Recurrent Acute Chest Syndrome Research Articles

Prolonged QTc interval in children and young adults with sickle cell disease at steady state

Prolongation of the QTc interval may be more common than previously believed among individuals with sickle cell disease (SCD). The clinical associations and natural history of QTc prolongation remain unclear in this population. Our objectives were to determine the prevalence of prolonged QTc and evaluate its relationship to clinical factors in children and young adults with SCD. We analyzed data from subjects 10 to 25 years old with SCD enrolled in our pulmonary hypertension screening protocol. Screening included echocardiography (ECHO), 12-lead electrocardiogram (ECG) and laboratory testing at steady state. QTc interval >440 msec was considered prolonged. ECG data from 76 subjects (57% male, mean age 14.2 +/- 3 years old, range 10-24) were analyzed. We observed prolonged QTc in 29/76 (38%) subjects. Despite evidence of left ventricular hypertrophy (LVH) in 50/76 (66%) subjects, the frequency of LVH was not significantly different in subjects with and without QTc prolongation. When compared to subjects with normal QTc, subjects with prolonged QTc had higher mean tricuspid regurgitant jet velocity (2.51 +/- 0.27 m/sec vs. 2.33 +/- 0.26 m/sec, P = 0.010) as well as higher mean lactate dehydrogenase (433 +/- 142 IU/L vs. 343 +/- 142 IU/L, P = 0.000) and aspartate aminotransferase (48 +/- 20 IU/L vs. 39 +/- 15 IU/L, P = 0.026). A larger proportion of subjects with prolonged QTc also had a history of recurrent acute chest syndrome (66% vs. 38%, P = 0.038). We conclude that QTc prolongation is a frequent finding in SCD not associated with LVH. Elevated pulmonary pressures, hemolysis and acute chest syndrome may represent risk factors for prolonged QTc in this population.

Haemoglobin F modulation in childhood sickle cell disease

While supportive care remains the best option for most well children with sickle cell disease (SCD), increasing awareness of early signs of chronic organ damage in childhood has focused attention on therapy which modulates the natural history of the disease. Since cure by stem cell transplantation is only feasible for a minority and gene therapy remains developmental, pharmacological modification by Haemoglobin F (HbF)-inducers, is the most widely used approach in SCD. Currently, the only HbF modulator with a clear place in the management of childhood SCD is hydroxycarbamide for which the main indications are frequent painful crises and recurrent acute chest syndrome. In the majority of SCD children treated with hydroxycarbamide there is clear evidence of clinical benefit and the drug is well tolerated. The main disadvantages are the need for frequent monitoring and uncertainity about long-term risks of carcinogenicity and impaired fertility, although these risks appear to be very low. The role of hydroxycarbamide in sickle-associated central nervous system disease remains to be established. Decitabine and butyrate derivatives show some promise although robust data in children with SCD are lacking. A number of other drugs are currently under investigation for their effects on HbF production including thalidomide and lenolidamide.

Low Dose Alemtuzumab Achieves Long-Term Engraftment with Low Level Mixed Chimerism in Related Haemopoietic Stem Cell Transplantation for Haemoglobinopathies

Haemopoietic stem cell transplantation (HSCT) is the only proven curative treatment available for haemoglobinopathies. To reduce transplant-related mortality and morbidity associated with graft-versus-host disease (GvHD) and facilitate donor engraftment we have used low-dose alemtuzumab in 43 consecutive patients (36 with thalassaemia and 7 with sickle cell disease; median age 6 years; range 2 to 16 years) transplanted since 2000. Donors were HLA-matched family donors in all cases. All patients were conditioned with oral busulfan 14 mg/kg (days -9 to -6), cyclophosphamide 200 mg/kg (days -5 to -2) and alemtuzumab 0.3 mg/kg (days -8 to -6) with post-HSCT methotrexate (10 mg/m2 days +4 and +7) and ciclosporin for six months. Hypertransfusion was initiated six weeks before conditioning and maintained until day +28 to suppress endogenous haemopoiesis and minimise graft rejection. Patients with thalassaemia were Pesaro class I or II. Patients with sickle cell disease were transplanted for stroke or recurrent vasooclusive crisis and/or acute chest syndrome not responding to hydroxycarbamide. The source of stem cells was bone marrow in all cases except one patient who received PBSC with a median cell dose of 3.08 x 108 TNC/kg (range 1.69 – 10.90 x 108 TNC/kg). Median follow up was 25.8 months (range 6.5 – 94.3 months). Chimerism studies were performed on peripheral blood genomic DNA using 8 microsatellites markers by genescanning. All patients are alive (43/43), 42 with long-term transfusion-independence and donor haematological values (5 years DFS 97.7%). One patient failed to engraft and was re-infused with autologous cells. Donor haemopoiesis was ≥ 95% on day +28 in all 42 patients who engrafted and was maintained at ≥ 95% in the majority of patients at 12 months post-HSCT. Eleven patients (11/42; 31%) have stable mixed chimerism at ≥ 12 months post-HSCT: donor haemopoiesis 90–94% (n=4); <90% (n=7; median 85%; range 45 – 89%). There have been no late relapses and no patients had falling donor haemopoiesis <90% after day +90. Acute GvHD ≥ grade 2 occurred in 5 patients (11.6%) and was steroid-responsive in all cases except the patient who received PBSC. Limited chronic GvHD was present in 2 patients (4.6%) >18 months post-HSCT (on no treatment) and Karnofsky score is 100% in all engrafted patients (42/42). In conclusion, addition of low-dose alemtuzumab (total dose 0.3 mg/kg) achieved long-term engraftment in almost all children undergoing HLA-matched family donor HSCT for haemoglobinopathies with minimal chronic GvHD and excellent DFS (97.7%).

Prediction of adverse outcomes in children with sickle cell anemia: a study of the Dallas Newborn Cohort

The Cooperative Study of Sickle Cell Disease reported that dactylitis, severe anemia, and leukocytosis in very young children with sickle cell disease (SCD) increased the risk of later adverse outcomes, including death, stroke, frequent pain, and recurrent acute chest syndrome. This model has not been validated in other cohorts. We evaluated its performance in the Dallas Newborn Cohort, a newborn inception cohort of children with SCD. We studied 168 children (55% male, 97% sickle cell anemia) with a mean follow-up of 7.1 years who provided 1188 patient-years of observation. Of the 23 (13.7%) subjects who experienced adverse events, 2 (1.2%) died, 14 (8.3%) had a stroke, 4 (2.4%) had frequent pain, and 3 (1.8%) had recurrent acute chest syndrome. No relationship existed between early clinical predictors and later adverse outcomes, with the possible exception of leukocyte count. Most subjects who experienced adverse events were predicted to be at low risk for those events. No subject who was predicted to be at high risk actually experienced an adverse outcome. The sensitivity of the model did not rise above 20% until specificity fell below 60%. We suggest that this model not be used as a criterion to initiate early interventions for SCD.

The Landscape of Thrombophilia in Sickling Disorders: Unfamiliar Terrain.

Sickling disorders have long been suspected of decreasing physiologic thresholds for thrombosis, and the sickling process in tissue of being abetted by elements of the hemostatic system. The landscape of the presumed hypercoagulable state, however, has been ill-defined and differences among sickling disorders with regard to its characteristics, if any, undelineated. Learning how this landscape may reflect the pathophysiology of the sickling process may help guide further study of the interactions among the vasculature and the varieties of abnormal erythrocytes resulting from these hemoglobinopathies and define new opportunities to ameliorate the clinical manifestations of "sickle cell disease."Methods: Using laboratory strategies developed to characterize thrombophilia in non-sickling patients with thrombosis, modified for a largely non-European population, 144 patients with sickling disorders were prospectively evaluated for predisposition to thrombosis. A standard group of hemostatic studies was performed using patient samples obtained during steady-state "non-sickling" conditions, by skilled venepuncturists working consistently with this patient group.Genotypes included: HbSS 96/144 (67%); Hb SC 26/144 (18%;) Hb SSTh; 14/144 (9.5%); Hb S/AThal 8/144 (5.5%). 49/144 (34%) patients (pts) received regular automated erythrocytapheresis for prior stroke, recurrent acute chest syndrome or severe pain episodes > 6/yr.Results: As expected, 2/144 (1.4%) of pts were heterozygous for the Factor V Leiden mutation, 0/144 for the Prothrombin 20210 mutation, and 20/144 (14%) heterozygous, 1/144 (<1%) homozygous for the MTHFR C677T mutation despite homocysteine levels > 12 ng/dL in 38/144 patients (26%). Protein S activity levels were <65% in 83/144 (58%) pts with commensurate free Protein S levels. Total Protein S levels varied widely with no correlation to sickling genotypes, suggesting -as with homocysteine levels -dietary variation. Hb SC genotype was strongly associated with von Willebrand antigen (vWA) levels > 175%, frequently with lesser vWFactor activity (vWF) levels, whereas Hb SSt and SThal more frequently exhibited normal vWA/vWF profiles. Factor VIII activity varied widely, exhibiting no correlation to vWF antigen or activity levels in any of the Hb genotypes. Other thrombophilic conditioners, e.g. antithrombin III activity/Ag, Factor VIII activity, plasmnogen activator inhibitor, and b2-glycoprotein I antibodies were either normal or varied as expected in a " normal," e.g European population, with no correlation to Hb genotype.Conclusions: Thrombophilia in patients with sickling disorders appears to have varied contributors: Hb SC appears most thrombophilic with levels of vWF antigen suggestive of vascular dysfunction and supportive of intravscular platelet adhesion a aggregation. Other genotypes exhibit variable phenotypes, with Hb SThal exhibiting the least thrombogenic phenotype from a aboratory assessment perspective. vWF antigen and Protein S abnormalities emphasize the likely role of inflammation and vascular dysfunction but the dysjunction of vWF and Factor VIII activity hint at greater complexity. Further study of these phenomena and the inclusion of platelet function studies may yield additional insights as to the interaction of sickling erythrocytes, their products and vascular/hemostatic interactions. For now, routine thromboprophylaxis in patients with SC disease appears essential, and likely important in all other genotypes except Hb SThal.

Pulmonary Hypertension in Children and Adolescents with Sickle Cell Disease.

Pulmonary hypertension occurs in 20–40% of adults with sickle cell disease and has a poor prognosis; age of onset and prevalence in childhood are not well established. In adults, recurrent acute chest syndrome is associated with chronic sickle cell lung disease and perhaps pulmonary hypertension. Hematologically normal children with obstructive sleep apnea are at risk for pulmonary hypertension. We sought to determine the prevalence of pulmonary hypertension in children and adolescents with sickle cell disease, explore potential association with abnormal pulmonary function or sleep apnea, and identify other clinical or laboratory factors associated with this potentially life-threatening complication. Forty-eight patients (age 5–21 years, median 12 years) consented to participate. Thirty-eight (79%) had Hb SS; five each had Hb SC and S-beta thalassemia (three beta plus and two beta zero) (10.4%). Eleven (22.9%) were on chronic transfusion (seven for stroke, three for abnormal TCD velocity screening, and one for recurrent pain crises); nineteen (39.5%) were on hydroxyurea (ten for recurrent acute chest syndrome and nine for recurrent pain). A detailed history and physical examination were done on all enrolled subjects (history was comprehensive, but specifically included cardiopulmonary symptoms; neurological problems; number of pain crises and acute chest syndrome; blood transfusions; use of hydroxyurea; and a screening for obstructive sleep apnea). If apnea history was suggestive, polysomnography was done. In addition, all study subjects had Doppler echocardiography and pulmonary function tests (PFT). Pulmonary hypertension was defined as an age and body mass index-adjusted tricuspid regurgitant jet velocity (TRV) of greater than 2.5 mm/sec. Among the study group, 31 (64.5%) had pulmonary function tests; 17 (54.8%) had restrictive abnormalities on PFT, three (9.6%) had obstructive changes and 11 (35.4%) had normal PFT. Three patients (6.2%) had a history suggestive of apnea, then polysomnography; one was normal and two had OSA. Four of the 48 patients (8.3%) had PHT (TRV values 2.52, 2.55, 2.61, and 2.91). All had Hb SS. Two were age 17 and 18 years and two were 10 and 11. All were asymptomatic. One had restrictive PFT and none had OSA. There was no correlation between the presence of PHT and pulmonary function abnormalities or sleep apnea. Of the various other clinical and laboratory parameters examined, only an elevated serum indirect bilirubin was associated with PHT; there was a trend toward association with elevated reticulocyte count and low fetal Hb levels. In summary, the prevalence of PHT our pediatric sickle cell population is 8.3%. As reported in adults, there may be an association between PHT and more severe hemolysis. We could find no association with abnormal pulmonary function or obstructive sleep apnea.Characteristics of study patientsPHTNo PHTP ValueFetal Hb(%) (Mean)3.77.9.154Age (Mean)13.5 years12 years.564Reticulocytes (%)13.88.25.087Indirect bilirubin (mg/dl) (Mean)5.42.2.027

Prediction of Adverse Outcomes in Children with Sickle Cell Anemia: Testing the CSSCD Early Prediction Model in the Dallas Newborn Cohort.

The Cooperative Study of Sickle Cell Disease (CSSCD) reported that dactylitis, severe anemia, and leukocytosis in very young children with SCD increased the risk of later adverse outcomes, including death, stroke, recurrent acute chest syndrome (ACS), and frequent pain (NEJM 2000; 342:83). Specifically, in the CSSCD infant cohort, the occurrence of dactylitis in the first year of life (“early dactylitis”) and a steady-state hemoglobin (Hgb) concentration <7 g/dL in the second year of life (“severe anemia”) together predicted a high risk (0.36 probability) of a later adverse outcome. A steady-state leukocyte count of approximately 20,000/mm3 or higher in the second year of life (“leukocytosis”) in combination with either early dactylitis or severe anemia also predicted a high risk of an adverse outcome. The testing of this model in other cohorts has not been reported, so we evaluated its performance characteristics in the Dallas Newborn Cohort (Blood 2004; 103:4023). We studied all cohort members with sickle cell anemia (SS) or sickle-β0-thalassemia (Sβ0) who had 5 or more years of follow-up and complete laboratory data and medical records. We searched our electronic database and patients' medical records to ascertain the occurrence of the three predictors (early dactylitis, severe anemia, and leukocytosis) and the four adverse events [death; clinically overt first stroke; frequent pain (average of 2 or more painful events/year for the entire follow-up period, with ≥2 events/year for 3 consecutive years); and recurrent ACS (average of 1 or more episode/year with ≥1 episode/year for 3 consecutive years)]. We only considered hospitalizations for pain in this analysis, unlike the CSSCD, because we do not systematically track episodes of pain treated only at home or in outpatient facilities. We studied a total of 119 children (68% male, 97% SS) who had a mean follow-up of 9.7 years (range 5 – 15.4). Twenty-four (20%) had early dactylitis, 5 (4%) had severe anemia, and 15 (12.6%) had leukocytosis. Eighteen subjects (15.1%) experienced adverse events: 2 (1.7%) died, 13 (10.9%) had a stroke, 3 (2.5%) had frequent pain, and 1 (0.8%) had recurrent ACS. Sensitivity and specificity of the model were 0 and 97%. Positive and negative predictive values were 0 and 84%. We used binary logistic regression to further evaluate the model. The whole model test was not significant (P=0.21), and R2 was 0.044. The area under the ROC curve was 0.64 (Figure), and better-performing cut-points for Hgb and leukocyte count could not be found. In summary, the CSSCD early prediction model had very low sensitivity and positive predictive value in the Dallas Newborn Cohort. Specificity and negative predictive value were high, however. This retrospective analysis has several limitations and biases, but it suggests that the CSSCD model does not well predict adverse outcomes in the Dallas Newborn Cohort. [Display omitted]

Primary Hyperparathyroidism Mimicking Vaso-occlusive Crises in Sickle Cell Disease

We report a case of bone pain associated with primary hyperparathyroidism in a patient with sickle cell disease. A 17-year-old girl with sickle cell disease (SS phenotype) was seen for bilateral knee and back pain. She had had recurrent severe vaso-occlusive crises and acute chest syndrome in the course of her disease. In the last 2 years, she had frequent visits to the emergency department for severe bone pain. She complained of long-standing fatigue and lethargy. Her physical examination was normal. Hydroxyurea treatment, as well as and long- and short-acting narcotics were given, with little improvement in symptoms. Poor compliance with medication, family dysfunction, and potential narcotic addiction were felt to be significant contributors to the patient's symptoms. She was incidentally found to have an extremely elevated total calcium level of 3.19 mmol/L (range: 2.25-2.76) with an ionized calcium level of 1.9 mmol/L (range: 1.15-1.35). Phosphorus level was 0.82 mmol/L (range: 0.90-1.50), alkaline phosphatase level was elevated at 519 U/L (range: 10-170), and parathyroid hormone level was extremely high at 1645 pg/mL (range: 10-60). Her renal function was normal. Ultrasonography of the neck and a Sestamibi scan revealed a single left inferior parathyroid adenoma adjacent to the thyroid lobe. There was no evidence of an underlying multiple endocrine neoplasia. The patient was diagnosed with primary hyperparathyroidism. Fluid hydration, hydrocortisone, calcitonin, and bisphosphonates were initiated for acute hypercalcemia management before surgical excision of the left parathyroid adenoma. On review of previous blood work, a borderline calcium level of 2.72 was present 18 months before this admission. Two years postsurgery, she has normal renal function, calcium, and parathyroid hormone levels. The weekly visits to the emergency department for pain episodes decreased to 1 every 2 months within the first few months after her surgery. The decrease in pain episodes, even if it coincided with the treatment of primary hyperparathyroidism, may still reflect the natural evolution of sickle cell disease in this patient. However, the high morbidity associated with primary hyperparathyroidism was successfully prevented in this patient. Primary hyperparathyroidism is rare in childhood. In a recent study, it occurred more commonly in female adolescents and was because of a single adenoma, as in our patient. Significant morbidity, mainly secondary to renal dysfunction, was because of the delay in diagnosis after the onset of symptoms (2.0-4.2 years), emphasizing the need for a rapid diagnosis. Sickle cell disease affects approximately 1 of every 600 blacks in North America. Acute episodes of severe vaso-occlusive crisis account for > 90% of sickle cell-related hospitalizations and are a significant cause of morbidity in patients. There is no known association between sickle cell disease and primary hyperparathyroidism, and this case is most probably a random occurrence. However, as emphasized by this case report, pain may also be a harbinger of other disease processes in sickle cell disease. Because management may vary, we suggest that care providers consider the diagnosis of vaso-occlusive crisis as the diagnosis of exclusion and that other etiologies for pain be envisaged in this patient population, especially in the presence of prolonged pain or unusual clinical, radiologic, or biological findings.

Adverse Events in Sickle Cell Patients with Nocturnal Hypoxia.

The relationship between hemoglobin dexoygenation and sickling is well known. However, the relationship between hypoxia and severity of disease in sickle cell patients has not been well established. Recently, nocturnal hypoxemia has been associated with higher incidence of CNS events including strokes, and elevated TCDs. We present our case series on 13 patients(12 SS, 1 SC) with sickle cell disease (SCD) who have nocturnal hypoxia. Approximately 75 patients were screened at the University of Michigan Sickle Cell clinic for nocturnal hypoxia either by symptoms of obstructive sleep apnea or by longitudinal baseline clinic 02 saturations (02 Sat <92%). Of the 13 hypoxic pts, median baseline O2 Sat 90%(n=13, mean 90) and the median nocturnal O2sat (Nctnl 02 sat) 84%(n=13, mean 80%) with 10/13 with moderate-severe nocturnal hypoxia (O2sats<85%)based on sleep studies. Multiple adverse events noted in the cohort were pulmonary hypertension (PHTN TRJV>2.5, n=9, median 2.74/mean 2.74,) frequent pain episodes(>3visits to ER or hospitalizations/year, n=7, with 5 pts >5/year ), recurrent acute chest syndrome( ≥ 3 episodes, n= 10), CNS events (n=3 silent infarcts, vascular stenosis), priapism( (n=4, among 6 males ). Also reported were possible causes of the underlying hypoxia including obstructive sleep apnea(OSA)(n=7 of 11 pts), asthma(n= 10 of 13 pts), and chronic lung disease( n=8). In conclusion, the persistence of nocturnal hypoxia in pediatric sickle cell disease could possibly contribute to the development of severe complications of sickle cell disease. Treatment of underlying hypoxia (ie nighttime oxygen, maximize asthma treatment, T&A for OSA)may help prevent complications and lead to the improvement clinical symptoms. Further, chronic nocturnal hypoxia may complicate pulmonary disease and accelerated the development of PHTN. More studies are needed to clarify the mechanism of hypoxia in SCD.Table IClinical &Demographic Data of 13 SCD Patients with Nocturnal Hypoxia.Age:(6–22y/o, mean 15)Sex: M=6F=7Clinical:TotalMildModSev.Genotype: SS=12, SC=1MeanRangeNctnl Hypoxia(<%)1335(<85)5(<80)Baseline O2 Sat(%)90 +3.086–97Obstr Sleep Apnea7331Nctnl 02 sat (%)80+8.459–87Pulm HTN9441Total #Apneic Events(11)65.6+806–256Rest. Lung Ds.8251Obstr. Apneic Events(7)27+68.50–221# of Episodes<33–4>4Hypopneic Events(9)32.5+380–132ACS255TRJet Velocity2.74+.422–3.5Severe Pain Crises/yr125

Chronic Transfusion Therapy for Children With Sickle Cell Disease and Recurrent Acute Chest Syndrome

The objective was to study the effects of chronic transfusion therapy (CTX) on the prevention of new episodes of acute chest syndrome (ACS) in children with sickle cell disease (SCD) and recurrent or unusually severe ACS. A retrospective chart review was performed of patients given CTX for recurrent or severe ACS. Frequency, median severity score, and median hospital stay for ACS episodes were determined. Differences in these values before and during CTX were analyzed. Twenty-seven patients were identified. Before treatment, the ACS incidence was 1.3 episodes per patient-year; during treatment, it decreased to 0.1 episodes per patient-year (P < 0.0001). The median severity score for ACS episodes was 0.8 (range 0-5) before CTX and 0.5 (0-3) during CTX (P = 0.84). The median hospital stay was 5 days (range 3-15 days) before CTX and 3 days (2-7 days) during CTX (P = 0.38). CTX significantly reduces the incidence of ACS events among patients with a history of recurrent or severe episodes but does not significantly decrease their severity. The effectiveness of CTX should be prospectively compared with that of hydroxyurea and stem cell transplantation.

Therapeutic challenges in childhood sickle cell disease. Part 2: a problem-orientated approach.

The major clinical problems arising in children with severesickle cell disease are stroke, recurrent acute chest syn-drome and frequent, debilitating vaso-occlusive crises. Inthe second part of this review, we aim to provide anevidence-based, problem-orientated approach to the currentmanagement of these problems in children. We review therisks and benefits for the various therapies available for eachof these complications and provide evidence-based guide-lines on their management.INTRODUCTIONSickle cell disease (SCD) is the commonest haemoglobin-opathy and one of the commonest inherited diseases in theUK, affecting approximately 1 in 4000 live births every yearin England (Hickman et al, 1999). The most widely recog-nized complication is the painful crisis which accounts forover 90% of sickle-cell-related hospital admissions and is asignificant cause of morbidity in these patients (Platt et al,1994). However, the most important causes of prematuredeath and disability in SCD are the acute chest syndromeand sickle-related central nervous system (CNS) disease.Acute chest syndrome is the principal cause of mortalityboth in children and adults (Castro et al, 1994; Platt et al,1994). Fatal chest syndrome has an incidence of 12AE8 per100 patient-years (Castro et al, 1994) and accounts forapproximately one-third of sickle-related deaths (Gray et al,1991). Acute chest syndromes often recur and may lead tolong-term damage in the form of pulmonary fibrosis orchronic sickle cell lung disease (Powars et al, 1988). Strokeis the most disabling complication of SCD and also asignificant cause of death, accounting for about 6% ofsickle-cell-related deaths (Gray et al, 1991; Platt et al,1994). Approximately 10% of patients with SCD sufferfrom symptomatic infarction with paresis (Powars et al,1978; Ohene-Frempong et al, 1998) and twice as manyhave been shown to have silent infarction by modernneuroimaging techniques (Kinney et al, 1999; Powars et al,1999; Pegelow et al, 2002). If patients who have had aprevious stroke are untreated, two-thirds will experiencerecurrence (Powars et al, 1978).Although improved management of the disease hasprolonged survival in recent years (Lee et al, 1995), evenin the developed world the median survival of homozygouspatients has been estimated as 42 years for men and48 years for women (Platt et al, 1994). The mainstay ofmanagement is preventative and supportive care. Thegeneral management of SCD has been the subject of twoexcellent recent reviews (Castro, 1999; Steinberg, 1999).This review is the second of two parts; in Part 1,wereviewed the three principal current therapeutic modalitiesfor childhood SCD [blood transfusion, hydroxyurea andbone marrow transplantation (BMT)] and potential futuretreatments. In Part 2, we aim to provide an evidence-based,problem-orientated approach to the current management ofsevere SCD in childhood, focusing on the three problemsmost prevalent in paediatric practice in developed countries:sickle-related CNS disease, recurrent acute chest syndromeand frequent, debilitating vaso-occlusive crises.PROBLEM ORIENTATED APPROACHTO THE CHILD WITH SEVERE SCD:THE CHILD WITH STROKE AND⁄ OR OTHERFORMS OF SICKLE-RELATED CNS DISEASEStroke occurs in up to 6% of patients with SCD (Powarset al, 1978; Ohene-Frempong et al, 1998) with a peakincidence of first stroke between the ages of 2–9 years and asecond peak above the age of 30 years (Ohene-Fremponget al, 1998). The real prevalence of cerebrovascular diseasein these patients is even higher with subclinical lesionsdetected by magnetic resonance imaging (MRI) in around22% of patients with SCD (Pegelow et al, 2002). Many ofthese patients will not have reported symptoms but showreduced scores on formal neuropsychometric testing (Wanget al, 2001). Patients who have suffered one stroke have anover 60% risk of recurrence if untreated (Powars et al,1978). Thus, the main two clinical problems are:1. What is the best approach to preventing recurrence ofstroke?2. What is the best approach to preventing a first stroke inpatients with evidence of occult CNS disease revealed byDoppler studies and ⁄or MRI?The options for management are: hydroxyurea, bloodtransfusion and BMT.Hydroxyurea for sickle-related CNS disease in childrenAlthough some studies have reported patients with previousstroke who have remained free of new neurological man-ifestations on hydroxyurea therapy (Ferster et al, 2001),there is no convincing evidence that hydroxyurea reducesthe risk of stroke in SCD. Indeed both primary and recurrent

Therapeutic challenges in childhood sickle cell disease. Part 1: current and future treatment options.

Therapeutic challenges in childhood sickle cell disease. Part 1: current and future treatment options.

Predicting Adverse Outcomes in Sickle Cell Disease

Source: Miller ST, Sleeper LA, Pegelow CH, et al. Prediction of adverse outcomes in children with sickle cell disease. N Engl J Med. 2000;342:83–89.Knowing which children with sickle cell anemia are most likely to develop complications might help pediatricians to tailor therapy, counsel families, and design research studies for new treatments. Miller et al sought to determine early predictors of complications of sickle cell disease in a prospective study of 392 children followed from early infancy to about age 10. In multiple sites across the United States, 414 infants with homozygous sickle cell anemia or sickle cell–ß°-thalassemia were enrolled before age 6 months. Twenty-two (5%) were lost to follow-up. Of 392 remaining children, 70 (18%) had an adverse outcome, defined as death (n=18), stroke (n=25), frequent pain (average of 2 events/year, n=17), or recurrent acute chest syndrome (average of 1 episode/year, n=10). After multivariate analysis, 3 statistically significant predictors of future adverse outcome were: dactylitis before age 1 (relative risk, 2.55; 95% CI, 1.39 to 4.67); hemoglobin < 7 g/dL (relative risk, 2.47; 95% CI, 1.14 to 5.33); and leukocytosis in the absence of infection during well child visits (relative risk, 1.80; 95% CI, 1.05–3.09; median leukocyte count 13.7 ± 4.5 x 103). Elevated pocked-red-cell count before one year was predictive of severe disease, but was only measured in 40% of the cohort. In a comparison cohort, 20% of patients with severe disease were identified using a predictive model generated from these data, with a 1% false positive rate. The authors conclude that the risk of severe complications later in life can be predicted by features of sickle cell disease that can be readily detected in the first 2 years of life: dactylitis, severe anemia, and leukocytosis.Research on the pathophysiology of sickle cell anemia has been translated into clinical applications that have increased survival and improved quality of life, including prophylactic penicillin and vaccination to prevent sepsis and hydroxyurea to treat crises.1 New therapies such as stem cell transplantation offer hope for cure, but carry significant risks.2 These new therapies are most beneficial if employed early in life prior to the onset of significant organ damage. Therefore, we need ways to identify, early in life, those patients at risk for frequent pain, stroke, acute chest syndrome, or death. This study attempts to construct a predictive model to identify such children. The authors determined that 3 easily measured parameters—dactylitis, hemoglobin <7 g/dL and leukocytosis >13,000/cu.mm in the absence of infection—were predictive of severe disease. Elevated pocked-red-blood cell count was also predictive of severity in the 40% of patients in whom it was measured, but this test is not readily available. Leukocytosis may predict severity by reflecting damage to the vascular endothelium, related in part to abnormal leukocyte adhesions and/or release of cytotoxic enzymes, and by increasing platelet adhesion, which increases the risk of stroke.3–4To minimize the likelihood that a patient who would not develop severe disease would be referred for transplantation or undergo therapies that carry a significant risk, the authors adopted a classification that was associated with a low false positive rate. Using a predicted probability of severe disease of 36% derived from a receiver-operating-characteristic curve, their model has a sensitivity of 20% and a specificity of 99%. In other words, only about one-fifth of patients with severe disease would be identified, but only about 1% of patients identified as high risk would be misclassified. This model is potentially useful to clinicians managing patients for whom risky therapeutic interventions are contemplated.

Pulmonary function in sickle cell disease with or without acute chest syndrome.

Recurrent acute chest syndrome (ACS) has been suggested as a risk factor for chronic lung dysfunction in sickle cell disease. To investigate this hypothesis, lung function tests were performed in 49 sickle cell disease outpatients whose condition was stable, including 23 patients with a history of two to four episodes of ACS (ACS+) and 26 with no history of ACS (ACS-). The two groups were comparable regarding the sex ratio, body mass index, smoking history, physical characteristics, clinical history and usual lung function tests. Respiratory resistance (Rrs), measured using the forced oscillation technique, increased with the number of ACS episodes (r=0.55, p<0.0001) and a significant relationship was observed between Rrs as an independent variable and the expiratory flow rates at 25, 50 and 25-75% of the forced vital capacity as explanatory variables (r= 0.36, p<0.02; r=0.35, p<0.02; and r=0.4, p<0.006, respectively), with higher Rrs being associated with lower expiratory flow rates. The transfer factor (TL,CO) and transfer coefficient (KCO) for CO were significantly higher in the ACS+ group than in the ACS-group (TL,CO=84+/-4 versus 71+/-3%, p<0.004 and KCO=102+/-5 versus 90+/-3%, p<0.05, respectively). The data demonstrate that obstructive lung dysfunction is fairly common in sickle cell disease and suggest that recurrent acute chest syndrome may contribute specific obstructive defects. The increase in respiratory resistance associated with acute chest syndrome was accompanied by an increase in diffusion capacity, suggesting that it may have been related to an increase in lung blood volume.

Bone marrow transplantation for sickle cell disease.

Background We investigated the risks and benefits of allogeneic bone marrow transplantation in children with complications of sickle cell disease. Methods Twenty-two children less than 16 years of age who had symptomatic sickle cell disease received marrow allografts from HLA-identical siblings between September 1991 and April 1995. The indications for transplantation included a history of stroke (n = 12), recurrent acute chest syndrome (n = 5), and recurrent painful crises (n = 5). Patients were prepared for transplantation with busulfan, cyclophosphamide, and antithymocyte globulin. Results Twenty of the 22 patients survived, with a median follow-up of 23.9 months (range, 10.1 to 51.0), and 16 patients had stable engraftment of donor hematopoietic cells. In three patients the graft was rejected and sickle cell disease recurred; in a fourth patient graft rejection was accompanied by marrow aplasia. In 1 of the 16 patients with engraftment, there was stable mixed chimerism. Two patients died of central ne...