- Email: [email protected]
Blood transfusion in sickle cell disease: a cautionary tale
CORRESPONDENCE
discharged from hospital. All these factors add to the expense. Peter M Dunn Perinatal Medicine and Child Health, University of Bristol, Southmead Hospital, Southmead, Bristol, BS10 5NB, UK (e-mail: [email protected]) 1 2
3
4
5
Eastwood DM. Neonatal hip screeing. Lancet 2003; 361: 595–97. Marks DS, Clegg J, Al-Chababi AN. Routine ultrasound screening for neonatal hip instability: can it abolish late-presenting congenital dislocation of the hip? J Bone Joint Surg 1994; 76B: 534–38. Goss PW. Successful screening for neonatal hip instability in Australia. J Paediatr Child Health 2002: 38: 469–74. Dunn PM. Congenital dislocation of the hip: screening, diagnosis and management. In: Koppe JG, Eskes TKAB, eds. Care, concern and cure in perinatal medicine. Carnforth: The Parthenon Publishing Company, 1993: 297–309. Standing Medical Advisory Committee and Standing Nursing and Midwifery Advisory Committee. Screening for the detection of congenital dislocation of the hip. London: Department of Health and Social Security, 1986.
much variability in rates of follow-up investigations, and children screened by orthopaedic specialists have follow-up and treatment rates twice as high as those screened by paediatricians.4 About 98% of newborn babies are expected to have normal hips, so the ability of the screening test to correctly identify the unaffected—ie, its specificity—is of utmost importance. Given the wide gap in quality between centres of excellence and clinical routine, independent quality-control measures need to be in place when a screening programme starts. In Germany, where such measures do not exist, the low specificity of ultrasonography has become the Achilles heel of neonatal hip screening. A potentially beneficial preventive activity is thus associated with over-diagnosis and overtreatment, inadvertently channelling many healthy babies into the curative care system.5 *Albrecht Jahn, Oliver Razum
Sir—In her otherwise well-founded Rapid review, Deborah Eastwood1 states that clinical screening for developmental dysplasia of the hip (DDH) has a specificity of almost 100%. However, M Boere-Boonekamp and colleagues2 found that even specially trained clinical examiners in child clinics achieve a specificity of only 82%. The specificity of ultrasonography-based neonatal hip screening is in a comparable range. As Eastwood observes, a low specificity will lead to false-positive results and overtreatment. This problem is a cause for concern in a rare condition such as DDH, because the positive predictive value of the screening examination will be low. In other words, most newborn babies treated for DDH because of a positive screening result will not actually have the condition. These babies will unnecessarily be put at risk of the sideeffects of treatment. In Germany, ultrasonography hip screening was promoted by professional associations in paediatrics, orthopaedics, and radiology, despite unfavourable international reviews3 and without any evidence of efficacy. In 1996, such screening became part of the routine neonatal examination at the 4–6 week health check, which is done locally by doctors in private practice. F Niethard and co-workers4 found that primary screening has a low specificity with 23·7% repeat examinations and a treatment rate of 6·7%. This treatment rate is three times higher than the estimated DDH prevalence at birth (2%), and 30 times higher than the prevalence of clinically relevant DDH (0·2%).1 Moreover, ultrasonography hip screening in Germany is not subject to systematic quality assurance. There is
Department of Tropical Hygiene and Public Health, Neuenheimer Feld 324, 69120 Heidelberg, Germany (e-mail: [email protected]) 1 2
3
4
5
Eastwood DM. Neonatal hip screening. Lancet 2003; 361: 595–97. Boere-Boonekamp MM, Kerkhoff TH, Schuil PB, Zielhuis GA. Early detection of developmental dysplasia of the hip in The Netherlands: the validity of a standardized assessment protocol in infants. Am J Public Health 1998; 88: 285–88. Hernandez RJ, Cornell RG, Hensinger RN. Ultrasound diagnosis of neonatal congenital dislocation of the hip: a decision analysis assessment. J Bone Joint Surg Br 1994; 76: 539–43. Niethard FU, Günther KP, von Kries R, Allhoff P, Altenhofen L. Klinisches und sonographisches Screening der Säuglingshüfte [Evaluation of Ultrasound Examination of Hip Screening]. Deutsches Ärzteblatt 2000; 97: 1593–99. Jahn A. Screening—the Trojan horse in preventive medicine? Trop Med Int Health 2002; 7: 295–97.
Clever idiot? Sir—To review a scientific paper is a time-consuming task. I do about two reviews a month and am sure many of your readers have even more review commissions than me. Recently, I agreed to review an article submitted to a well known scientific journal, with a high impact factor. The paper concerned a research area I have been involved in, so I was happy to help. I read the paper several times and spent hours analysing the data. At last I was satisfied and believed I had contributed to the quality of the manuscript. I did the review during my working day at the hospital and during my leisure time. A couple of days later, I read an article about the Science and Medical sector of
THE LANCET • Vol 361 • May 10, 2003 • www.thelancet.com
Reed Elsevier, a large publishing company of several well known journals, including The Lancet. Their turnover in 2001 was £1024 million, and their adjusted operating profit £344 million. Then I thought about my own research activity; I spend months planning and then undertaking a study and at last writing a paper about the results. Subsequently, I give away the copyright to the publisher. In some instances, I even pay the printing cost. Then, the library of my institution (who is paying me to do research) pays millions of pounds for subscription to these journals. Thus, first the institution pays me to do research, then I give away the copyright of the results to the publisher, then the library of the institution buys the right to print my paper back from the publisher. I cannot avoid wondering how the management of such publishing companies view myself and others who do research and who also accept review commitments. Stefan Agewall Department of Cardiology, Karolinska Institute, Huddinge University Hospital, S 141 86 Stockholm, Sweden (e-mail: [email protected])
Blood transfusion in sickle cell disease: a cautionary tale Sir—A US civil suit in an Atlanta courthouse in October, 2002, centred on a blood transfusion given to an individual with homozygous sickle cell (SS) disease. As with any potentially dangerous therapy, the benefits of transfusion should always be balanced against any possible risks. In a person with a haemoglobin concentration strikingly lower than steady-state values—whether acutely because of aplastic crisis or acute splenic sequestration, or chronically because of end-stage renal failure—the potential benefits of the procedure outweigh the risks. However, to undertake a transfusion simply to reduce the amount of sickle cell haemoglobin present is more controversial. Rapid exchange transfusion can be lifesaving if a patient with sickle cell disease develops acute chest syndrome, and chronic transfusion programmes do prevent stroke recurrence, but its use in the management of avascular necrosis of the femoral head, stuttering priapism, or to improve school attendance is questionable. Most controversial is use of transfusion to increase oxygen delivery when haemoglobin con-
1659
For personal use. Only reproduce with permission from The Lancet Publishing Group.
CORRESPONDENCE
1660
DEPARTMENT OF ERROR
US$11·5 million recommended by the jury in this case could have been avoided.
Calverley P, Pauwels R, Vestbo J, et al. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2003; 361: 449–56—In this Article (Feb 8), the address for N Pride should have read “Department of Thoracic Medicine, National Lung and Heart Institute, London, UK”, and the address for A Gulsvik should have read “Department of Thoracic Medicine, Institute of Medicine, University of Bergen, Bergen, Norway”. Furthermore, in figure 1, the trial profile should have shown that 140 patients withdrew from the placebo group, and that 500 g of fluticasone was given twice daily. In the list of TRISTAN Investigators, Goran Borg (Sweden) should be replaced by Lennart Nilholm. On p 453, the penultimate line of the second column should have read “We did not detect any changes on electrocardiograms . . .”
Graham Serjeant 14 Milverton Crescent, Kingston 6, Jamaica, West Indies (e-mail: [email protected]) 1
2
3
4
5
Wasi P, Na-Nakorn S, Pootrakul P, Sonakul D, Piankijagum A, Pacharee P. A syndrome of hypertension, convulsion, and cerebral haemorrhage in thalassaemic patients after multiple blood transfusions. Lancet 1978; 2: 602–04. Royal JE, Seeler RA. Hypertension, convulsions, and cerebral haemorrhage in sickle-cell anaemia patients after bloodtransfusions. Lancet 1978; 2: 1207. Rackoff WR, Ohene-Frempong K, Month S, Scott JP, Neahring B, Cohen AR. Neurologic events after partial exchange transfusion for priapism in sickle cell disease. J Pediatr 1992; 120: 882–85. Hamdan JA, Mallouh AA, Ahmad MS. Hypertension and convulsions complicating sickle cell anaemia: possible role of transfusion. Ann Trop Paediatr 1984; 4: 41–43. Warth JA. Hypertension and a seizure following transfusion in an adult with sickle cell anemia. Arch Intern Med 1984; 144: 607–08.
A
Henry G, Li W, Garner W, Woodley D T. Migration of human keratinocytes in plasma and serum and wound re-epithelialisation. Lancet 2003; 361: 574–76—In this Research letter (Feb 15), figure 2 should be as printed below.
Plasma +
–
Collagen:
Serum + Phospho-p38
p38 1 B
2
3 Transfection
Lentiviral infection
FACS: C
96%
18%
40 Migration Index (%)
centrations are within the normal range, which in patients of African origin who have sickle cell (SS) disease is usually about 60–100 g/L. In this situation, transfusion with stored, 2,3-diphosphoglycerate-depleted blood, which has a relatively high oxygen affinity, can worsen oxygen delivery in the short term and have serious consequences in the long term; sudden changes in packedcell volume or blood pressure in individuals with sickle cell (SS) disease who have adapted to survive on low haemoglobin concentrations can have serious consequences. A patient from Jamaica with sickle cell (SS) disease, who was treated at the Sickle Cell Clinic of the University Hospital of the West Indies, Kingston, Jamaica, from 1955 (from age 18 months) to 1997, ran a fairly benign clinical course with only two painful crises, one acute chest syndrome and intermittent chronic leg ulceration. She qualified as a pharmacist at age 25 years and worked full-time with one uneventful pregnancy in 1980. Throughout life, her steady state haemoglobin concentration remained at the lower end of the normal range (50–70 g/L), and from 1990 there was a gradual asymptomatic fall common to many patients older than 30 years; she never received a blood transfusion since there seemed to be no clinical indication for one. She was last seen at the clinic in Jamaica in 1994, when she had a haemoglobin value of 39 g. She emigrated to the USA in 1997, still in full-time employment and in reasonable health. On a routine visit to her family doctor in August, 1999, her haemoglobin concentration was measured at 38 g, and admission to hospital was recommended. She received 2 units of blood, which raised her haemoglobin value to 49 g. She was then given a further 4 units within the same 24 h. Her packed-cell volume rose from 11% to 31%, systolic and diastolic pressures increased by 30 mm Hg, and she developed headaches within 9 h of the last transfusion. She developed a cerebral haemorrhage within 72 h and later died. Although few doctors experienced in sickle cell disease would approve transfusion of 6 units of blood within 24 h on the basis of improving oxygen delivery, the haemodynamic consequences of such action might not be widely recognised. A syndrome of hypertension, convulsions, and sometimes cerebral haemorrhage can follow rapid transfusion in  thalassaemia1 and sickle cell (SS) disease for priapism2,3 and for other complications.4,5 If this fact were more widely known, the award of
C+S C+S
30 20
C+S
C+P
c
C+P
2
3
C+P
10 pl
0 1
4
5
6
Wt-p38 D _
7
8
DN-p38
MMP Plasma Serum extract
119 94
Pro-MMP-9 Activated MMP-9 MMP-9 isoform
51 34 1
2
3
4
THE LANCET • Vol 361 • May 10, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
discharged from hospital. All these factors add to the expense. Peter M Dunn Perinatal Medicine and Child Health, University of Bristol, Southmead Hospital, Southmead, Bristol, BS10 5NB, UK (e-mail: [email protected]) 1 2
3
4
5
Eastwood DM. Neonatal hip screeing. Lancet 2003; 361: 595–97. Marks DS, Clegg J, Al-Chababi AN. Routine ultrasound screening for neonatal hip instability: can it abolish late-presenting congenital dislocation of the hip? J Bone Joint Surg 1994; 76B: 534–38. Goss PW. Successful screening for neonatal hip instability in Australia. J Paediatr Child Health 2002: 38: 469–74. Dunn PM. Congenital dislocation of the hip: screening, diagnosis and management. In: Koppe JG, Eskes TKAB, eds. Care, concern and cure in perinatal medicine. Carnforth: The Parthenon Publishing Company, 1993: 297–309. Standing Medical Advisory Committee and Standing Nursing and Midwifery Advisory Committee. Screening for the detection of congenital dislocation of the hip. London: Department of Health and Social Security, 1986.
much variability in rates of follow-up investigations, and children screened by orthopaedic specialists have follow-up and treatment rates twice as high as those screened by paediatricians.4 About 98% of newborn babies are expected to have normal hips, so the ability of the screening test to correctly identify the unaffected—ie, its specificity—is of utmost importance. Given the wide gap in quality between centres of excellence and clinical routine, independent quality-control measures need to be in place when a screening programme starts. In Germany, where such measures do not exist, the low specificity of ultrasonography has become the Achilles heel of neonatal hip screening. A potentially beneficial preventive activity is thus associated with over-diagnosis and overtreatment, inadvertently channelling many healthy babies into the curative care system.5 *Albrecht Jahn, Oliver Razum
Sir—In her otherwise well-founded Rapid review, Deborah Eastwood1 states that clinical screening for developmental dysplasia of the hip (DDH) has a specificity of almost 100%. However, M Boere-Boonekamp and colleagues2 found that even specially trained clinical examiners in child clinics achieve a specificity of only 82%. The specificity of ultrasonography-based neonatal hip screening is in a comparable range. As Eastwood observes, a low specificity will lead to false-positive results and overtreatment. This problem is a cause for concern in a rare condition such as DDH, because the positive predictive value of the screening examination will be low. In other words, most newborn babies treated for DDH because of a positive screening result will not actually have the condition. These babies will unnecessarily be put at risk of the sideeffects of treatment. In Germany, ultrasonography hip screening was promoted by professional associations in paediatrics, orthopaedics, and radiology, despite unfavourable international reviews3 and without any evidence of efficacy. In 1996, such screening became part of the routine neonatal examination at the 4–6 week health check, which is done locally by doctors in private practice. F Niethard and co-workers4 found that primary screening has a low specificity with 23·7% repeat examinations and a treatment rate of 6·7%. This treatment rate is three times higher than the estimated DDH prevalence at birth (2%), and 30 times higher than the prevalence of clinically relevant DDH (0·2%).1 Moreover, ultrasonography hip screening in Germany is not subject to systematic quality assurance. There is
Department of Tropical Hygiene and Public Health, Neuenheimer Feld 324, 69120 Heidelberg, Germany (e-mail: [email protected]) 1 2
3
4
5
Eastwood DM. Neonatal hip screening. Lancet 2003; 361: 595–97. Boere-Boonekamp MM, Kerkhoff TH, Schuil PB, Zielhuis GA. Early detection of developmental dysplasia of the hip in The Netherlands: the validity of a standardized assessment protocol in infants. Am J Public Health 1998; 88: 285–88. Hernandez RJ, Cornell RG, Hensinger RN. Ultrasound diagnosis of neonatal congenital dislocation of the hip: a decision analysis assessment. J Bone Joint Surg Br 1994; 76: 539–43. Niethard FU, Günther KP, von Kries R, Allhoff P, Altenhofen L. Klinisches und sonographisches Screening der Säuglingshüfte [Evaluation of Ultrasound Examination of Hip Screening]. Deutsches Ärzteblatt 2000; 97: 1593–99. Jahn A. Screening—the Trojan horse in preventive medicine? Trop Med Int Health 2002; 7: 295–97.
Clever idiot? Sir—To review a scientific paper is a time-consuming task. I do about two reviews a month and am sure many of your readers have even more review commissions than me. Recently, I agreed to review an article submitted to a well known scientific journal, with a high impact factor. The paper concerned a research area I have been involved in, so I was happy to help. I read the paper several times and spent hours analysing the data. At last I was satisfied and believed I had contributed to the quality of the manuscript. I did the review during my working day at the hospital and during my leisure time. A couple of days later, I read an article about the Science and Medical sector of
THE LANCET • Vol 361 • May 10, 2003 • www.thelancet.com
Reed Elsevier, a large publishing company of several well known journals, including The Lancet. Their turnover in 2001 was £1024 million, and their adjusted operating profit £344 million. Then I thought about my own research activity; I spend months planning and then undertaking a study and at last writing a paper about the results. Subsequently, I give away the copyright to the publisher. In some instances, I even pay the printing cost. Then, the library of my institution (who is paying me to do research) pays millions of pounds for subscription to these journals. Thus, first the institution pays me to do research, then I give away the copyright of the results to the publisher, then the library of the institution buys the right to print my paper back from the publisher. I cannot avoid wondering how the management of such publishing companies view myself and others who do research and who also accept review commitments. Stefan Agewall Department of Cardiology, Karolinska Institute, Huddinge University Hospital, S 141 86 Stockholm, Sweden (e-mail: [email protected])
Blood transfusion in sickle cell disease: a cautionary tale Sir—A US civil suit in an Atlanta courthouse in October, 2002, centred on a blood transfusion given to an individual with homozygous sickle cell (SS) disease. As with any potentially dangerous therapy, the benefits of transfusion should always be balanced against any possible risks. In a person with a haemoglobin concentration strikingly lower than steady-state values—whether acutely because of aplastic crisis or acute splenic sequestration, or chronically because of end-stage renal failure—the potential benefits of the procedure outweigh the risks. However, to undertake a transfusion simply to reduce the amount of sickle cell haemoglobin present is more controversial. Rapid exchange transfusion can be lifesaving if a patient with sickle cell disease develops acute chest syndrome, and chronic transfusion programmes do prevent stroke recurrence, but its use in the management of avascular necrosis of the femoral head, stuttering priapism, or to improve school attendance is questionable. Most controversial is use of transfusion to increase oxygen delivery when haemoglobin con-
1659
For personal use. Only reproduce with permission from The Lancet Publishing Group.
CORRESPONDENCE
1660
DEPARTMENT OF ERROR
US$11·5 million recommended by the jury in this case could have been avoided.
Calverley P, Pauwels R, Vestbo J, et al. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2003; 361: 449–56—In this Article (Feb 8), the address for N Pride should have read “Department of Thoracic Medicine, National Lung and Heart Institute, London, UK”, and the address for A Gulsvik should have read “Department of Thoracic Medicine, Institute of Medicine, University of Bergen, Bergen, Norway”. Furthermore, in figure 1, the trial profile should have shown that 140 patients withdrew from the placebo group, and that 500 g of fluticasone was given twice daily. In the list of TRISTAN Investigators, Goran Borg (Sweden) should be replaced by Lennart Nilholm. On p 453, the penultimate line of the second column should have read “We did not detect any changes on electrocardiograms . . .”
Graham Serjeant 14 Milverton Crescent, Kingston 6, Jamaica, West Indies (e-mail: [email protected]) 1
2
3
4
5
Wasi P, Na-Nakorn S, Pootrakul P, Sonakul D, Piankijagum A, Pacharee P. A syndrome of hypertension, convulsion, and cerebral haemorrhage in thalassaemic patients after multiple blood transfusions. Lancet 1978; 2: 602–04. Royal JE, Seeler RA. Hypertension, convulsions, and cerebral haemorrhage in sickle-cell anaemia patients after bloodtransfusions. Lancet 1978; 2: 1207. Rackoff WR, Ohene-Frempong K, Month S, Scott JP, Neahring B, Cohen AR. Neurologic events after partial exchange transfusion for priapism in sickle cell disease. J Pediatr 1992; 120: 882–85. Hamdan JA, Mallouh AA, Ahmad MS. Hypertension and convulsions complicating sickle cell anaemia: possible role of transfusion. Ann Trop Paediatr 1984; 4: 41–43. Warth JA. Hypertension and a seizure following transfusion in an adult with sickle cell anemia. Arch Intern Med 1984; 144: 607–08.
A
Henry G, Li W, Garner W, Woodley D T. Migration of human keratinocytes in plasma and serum and wound re-epithelialisation. Lancet 2003; 361: 574–76—In this Research letter (Feb 15), figure 2 should be as printed below.
Plasma +
–
Collagen:
Serum + Phospho-p38
p38 1 B
2
3 Transfection
Lentiviral infection
FACS: C
96%
18%
40 Migration Index (%)
centrations are within the normal range, which in patients of African origin who have sickle cell (SS) disease is usually about 60–100 g/L. In this situation, transfusion with stored, 2,3-diphosphoglycerate-depleted blood, which has a relatively high oxygen affinity, can worsen oxygen delivery in the short term and have serious consequences in the long term; sudden changes in packedcell volume or blood pressure in individuals with sickle cell (SS) disease who have adapted to survive on low haemoglobin concentrations can have serious consequences. A patient from Jamaica with sickle cell (SS) disease, who was treated at the Sickle Cell Clinic of the University Hospital of the West Indies, Kingston, Jamaica, from 1955 (from age 18 months) to 1997, ran a fairly benign clinical course with only two painful crises, one acute chest syndrome and intermittent chronic leg ulceration. She qualified as a pharmacist at age 25 years and worked full-time with one uneventful pregnancy in 1980. Throughout life, her steady state haemoglobin concentration remained at the lower end of the normal range (50–70 g/L), and from 1990 there was a gradual asymptomatic fall common to many patients older than 30 years; she never received a blood transfusion since there seemed to be no clinical indication for one. She was last seen at the clinic in Jamaica in 1994, when she had a haemoglobin value of 39 g. She emigrated to the USA in 1997, still in full-time employment and in reasonable health. On a routine visit to her family doctor in August, 1999, her haemoglobin concentration was measured at 38 g, and admission to hospital was recommended. She received 2 units of blood, which raised her haemoglobin value to 49 g. She was then given a further 4 units within the same 24 h. Her packed-cell volume rose from 11% to 31%, systolic and diastolic pressures increased by 30 mm Hg, and she developed headaches within 9 h of the last transfusion. She developed a cerebral haemorrhage within 72 h and later died. Although few doctors experienced in sickle cell disease would approve transfusion of 6 units of blood within 24 h on the basis of improving oxygen delivery, the haemodynamic consequences of such action might not be widely recognised. A syndrome of hypertension, convulsions, and sometimes cerebral haemorrhage can follow rapid transfusion in  thalassaemia1 and sickle cell (SS) disease for priapism2,3 and for other complications.4,5 If this fact were more widely known, the award of
C+S C+S
30 20
C+S
C+P
c
C+P
2
3
C+P
10 pl
0 1
4
5
6
Wt-p38 D _
7
8
DN-p38
MMP Plasma Serum extract
119 94
Pro-MMP-9 Activated MMP-9 MMP-9 isoform
51 34 1
2
3
4
THE LANCET • Vol 361 • May 10, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.