel’s literature search turned up 12,532 references for initial review. The final analysis included 1575 original studies, and the panel also included evidence-based clinical practice guidelines as well as the expertise of panel members.

Still, overall, the literature lacks comprehensive evidence, the panel writes.

They conclude, “The process of developing guidelines for the management of children, adolescents, and adults with SCD has been challenging because high-quality evidence is limited in virtually every area related to SCD management…. The expert panel realizes that this summary report and the guidelines leave many uncertainties for health professionals caring for individuals with SCD and highlight the importance of collaboration between primary care health professionals and SCD experts. However, we hope that this summary report and the SCD guideline begins to facilitate improved and more accessible care for all affected individuals, and that the discrepancies in the existing data will trigger new research programs and processes to facilitate future guidelines.”

Discovery of new gene regulator could precisely target sickle cell disease.

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A research team from Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and other institutions has discovered a new genetic target for potential therapy of sickle cell disease (SCD). The target, called an enhancer, controls a molecular switch in red blood cells called BCL11A that, in turn, regulates hemoglobin production.

The researchers — led by Daniel Bauer, MD, PhD, and Stuart Orkin, MD, of Dana-Farber/Boston Children’s — reported their findings today in Science.

Prior work by Orkin and others has shown that when flipped off, BCL11A causes red blood cells to produce fetal hemoglobin that, in SCD patients, is unaffected by the sickle cell mutation and counteracts the deleterious effects of sickle hemoglobin. BCL11A is thus an attractive target for treating SCD.

The disease affects roughly 90,000 to 100,000 people in the United States and millions worldwide.

However, BCL11A plays important roles in other cell types, including the immune system’s antibody-producing B cells, which raises concerns that targeting it directly in sickle cell patients could have unwanted consequences.

The discovery of this enhancer — which regulates BCL11A only in red blood cells — opens the door to targeting BCL11A in a more precise manner. Approaches that disable the enhancer would have the same end result of turning on fetal hemoglobin in red blood cells due to loss of BCL11A, but without off-target effects in other cell types.

The findings were spurred by the observation that some patients with SCD spontaneously produce higher levels of fetal hemoglobin and enjoy an improved prognosis. The researchers found that these individuals possess naturally occurring beneficial mutations that function to weaken the enhancer, turning BCL11A’s activity down and allowing red blood cells to manufacture some fetal hemoglobin.

“This finding gives us a very specific target for sickle cell disease therapies,” said Orkin, a leader of Dana-Farber/Boston Children’s who serves as chairman of pediatric oncology at Dana-Farber Cancer Institute and associate chief of hematology/oncology at Boston Children’s Hospital. “Coupled with recent advances in technologies for gene engineering in intact cells, it could lead to powerful ways of manipulating hemoglobin production and new treatment options for hemoglobin diseases.”

“This is a very exciting study,” said Feng Zhang, PhD, a molecular biologist and specialist in genome engineering at the McGovern Institute for Brain Research at the Massachusetts Institute of Technology (MIT) and the Broad Institute of MIT and Harvard, who was not involved in the study. “The findings suggest a potential new approach to treating sickle cell disease and related diseases, one that relies on nucleases to remove this regulatory region, rather than adding an exogenous gene as in classic gene therapy.”

Source:DFCI

 

 

 

Global Burden of Sickle Cell Anaemia in Children under Five, 2010–2050: Modelling Based on Demographics, Excess Mortality, and Interventions.

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Abstract

Background

The global burden of sickle cell anaemia (SCA) is set to rise as a consequence of improved survival in high-prevalence low- and middle-income countries and population migration to higher-income countries. The host of quantitative evidence documenting these changes has not been assembled at the global level. The purpose of this study is to estimate trends in the future number of newborns with SCA and the number of lives that could be saved in under-five children with SCA by the implementation of different levels of health interventions.

Methods and Findings

First, we calculated projected numbers of newborns with SCA for each 5-y interval between 2010 and 2050 by combining estimates of national SCA frequencies with projected demographic data. We then accounted for under-five mortality (U5m) projections and tested different levels of excess mortality for children with SCA, reflecting the benefits of implementing specific health interventions for under-five patients in 2015, to assess the number of lives that could be saved with appropriate health care services. The estimated number of newborns with SCA globally will increase from 305,800 (confidence interval [CI]: 238,400–398,800) in 2010 to 404,200 (CI: 242,500–657,600) in 2050. It is likely that Nigeria (2010: 91,000 newborns with SCA [CI: 77,900–106,100]; 2050: 140,800 [CI: 95,500–200,600]) and the Democratic Republic of the Congo (2010: 39,700 [CI: 32,600–48,800]; 2050: 44,700 [CI: 27,100–70,500]) will remain the countries most in need of policies for the prevention and management of SCA. We predict a decrease in the annual number of newborns with SCA in India (2010: 44,400 [CI: 33,700–59,100]; 2050: 33,900 [CI: 15,900–64,700]). The implementation of basic health interventions (e.g., prenatal diagnosis, penicillin prophylaxis, and vaccination) for SCA in 2015, leading to significant reductions in excess mortality among under-five children with SCA, could, by 2050, prolong the lives of 5,302,900 [CI: 3,174,800–6,699,100] newborns with SCA. Similarly, large-scale universal screening could save the lives of up to 9,806,000 (CI: 6,745,800–14,232,700) newborns with SCA globally, 85% (CI: 81%–88%) of whom will be born in sub-Saharan Africa. The study findings are limited by the uncertainty in the estimates and the assumptions around mortality reductions associated with interventions.

Conclusions

Our quantitative approach confirms that the global burden of SCA is increasing, and highlights the need to develop specific national policies for appropriate public health planning, particularly in low- and middle-income countries. Further empirical collaborative epidemiological studies are vital to assess current and future health care needs, especially in Nigeria, the Democratic Republic of the Congo, and India.

Multiple warnings regarding the effect of epidemiological and demographic transitions in low-income countries and their consequences for SCA burden have been published . By quantifying this increase from 2010 to 2050 using evidence-based data and identifying potential changes in the distribution of areas the most affected, we hope (i) to highlight further the need for greater awareness of SCA, appropriate public health policies, and funding; (ii) to guide the implementation of appropriate policies; and (iii) to provide a framework that could be applied to other birth defects. In most countries, the burden of SCA has so far not been recognised. Its long-term toll is nevertheless significant. These results highlight once more the need for further epidemiological collaborative studies, particularly in Nigeria, the DRC, and India, to define more accurately the current and future health burden of SCA.

Source: PLOS

Sickle Cell Anaemia in a Changing World.

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Populations and their health are dynamic. Societal, environmental, and economic changes lead to changes in rates of birth, death, and disease, often described as transitions in mortality, demography, and epidemiology. The notion of epidemiologic transition provides an insight into the relationship between levels of overall mortality and the distribution of its causes [1]–[3], in which the greatest changes arise from the survival of children and young women. Recent falls in global child mortality are good news [4], but will lead to increases in the relative burdens of morbidity and disability in children who would previously have died, and of congenital malformations and inherited disorders. The work of Frédéric Piel and colleagues on sickle cell anaemia (SCA), published in this week’s PLOS Medicine [5], speaks strongly to this point: SCA is an inherited disease whose global importance will increase in terms of absolute numbers and relative population burden. SCA occurs when individuals are homozygous for sickle haemoglobin (HbS) in place of normal adult haemoglobin, and is the most common form of sickle cell disorder (SCD) [6]. Piel and colleagues have collated HbS allele frequency surveys and used them in models to generate a global distribution map and estimate the numbers of infants born heterozygotic and homozygotic for HbS. Using population and mortality projections, they predict an increase in the numbers of newborns with SCA to over 400,000 in 2050. They also estimate the potential mortality effects of four care-provision scenarios, with a best-case scenario that between 7.5 and 15.5 million newborn lives could be saved, most of them in Africa.

Modelled estimates are a growth area in global health. Whilst useful at supra-national and national levels, their emergence highlights the lack of reliable data on populations, disease, and mortality across most of the world: precisely the sort of information that policy makers and health planners need. The utility of estimates for planning screening programmes, infrastructural and human resource requirements, and clinical care protocols at sub-national levels is likely to be limited where the generalisability of assumptions is challenged by diversity at the local level. Even at a global level, estimates can cause confusion. Research teams using different models may, for example, come to different conclusions [7]. Piel et al. have combined available data, statistical methods, and assumptions to predict current burdens and future trends. Their uncertainties are described clearly, and a preoccupation with methodological critiques can easily distract us from the public health concerns that estimates raise.

The epidemiologic transition has been reframed as a health transition that involves sociocultural, behavioural, and health service factors [8], and policy and health services must respond to changing disease burdens. Unfortunately, the notion of transitions is general. Parallel transitions are happening in different groups within one nation, the best example being differences between socioeconomic groups. Rates of transition vary with local environment, and counter-transition is even possible [9]. Policy makers must set priorities in an environment of multiple burdens, unfinished agendas, competing discourses, and the voices of interest groups[10], a process that has been described as a chaos of purposes and accidents [11]. In an environment of Realpolitik, the generation of estimates of burden is important for advocacy. Characteristically, investigators working in an important public health field that has not received global attention lay down the strategic epidemiology [7],[12], as Piel and colleagues are doing, demonstrating that lack of progress will hinder efforts to attain targets such as those of the Millennium Development Goals.

Quantifying the problem is important, but not sufficient. In a consideration of issue attention for newborn health, Jeremy Shiffman considered four elements: the power of the actors involved, new ideas that can be brought to the table, the characteristics of the issue in terms of attractiveness and tractability, and political context [13]. The kind of strategic epidemiology that the SCA figures exemplify needs to be linked with granular understanding of local epidemiology and service provision [7]. SCA poses a particular challenge in terms of tractability. Haematopoietic stem cell transplantation, an emerging cure, is currently too costly a technology for the countries on which the burden predominantly falls, as is hydroxyurea therapy for children at high risk of illness. Survival, health, and well-being can all be improved substantially, but rely on health care systems with a certain level of functionality. Piel and colleagues suggest that the priority is to identify births of infants with SCA, but that such births could be avoided through genetic counselling and prenatal diagnosis. Termination of pregnancy is one of several options, which include preconception genetic screening and strategic reproductive choices, education for carrier parents, and holistic management from infancy. Quite apart from the logistic and financial challenges, these approaches raise substantial ethical questions summarised in recent work from Ghana [14].

Several interventions would be enormously helpful. Routine newborn screening remains costly—but is likely to become less so—and may miss infants born at home. Penicillin prophylaxis and pneumococcal immunisation are possible in most health care systems. The most beneficial approach involves comprehensive care [15]: family education, routine immunisation, malaria prevention, nutrition and hydration, prophylactic antibiotics, folic acid supplements, transfusion when required, support groups for children and their families, protocols for the management of acute events by health workers and—most importantly—regular follow-up. Human resources for health need to be well trained, and the medicines required need to be affordable and available, including the pain relief required by many people with SCD [16].

Steps towards a systematic approach are being taken [17]. A 2006 World Health Assembly resolution on SCA recommends increased awareness in the international community and emphasises collaboration between countries, including technical support, development of practice models, and coordination [18]. The World Health Organization has published a strategy for the African Region, with targets that include development and implementation of national control programmes in member states with high SCD prevalence, adoption of comprehensive health care management, and establishment of surveillance systems [19]. The estimates from Piel and colleagues underscore the need for both collaborative responses and better data for planning and monitoring.

Source: PLOS