 |
 |
|
||
|
|
|
Sickle Cell Disease in Cuba:
15-17 February 2001
Kenneth R. Bridges, M.D., The United States has maintained an economic embargo of Cuba for 40 years. The world's geopolitical landscape has changed dramatically during this time. President Nixon opened the door to mainland China in 1972. We now have a brisk and growing trade relationship with the world's sole remaining major communist economic and military power. The collapse of the Soviet Union and the disintegration of the Warsaw Pact transformed the economic and strategic face of Europe. Poland, Hungary and the Czech Republic have joined NATO as democratic states. The Cuban economic embargo is a relic of a world that exists now only as a specter in nightmares of aging anachronistic Cold Warriors. An examination of the biomedical impact of the embargo is long overdue. Unlike political dogma, illness, injury and suffering know no national boundary. Sickle cell disease is a scourge both in the United States and Cuba. The embargo has injured people suffering from the disease in both nations. An Overview of Sickle Cell Disease Sickle cell disease results from a mutation in the b-globin gene that substitutes a valine residue for glutamic acid at position 6. This single alteration profoundly changes the biophysical properties of the hemoglobin molecule. Hemoglobin (inside red blood cells) picks up oxygen in the lungs and releases it to the peripheral tissues. Normal and sickle hemoglobin bind and release oxygen identically. The key difference between the two molecules is their behavior after oxygen is released. Deoxygenated normal hemoglobin retains its solitary existence in the red cell. In contrast, deoxygenated sickle hemoglobin molecules adhere to form long chains or polymers. The molecules in the polymers dissociate when the red cells return to the lungs and pick up oxygen. The sickle hemoglobin polymers form stiff rods that stretch and distort the red cells. These distorted cells can obstruct blood flow through the small vessels in the tissues. The restricted oxygen delivery to the tissues damages cells, injures organs and produces pain. Pain is the primary manifestation of sickle cell disease. The disorder varies tremendously in severity. Some people have only occasional pain episodes that require nothing stronger than over-the-counter pain relievers. Other people experience pain of such severity and frequency that only powerful, long-acting narcotic analgesics provide relief. Poor tissue oxygenation damages organs. Sickle cell disease can injure every organ in the body. Strokes, bone degeneration, chronic leg ulcers and kidney failure are a few of the many problems that can follow in the wake of sickle cell disease. Sickle cell disease begins to produce problems in the first 6 to 12 months of life. The condition often waxes and wanes in severity over the course of a person's life. Fixed organ injury often manifests in adults due to accumulating cell damage. World Distribution of Sickle Cell Disease The sickle gene mutation arose in tropical areas of the old world as a defense against malaria. People with one sickle gene and one normal gene (sickle cell trait) suffer none of the ill effects seen with sickle cell disease (two sickle genes). People with sickle cell trait are more resistant to malaria, on average, than are people who have two normal hemoglobin genes. People with two sickle cell genes were likely to die of sickle cell disease. People with two normal genes were likely to fall victim of malaria. People with sickle cell trait survived and passed their genes (both normal and sickle) on to the next generation. The incidence of sickle cell trait reaches levels of 30% to 40% in equitorial Africa and India. The sickle gene arose independently in these two regions of the world. Sickle cell disease in the Americas largely reflects the African slave trade. People captured in Africa were transported to the New World, with the Carribean islands serving as the initial triage point. These islands retained some people to work in the burgeoning sugarcane industry. Others were transported to continental slave markets, including those in North America. A person suffering from sickle cell disease lives in Cuba or the United States solely by luck-of-the-draw of long-forgotten ancestors. Advances in the Management of Sickle Cell Disease Sickle cell disease first appeared in the medical literature in 1910 in a report by Herrick.[1] In 1956, Ingram and colleagues at the MRC in Cambridge, UK defined the mutation in the hemoglobin molecule responsible for sickle cell disease.[2] Despite detailed knowledge of the mutation that produces sickle hemoglobin, no cure exists. Significant advances in the management of sickle cell disease have been made over the past 15 years, nonetheless. Early childhood mortality from overwhelming infection is a major risk for children with sickle cell disease. A study sponsored by the US National Institutes of Health showed unequivocally in 1986 that daily treatment with penicillin (called prophylaxis) dramatically lowers this risk.[3] The data from the study were so compelling that the study was curtailed early with the recommendation that all infants and young children be placed on penicillin prophylaxis. A second major advance was the introduction of hydroxurea to treat people with very severe sickle cell disease. A randomized, controlled multicenter study of hydroxurea in sickle cell anemia was terminated earlier than planned when the drug prevented severe problems including pain crises and a particularly deadly complication called "acute chest syndrome".[4] Patients respond variably to hydroxurea and some derive no benefit at all. Perhaps 25% of patients improve dramatically to hydroxurea, some almost miraculously so. Hydroxurea is now an essential part of the treatment armamentarium for sickle cell disease. A number of other interventions have improved the clinical outlook and quality of life for patients with sickle cell disease. A number of additional therapies are currently being investigated. As a result, the next five to ten years hold great promise for patients with sickle cell disease and their families. The Embargo and Sickle Cell Disease Cuba has a newborn screening program to identify all infants with sickle cell disease. A program of prophylactic penicillin currently exists. The US economic embargo has produced shortages of drugs at times, including antibiotics. Fortunately, these shortages have not disrupted the prophylactic penicillin program. This program, along with other health measures, has substantially reduced the incidence of childhood mortality from sickle cell disease among Cuban children. Patients with more clinically severe sickle cell disease are treated with hydroxurea. A cohort of Latin American countries recently instituted a multinational study of hydroxurea in children with sickle cell disease. Cuban investigators are leading this effort because of their extensive experience in conducting clinical trials. The National Institutes of Health in the US recently conducted a trial of hydroxurea in children (HUG Study) that demonstrated the short-term safety of this drug. This agency is poised to begin another study, this one examining hydroxurea in infants six months of age and older. Both penicillin and hydroxurea are generic drugs, making them easier for Cuban physicians to acquire. Penicillin is relatively inexpensive. Hydroxurea is not. The economic embargo strains the Cuban economy such that the availability of hydroxurea is suboptimal. For the first time, several drugs and interventions for patients with sickle cell disease are being investigated. These include clotrimazole, nitric oxide, Fluocorä and non-ablative bone marrow transplantation. Not all these approaches will prove to be clinically useful in the treatment of sickle cell disease. Cuban patients suffering from sickle cell disease may not have access to interventions and drugs that are efficacious due to the economic embargo. The economic embargo promotes unwarranted suffering and even death due to the restrictions in access to medical care. The economic embargo also injures people in the US afflicted with sickle cell disease. Approximately 70,000 Americans suffer from sickle cell disease. Most are not followed at comprehensive medical centers that perform clinical trials. Neither a registry nor a clinical trials network exists in the US. The National Institutes of Health funds ten Comprehensive Sickle Cell Centers. For a variety of reasons these centers have given clinical trials a low priority. Slow patient accrual has limited the pace of clinical trials in the US. Cuba has a well-established patient care network. Excellent facilities for patient trials exist both in Havana and Santiago de Cuba. Cuba has a registry of patients with sickle cell disease, which is a valuable tool in clinical investigation. Lifting the economic embargo, at least as it applies to medical care, would allow American and Cuban physicians to work together on the problems of sickle cell disease. Thirteen percent of Cubans of African descent have sickle cell trait. The incidence is highest in the eastern provinces where 6-11% of all Cubans have sickle cell trait. Patients with sickle cell disease in these regions alone would significantly expand the number of people enrolled in multinational trials. Enrollment of patients in joint research protocols would speed the process of identifying useful interventions for sickle cell disease. Lifting the embargo would greatly benefit a most vulnerable group of Americans with a debilitating and often deadly disease. Useful Websites:
References [1] Herrick, JB 1910. Peculiar elongated and sickle shaped red blood corpuscles in a case of sever anemia. Arch. Int. Med. 6: 517-527. [2] Ingram, V.M. (1956) A specific chemical difference between globins of normal and sickle-cell anoemia hemoglobins. Nature 178, 792-794. [3] Gaston MH, Verter JI, Woods G, et al. 1986. Prophylaxis with oral penicillin in children with sickle cell anemia. A randomized trial. N Engl J Med 314: 1593-1599. [4] Charache S, et al. 1995. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N. Engl. J. Med. 322:1317. |
