By Allan Platt PA-C and James Eckman, MD
A thankful teenager, Keon Penn of Atlanta celebrates his 14th birthday after being declared “cured” from sickle cell disease. Two years ago Keon underwent the world’s first unrelated stem-cell transplant at Egelston Children’s Hospital in Atlanta on December 11, 1998. Two years post transplant, Keone is free of sickle cell, but has chronic graft-versus-host disease, treated with steroids. He has avascular necrosis of the hips secondary to the chronic steroid use. He does not need the monthly blood transfusions—the only effective preventive measure against a second stroke, after his first at age five.
Fifteen other Atlanta children have had successful human leukocyte antigen (HLA) matched sibling donor transplants, mainly for prior strokes. All are doing well without evidence of sickle cell. (Bone Marrow- Stem Cell Information)
An estimated 70,000 or more Americans have sickle cell disease, the most common genetic disease in the US. It’s most common in people who are descendents of residents of malaria-endemic areas of the world. Sickle hemoglobin is found in Africans, Arabs, Turks,Greeks, Italians, Iranians and Asiatic Indians Inheriting one sickle gene or sickle cell trait provides some protection from the red cell parasite malaria. The carrier state is usually asymptomatic, but hematuria and sickle complications can occur under severe dehydration, temperature or pressure change or other bodily stress. 2
Management of acute events includes a thorough history, physical examination, laboratory workup and radiologic exam if necessary. Precipitating causes such as infection, dehydration, hypoxia and temperature exposure must be identified and corrected. 3
Preventive therapy includes annual health checks, daily supplemental folic acid, good hydration, rapid treatment of infections and avoidance of temperature extremes. Children should be placed on prophylactic penicillin from birth until age six.. In February 2000, a 7-valent pneumococcal polysaccharide-protein conjugate vaccine (Prevnar, marketed by Wyeth Lederle Vaccines) was licensed for use among infants and young children. CDC’s Advisory Committee on Immunization Practices (ACIP) recommends that the vaccine be used for all children aged 2-23 months and for children aged 24-59 months with sickle cell disease. 4-6 (Preventing pneumococcal disease among infants and young children.
MMWR Morb Mortal Wkly Rep. 2000 Oct 6;49(RR-9):1-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11055835&dopt=Abstract
TREATMENT AND PREVENTION
New treatments and preventive therapies include hydroxyurea for pain prevention, new guidelines for preoperative transfusion, bone marrow transplantation for cure, new insights into the etiology of acute chest syndrome (ACS), transcranial Doppler screening to prevent childhood strokes and preimplantation genetic diagnosis to prevent the disease.
The chemotherapeutic agent hydroxyurea (link to Bristol-Myers Squibb) stimulates the production of protective fetal hemoglobin within the red cells. Fetal hemoglobin is the predominant hemoglobin in utero that tightly binds oxygen coming across the placenta. Production of this hemoglobin usually ceases after birth. Patients begin with low daily doses of 500 mg and are monitored with frequent complete blood counts for evidence of bone marrow suppression. Adult patients on hydroxyurea have 50 percent fewer pain episodes, 50 percent fewer blood transfusions and 50 percent less need for hospitalization.7 Studies in children have shown efficacy and short term safety, but the long term effects are unknown.
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. Effect of Hydroxyurea on Mortality and Morbidity in Adult Sickle Cell Anemia JAMA. 2003;289:1645-1651. http://jama.ama-assn.org/cgi/content/abstract/289/13/1645
Researchers conducted a multicenter study to compare the rates of perioperative complications among patients receiving an aggressive transfusion with those receiving a conservative regimen. Patients undergoing a total of 604 operations were randomly assigned to receive either an aggressive transfusion regimen designed to decrease the hemoglobin S (sickle) level to less than 30 percent, or a conservative regimen designed to increase the hemoglobin level to 10 g/dL.8
The researchers determined that 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.
At the Bone Marrow Transplantation for Sickle Cell Anemia National Collaborative Study Meeting in December 1998, the following results were presented: At 47 participating sickle cell centers, with 9,198 total patients, 627 (7 percent) meet the criteria for bone marrow transplantation. A total of 188 patients were HLA-typed, and only 82 had HLA-matched siblings identified as donors. Forty-nine of these patients have been transplanted, two died of graft vs. host disease, and four patients have had return of sickle cell disease. The probability of event-free survival is 84 percent.9,10
The problem with bone marrow transplantation is the lack of HLA-matched related donors. Using stem cells from cord blood samples from unrelated donors have the best promise of meeting this need. Keon Penn was the first patient to undergo this procedure.
Acute chest syndrome is an important cause of morbidity and mortality in sickle cell disease. The etiology of ACS includes viruses, atypical bacteria, bone marrow necrosis with fat embolism and bacteria.
The Cooperative Study of Sickle Cell Disease prospectively followed 3,751 patients enrolled from birth to the age of 66 for ACS. There were 1,722 ACS episodes in 939 patients. Young children (age 2 to 4 years) presented with fever, cough and a negative physical exam and rarely had pain. Adults were often afebrile and complained of shortness of breath, chills and severe pain. Severe hypoxia occurred in 18 percent of adults and could not be predicted by examination or laboratory findings. The death rate was four times higher in adults than in children.11
Bronchoscopy may be diagnostic and therapeutic in cases of ACS. Patients should be treated with transfusions and antibiotics that cover atypical bacteria and pneumococci. Postoperative ACS may be prevented by incentive spirometry.
Adams and colleagues described the use of transcranial Doppler (TCD) 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. A total of 130 patients were identified as positive on TCD; 63 were randomly assigned to receive transfusions and 67 to receive standard care. There were 10 cerebral infarctions and one intracerebral hematoma in the standard-care group, compared with one infarction in the transfusion group—a 92 percent difference in the risk of stroke. This result led to the early termination of the trial.12
The Journal of the American Medical Association (http://www.ama-assn.org/special/womh/library/readroom/vol_281c/joc81498.htm) featured a report of the first unaffected pregnancy resulting from preimplantation genetic diagnosis. A couple in Detroit, each with sickle cell trait, desired a child without sickle cell disease and wanted to avoid the decision to abort an affected fetus. In vitro fertilization was accomplished, and the embryo was tested with DNA analysis. The embryo without sickle cell disease was implanted successfully. There is a 25 percent probability of a couple each with sickle cell trait having a child with sickle cell disease.13 CNN Report at http://www.cnn.com/HEALTH/9905/11/sickle.cell.success/
The Cincinnati Enquirer Story: http://enquirer.com/editions/1999/09/15/loc_sickle_cell_testing.html
The Georgia Comprehensive Sickle Cell Center at Grady Health System in Atlanta is a model of sickle cell disease management. The clinic is staffed with four physician assistants, one nurse practitioner, four hematologists, a clinical nurse specialist in psychiatry, two social workers, six nurses, a newborn screening coordinator, clinic assistants, clerical and computer personnel. This is the only 24-hour acute care center with the same staff providing the acute care and the routine health maintenance care. This model has reduce the admission rate per active adult and decreased the need for emergency care. Over 80% of the patients treated for acute pain are well enough to go home after eight hours of aggressive pain management.
ON THE HORIZON
Current research is ongoing to find new treatments for treating acute pain episodes using nitric oxide (NO), CPC-111 and RheothRx. Preventive therapy with the antifungal clotrimazole and N-3 fatty acids (fish oil) also are being studied. Studies to prevent renal damage from sickle cells with the use of angiotensin-converting enzyme (ACE) inhibitors and to induce the ultimate cure with gene therapy are also under way.
Inhaled NO, even in small amounts, causes smooth muscle in the blood vessel wall to relax and the entire vessel to dilate. In one laboratory study, researchers measured the effects of four different concentrations of NO on purified, oxygen-free samples of sickle hemoglobin.14 Even at the lowest concentrations, NO slowed cell sickling and even promoted the unsickling of sickled cells. The higher the concentration of NO, the stronger NO’s favorable effect. NO causes sickle hemoglobin molecules to bind oxygen with greater affinity, which should reduce formation of the sickle cells. The result was seen both in laboratory studies and in several volunteer patients with sickle cell disease who breathed low concentrations of NO. Current studies are testing the effect of inhaled NO on the length and severity of acute pain episodes.15
CPC-111, from Cypros Pharmaceutical Corp., Carlsbad, Calif., (Cypros Pharmaceutical Corporation) reduces the red blood cell sickling that causes the blood starvation-induced tissue damage in sickle cell crisis. Using two different measures of pain, the drug-treated patients had significantly lower pain scores compared to placebo-treated patients. Three different doses of CPC-111 were evaluated, and the drug-treated groups had lower pain scores, with statistical significance attained in two of the three dose groups. Phase III trials are under way in patients with sickle pain episodes.
RheothRx (FlocorÔ ) (link to Cytrx -FLOCORTM); is an intravascular agent with pharmacologic properties that can be characterized as rheologic, cytoprotective and antiadhesive/antithrombotic. The active agent in Flocor is a highly purified form of poloxamer 188, which is a synthetic block copolymer composed of polyoxyethylene and polyoxypropylene. By essentially creating a coating on the damaged cells, Flocor is designed to allow blood cells to “slip over” one another, improving blood flow and restoring oxygen delivery, according to the manufacturer, Glaxo Wellcome, Research Triangle Park, N.C. Flocor is now in a phase III trial for sickle cell patients suffering from vascular occlusive crisis.
The Comprehensive Sickle Cell Center in Atlanta studied N3 fatty acids (fish oil) and the role of coagulation by administering N3 fatty acids in a double-blind trail to 10 sickle cell patients. Ten control patients received olive oil as a placebo. The 10 who were treated for one year with the N3 fatty acids had half as many pain events as did the 10 patients who received placebo. A multicenter trial is in progress to determine the efficacy of this treatment to prevent pain episodes and sickle complications.
Clotrimazole, an oral antifungal that blocks the loss of potassium from the red blood cell, prevents the increase in sickle cell hemoglobin concentration and reduces sickling. The mechanism by which clotrimazole keeps the red cells hydrated includes inhibition of potassium-chloride co-transport by increasing erythrocyte Mg2+ content and inhibition of the Ca2+ activated K-channel.17
Several studies have demonstrated that ACE inhibitors may prevent renal disease by reducing proteinuria. Many sickle cell patients have a progressive nephropathy detected by microalbuminuria. Current studies are underway to determine if ACE inhibitors, given over time, may slow the progression of the renal damage.18-20
Researchers at Duke University Medical Center have shown that they can use a new type of gene therapy to correct the sickle cell hemoglobin defect in human blood cells. The results of their laboratory studies, published in the June 5, 1998, issue of the journal Science, show that successful gene therapy may lie not in correcting faulty DNA, the storehouse of genetic information, but in correcting the RNA, which translates that genetic information to the protein synthesis machinery of a cell.21 The researchers plan to begin testing the therapy in sickle cell patients within a few years.
These new therapies are improving the lives of sickle cell patients with new hope on the horizon. Several patients have crossed over to normal lives and have been declared cured by bone marrow transplantation. The life expectancy and quality of life is improving yearly.
To keep informed about the current treatments and the progress on the research studies, visit The Sickle Cell Information Center at http://www.SCInfo.org/news.htm. This site is an information resource with clinical guidelines, patient information, tutorials, links, frequently asked questions, resources, clinic locations and research news.
Vichinsky E. New therapies in sickle cell disease. Lancet 2002 Aug 24;360(9333):629-31 This is an excellent review of the research in sickle cell disease. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12241949&dopt=Abstract
Available full text at http://www.thelancet.com (free registration)
Myriad of New Therapies Available for Sickle Cell Disease at http://www.ama-assn.org/ama/pub/article/4197-6324.html
Clinical Research trials underway at http://clinicaltrials.gov/ct/gui/c/b/action/FindCondition?ui=D000755&recruiting=true
See webcast of the Dec 2003 American Society of Hematology ASH meetings at http://www.hematology.org/
Sickle Cell research Update – An excellent review of therapy options in sickle cell disease from American Society of Hematology ASH – full text at http://www.asheducationbook.org/cgi/content/full/2003/1/14
American Society of Hematology Sickle Cell Update – an excellent review on the research progress from 2002 online at http://www.asheducationbook.org/cgi/content/full/2002/1/10?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&titleabstract=sickle&searchid=1047417786610_660&stored_search=&FIRSTINDEX=0&journalcode=bloodbook
Platt is program manager of the Comprehensive Sickle Cell Center at Grady Health System in Atlanta, a 24-hour acute care center for people with sickle cell disease. Dr. Eckman is medical director of the center and is also a professor of medicine at Emory University School of Medicine.
- Guthrie P. Atlanta Journal and Constitution.Follow-up article on Keonn Penn, First stem cell transplant in a sickle cell patient at http://www.accessatlanta.com/partners/ajc/reports/keonepenn/index.html
- Serjeant G. Sickle Cell Disease. 2nd ed. Oxford, England: Oxford University Press; 1992.
- Steinberg MH. Management of sickle cell disease. N Engl J Med. 1999;340:1021-1030.
- Werthers DL. Sickle Cell Disease in Childhood: Part I. Laboratory Diagnosis, Pathophysiology and Health Maintenance Am Fam Physician 2000; 62:1013-20,1027-8
- Preventing pneumococcal disease among infants and young children. MMWR Morb Mortal Wkly Rep. 2000 Oct 6;49(RR-9):1-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11055835&dopt=Abstract
- O’Brien KL, Swift AJ, Winkelstein JA, Santosham M, Stover B, Luddy R, Gootenberg JE, Nold JT, Eskenazi A, Snader SJ, Lederman HM. Safety and Immunogenicity of Heptavalent Pneumococcal Vaccine Conjugated to CRM(197) Among Infants With Sickle Cell Disease. 2000 Nov;106(5):965-972. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_
- Policy statement: recommendations for the prevention of pneumococcal infections, including the use of pneumococcal conjugate vaccine (Prevnar), pneumococcal polysaccharide vaccine, and antibiotic prophylaxis. Pediatrics. 2000 Aug;106(2 Pt 1):362-6.
- Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med. 1995;332:1317-1322.
- Vichinsky EP, Haberkern CM, Neumayr L, et al, and the Preoperative Transfusion in Sickle Cell Disease Study Group. A comparison of conservative and aggressive transfusion regimens in the perioperative management of sickle cell disease. N Engl J Med. 1995;333:206-213.
- Walters MC, Patience M, Leisenring W, et al. Bone marrow transplantation for sickle cell disease. N Engl J Med. 1996;335:369-376.
- Walters MC, Patience M, Leisenring W, et al. Collaborative multicenter investigation of marrow transplantation for sickle cell disease: current results and future directions. Biol Blood Marrow Transplant 1997;3:310-315.
- Vichinsky EP, Neumayr LD, Earles AN, Williams R, Lennette ET, Dean D, Nickerson B, Orringer E, McKie V, Bellevue R, Daeschner C, Manci EA. Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group. N Engl J Med. 2000 Jun 22;342(25):1855-65.
- Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med. 1998;339:5-11.
- Xu K, Shi ZM, Veeck LL, Hughes MR, Rosenwaks Z. First unaffected pregnancy using preimplantation genetic diagnosis for sickle cell anemia. JAMA. 1999:281;1701-1706.
- Atz AM, Wessel DL. Inhaled nitric oxide in sickle cell disease with acute chest syndrome. Anesthesiology. 1997;87:988-990.
- Gladwin MT, Schechter AN, Shelhamer JH, Ognibene FP. The acute chest syndrome in sickle cell disease: possible role of nitric oxide in its pathophysiology and treatment. Am J Respir Crit Care Med. 1999;159:1368-1376.
- Adams-Graves P, Kedar A, Koshy M, et al. RheothRx (poloxamer 188) injection for the acute painful episode of sickle cell disease: a pilot study. Blood. 1997;90:2041-2046.
- Brugnara C. Erythrocyte dehydration in pathophysiology and treatment of sickle cell disease. Curr Opin Hematol. 1995;2:132-138.
- Falk RJ, Scheinman J, Phillips G, Orringer E, Johnson A, Jennette JC. Prevalence and pathologic features of sickle cell nephropathy and response to inhibition of angiotensin-converting enzyme. N Engl J Med. 1992;326:910-915.
- Foucan L, Bourhis V, Bangou J, Mérault L, Etienne-Julan M, Salmi RL. A randomized trial of captopril for microalbuminuria in normotensive adults with sickle cell anemia. Am J Med. 1998;104:339-342.
- Aoki RY, Saad ST. Enalapril reduces the albuminuria of patients with sickle cell disease. Am J Med. 1995;98:432-435.
- Lan N, Howrey RP, Lee SW, Smith CA, Sullenger BA. Ribozyme-mediated repair of sickle ß-globin mRNAs in erythrocyte precursors. Science. 1998;280:1593-1596.