Article highlights advances in diagnosis and treatment in recent decades, but warns of the need to expand neonatal screening programs
The possibility of new treatments for sickle cell diseases – caused by genetic changes in hemoglobin, a protein that transports oxygen and gives the red color to blood – has never been greater. Still, constant investment in health policies, such as newborn screening programs, is necessary, especially in sub-Saharan Africa.
The conclusions are from a broad review study published in Nature Reviews Disease Primers and signed by experts from the United States, United Kingdom, Ghana and Brazil.
All disorders caused by changes in hemoglobin are called hemoglobinopathies. Among these disorders are sickle cell diseases, the most serious of which is sickle cell anemia. Other hemoglobinopathies with considerable medical importance are thalassemias, forms of hereditary chronic anemia with different degrees of severity.
“There have been great advances in recent years in diagnosis and treatment. And there will be others. However, in poor countries, the number of patients tends to grow. It is necessary to look above all at Africa and Asia, but also at Brazil, because here the resources for the public medical care system are not only not increasing, but also seem to be being reduced. All the progress we have made is at risk today,” he said. Fernando Ferreira Costa, researcher at the Hematology and Hemotherapy Center (Hemocentro) at Unicamp and the only Brazilian among the authors.
Costa refers to the existence of blood centers and the support of the Unified Health System (SUS) for the National Neonatal Screening Program (PNTN), which among other actions offers the heel prick test, capable of detecting hemoglobinopathies and six other diseases early. Furthermore, Costa highlights the importance of SUS in providing free of charge the main medicine used to treat sickle cell anemia, hydroxyurea, and in carrying out blood transfusions necessary for many patients.
“Brazil has made notable progress and managed to form centers of excellence. There has been great development in recent decades in diagnosis, treatment and research”, said Costa, responsible for the Thematic Project “Red blood cell diseases: pathophysiology and new therapeutic approaches”, financed by FAPESP.
The article highlights the decision of the FDA, the body that regulates medicines and foods in the United States, to consider the development of new treatments for sickle cell diseases a priority, which facilitated investments by the pharmaceutical industry. Because of this, many drugs that target one or more mechanisms that contribute to the development of some of these diseases are in the human testing phase.
“The prospects for new treatments in sickle cell disease have never been more favorable,” the authors wrote.
Hereditary mutation
Sickle cell anemia is the most serious and prevalent among sickle cell diseases. In people with the disease, red blood cells (RBCs) take on the shape of a crescent or sickle after oxygen is released – hence the name sickle cell. These deformed cells become rigid and prone to polymerization, that is, forming groups that adhere to the inner cell layer of blood vessels (endothelium), which makes blood circulation difficult.
The condition can lead to occlusion of blood vessels. In addition to causing unpredictable episodes of pain, it greatly increases the chances of myocardial infarction, stroke, chronic kidney disease and pulmonary embolism, among other complications. “It is a chronic disease, which requires monitoring for the rest of your life,” Costa told FAPESP Agency.
Hydroxyurea is the medicine used today to prevent this condition. It increases the production of a protein called fetal hemoglobin, which makes it difficult for defective hemoglobin to polymerize. This reduces the risk of vaso-occlusion.
In recent years, researchers at Hemocentro have discovered other uses of the drug, such as preventing the complications of hemolysis, destruction of red blood cells and subsequent release of the hemoglobin within them into the circulation, which can lead to a chronic inflammatory state (Read more at: http://agencia.fapesp.br/21900/).
The only treatment to cure sickle cell anemia, however, is a bone marrow transplant. In Brazil, the procedure became covered by the SUS only in 2015. Most of the transplants in patients with sickle cell anemia that occurred in Brazil, always between compatible siblings, were performed by the Cell Therapy Center (CTC). Based at the Faculty of Medicine of Ribeirão Preto of the University of São Paulo (FMRP-USP), the CTC is a Center for Research, Innovation and Dissemination (CEPID) financed by FAPESP (Read more at: agency.fapesp.br/21453).
The article highlights that gene therapy has been considered a promising treatment since the mid-1990s. Only recently, however, did the procedure using lentiviral vectors that insert modified genes capable of reducing in red blood cells the characteristic change of sickle cell diseases. Initial results are promising.
Other gene editing approaches such as the Crispr-Cas9 system (from English, clustered regularly interspaced short palindromic repeats associated gene 9), which allows the precise replacement of a specific region of DNA, are also considered promising for the treatment of sickle cell diseases. Currently, it is only used in mice and human cells in culture.
“Many ethical issues need to be resolved before these techniques can be used in humans: long-term follow-up will be necessary to confirm their safety and sustainability. Furthermore, the accessibility of gene therapy in high-prevalence, low-income areas needs to be assessed,” the authors wrote.
As the authors highlight in the article, the burden of sickle cell diseases is much greater in poor countries. In middle- and high-income nations, there has been a substantial change in the course of these illnesses since the 1970s, in both adults and children. In the United States and United Kingdom, survival rates for children with sickle cell anemia are similar to those of healthy children. In Africa, however, the chance of people with sickle cell anemia dying before the age of 5 is 50% to 90%. In rich countries, it is possible to live well with this and other sickle cell diseases even after the age of 60.
Unequal distribution
The Ministry of Health estimates that there are currently between 30 and 50 people with sickle cell disease in Brazil. Worldwide, estimates are that between 300 and 400 children are born each year with one of the genetic mutations, 230 in sub-Saharan Africa alone.
The fact that Brazil has reliable epidemiological data and can act even before sickle cell diseases manifest themselves is partly due to the PNTN. The heel prick test was officially implemented by the federal government in 2001, although it had already been applied in some states previously.
Still, there is inequality in coverage. In 2016, while 100% of hospitals in Minas Gerais carried out the test, in Amapá this occurred in just over half of them, compared Costa. Tracking made it possible to find out survival rates and the main causes of death among people with sickle cell disease. Furthermore, it allows preventive prophylaxis for patients with sickle cell anemia, with vaccination and administration of antibiotics (penicillin) up to 5 years of age, in order to avoid infections, the biggest cause of mortality.
Universal coverage is important because the distribution of sickle cell diseases is also unequal. In the North and Northeast, sickle cell anemia is more common than in other regions of the country. This is due to the fact that the mutation that causes the disease is more prevalent in populations with African ancestry, common in these regions.
On the other hand, thalassemia, especially its more severe form, is more common in populations of Mediterranean origin. Therefore, in Brazil, the prevalence is higher in the South and Southeast regions, where Italian descendants are concentrated.
The study points out that, in areas without neonatal screening programs like Brazil, the initial diagnosis occurs approximately at 21 months of life. For many patients, the first manifestation of sickle cell anemia is a fatal infection or an acute splenic sequestration crisis – a decrease in the concentration of hemoglobin in the blood that can generate hemorrhagic shock. Early diagnosis accompanied by prophylaxis reduces mortality in the first five years of life from 25% to 3%.
Still, accurate estimates of sickle cell anemia cases are difficult to obtain, even in countries with a good health system and universal screening programs like Brazil.
“However, new epidemiological data is constantly being generated. Sophisticated analytical methods, such as geospatial models, could make it possible to generate reasonable estimates of the number of people with sickle cell anemia around the world”, said Frédéric B. Piel, researcher at Imperial College, London, and one of the authors of the article.
“These projects depend on large collaborative networks and require data collection and processing, as well as the ability to analyze them, which requires substantial funding,” Piel told FAPESP Agency.
The article sickle cell disease (doi:10.1038/nrdp.2018.10), by Gregory J. Kato, Frédéric B. Piel, Clarice D. Reid, Marilyn H. Gaston, Kwaku Ohene-Frempong, Lakshmanan Krishnamurti, Wally R. Smith, Julie A. Panepinto, David J. Weatherall, Fernando F. Costa and Elliott P. Vichinsky, can be read at: www.nature.com/articles/nrdp201810.