Estcourt Lise J, Kimber Catherine, Hopewell Sally, Trivella Marialena, Doree Carolyn, Abboud Miguel R
NHS Blood and Transplant, Haematology/Transfusion Medicine, Level 2, John Radcliffe Hospital, Headington, Oxford, UK, OX3 9BQ.
Systematic Review Initiative, NHS Blood and Transplant, Oxford, UK.
Cochrane Database Syst Rev. 2020 Apr 6;4(4):CD012389. doi: 10.1002/14651858.CD012389.pub3.
Sickle cell disease (SCD) is one of the commonest severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta globin) genes. SCD can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Silent cerebral infarcts are the commonest neurological complication in children and probably adults with SCD. Silent cerebral infarcts also affect academic performance, increase cognitive deficits and may lower intelligence quotient.
To assess the effectiveness of interventions to reduce or prevent silent cerebral infarcts in people with SCD.
We searched for relevant trials in the Cochrane Library, MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1980), and ongoing trial databases; all searches current to 14 November 2019. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register: 07 October 2019.
Randomised controlled trials comparing interventions to prevent silent cerebral infarcts in people with SCD. There were no restrictions by outcomes examined, language or publication status.
We used standard Cochrane methodological procedures.
We included five trials (660 children or adolescents) published between 1998 and 2016. Four of the five trials were terminated early. The vast majority of participants had the haemoglobin (Hb)SS form of SCD. One trial focused on preventing silent cerebral infarcts or stroke; three trials were for primary stroke prevention and one trial dealt with secondary stroke prevention. Three trials compared the use of regular long-term red blood cell transfusions to standard care. Two of these trials included children with no previous long-term transfusions: one in children with normal transcranial doppler (TCD) velocities; and one in children with abnormal TCD velocities. The third trial included children and adolescents on long-term transfusion. Two trials compared the drug hydroxyurea and phlebotomy to long-term transfusions and iron chelation therapy: one in primary prevention (children), and one in secondary prevention (children and adolescents). The quality of the evidence was moderate to very low across different outcomes according to GRADE methodology. This was due to trials being at high risk of bias because they were unblinded; indirectness (available evidence was only for children with HbSS); and imprecise outcome estimates. Long-term red blood cell transfusions versus standard care Children with no previous long-term transfusions and higher risk of stroke (abnormal TCD velocities or previous history of silent cerebral infarcts) Long-term red blood cell transfusions may reduce the incidence of silent cerebral infarcts in children with abnormal TCD velocities, risk ratio (RR) 0.11 (95% confidence interval (CI) 0.02 to 0.86) (one trial, 124 participants, low-quality evidence); but make little or no difference to the incidence of silent cerebral infarcts in children with previous silent cerebral infarcts on magnetic resonance imaging and normal or conditional TCDs, RR 0.70 (95% CI 0.23 to 2.13) (one trial, 196 participants, low-quality evidence). No deaths were reported in either trial. Long-term red blood cell transfusions may reduce the incidence of: acute chest syndrome, RR 0.24 (95% CI 0.12 to 0.49) (two trials, 326 participants, low-quality evidence); and painful crisis, RR 0.63 (95% CI 0.42 to 0.95) (two trials, 326 participants, low-quality evidence); and probably reduces the incidence of clinical stroke, RR 0.12 (95% CI 0.03 to 0.49) (two trials, 326 participants, moderate-quality evidence). Long-term red blood cell transfusions may improve quality of life in children with previous silent cerebral infarcts (difference estimate -0.54; 95% confidence interval -0.92 to -0.17; one trial; 166 participants), but may have no effect on cognitive function (least squares means: 1.7, 95% CI -1.1 to 4.4) (one trial, 166 participants, low-quality evidence). Transfusions continued versus transfusions halted: children and adolescents with normalised TCD velocities (79 participants; one trial) Continuing red blood cell transfusions may reduce the incidence of silent cerebral infarcts, RR 0.29 (95% CI 0.09 to 0.97 (low-quality evidence). We are very uncertain whether continuing red blood cell transfusions has any effect on all-cause mortality, Peto odds ratio (OR) 8.00 (95% CI 0.16 to 404.12); or clinical stroke, RR 0.22 (95% CI 0.01 to 4.35) (very low-quality evidence). The trial did not report: comparative numbers for SCD-related adverse events; quality of life; or cognitive function. Hydroxyurea and phlebotomy versus transfusions and chelation Primary prevention, children (121 participants; one trial) We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: silent cerebral infarcts (no infarcts); all-cause mortality (no deaths); risk of stroke (no strokes); or SCD-related complications, RR 1.52 (95% CI 0.58 to 4.02) (very low-quality evidence). Secondary prevention, children and adolescents with a history of stroke (133 participants; one trial) We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: silent cerebral infarcts, Peto OR 7.28 (95% CI 0.14 to 366.91); all-cause mortality, Peto OR 1.02 (95%CI 0.06 to 16.41); or clinical stroke, RR 14.78 (95% CI 0.86 to 253.66) (very low-quality evidence). Switching to hydroxyurea and phlebotomy may increase the risk of SCD-related complications, RR 3.10 (95% CI 1.42 to 6.75) (low-quality evidence). Neither trial reported on quality of life or cognitive function.
AUTHORS' CONCLUSIONS: We identified no trials for preventing silent cerebral infarcts in adults, or in children who do not have HbSS SCD. Long-term red blood cell transfusions may reduce the incidence of silent cerebral infarcts in children with abnormal TCD velocities, but may have little or no effect on children with normal TCD velocities. In children who are at higher risk of stroke and have not had previous long-term transfusions, long-term red blood cell transfusions probably reduce the risk of stroke, and other SCD-related complications (acute chest syndrome and painful crises). In children and adolescents at high risk of stroke whose TCD velocities have normalised, continuing red blood cell transfusions may reduce the risk of silent cerebral infarcts. No treatment duration threshold has been established for stopping transfusions. Switching to hydroxyurea with phlebotomy may increase the risk of silent cerebral infarcts and SCD-related serious adverse events in secondary stroke prevention. All other evidence in this review is of very low-quality.
镰状细胞病（SCD）是世界上最常见的严重单基因疾病之一，由两个异常血红蛋白（β珠蛋白）基因遗传所致。SCD可导致严重疼痛、显著的终末器官损害、肺部并发症和过早死亡。无症状脑梗死是儿童以及可能成年SCD患者中最常见的神经并发症。无症状脑梗死还会影响学业成绩，增加认知缺陷，并可能降低智商。
评估减少或预防SCD患者无症状脑梗死的干预措施的有效性。
我们在Cochrane图书馆、MEDLINE（1946年起）、Embase（1974年起）、输血证据图书馆（1980年起）以及正在进行的试验数据库中检索相关试验；所有检索截至2019年11月14日。我们检索了Cochrane囊性纤维化和遗传疾病小组试验注册库：2019年10月7日。
比较预防SCD患者无症状脑梗死干预措施的随机对照试验。对所检查的结局、语言或发表状态没有限制。
我们采用标准的Cochrane方法学程序。
我们纳入了1998年至2016年间发表的5项试验（660名儿童或青少年）。5项试验中有4项提前终止。绝大多数参与者患有SCD的血红蛋白（Hb）SS型。1项试验侧重于预防无症状脑梗死或中风；3项试验用于一级中风预防，1项试验用于二级中风预防。3项试验比较了定期长期红细胞输血与标准治疗。其中2项试验纳入了此前未进行长期输血的儿童：1项针对经颅多普勒（TCD）速度正常的儿童；另1项针对TCD速度异常的儿童。第3项试验纳入了接受长期输血的儿童和青少年。2项试验比较了药物羟基脲和放血疗法与长期输血和铁螯合疗法：1项用于一级预防（儿童），1项用于二级预防（儿童和青少年）。根据GRADE方法，不同结局的证据质量为中度至极低。这是由于试验存在高偏倚风险，因为它们未设盲；间接性（现有证据仅针对HbSS型儿童）；以及结局估计不精确。长期红细胞输血与标准治疗 此前未进行长期输血且中风风险较高（TCD速度异常或有既往无症状脑梗死病史）的儿童 长期红细胞输血可能降低TCD速度异常儿童无症状脑梗死的发生率，风险比（RR）为0.11（95%置信区间（CI）0.02至0.86）（1项试验，124名参与者，低质量证据）；但对磁共振成像显示有既往无症状脑梗死且TCD正常或有条件正常的儿童无症状脑梗死的发生率影响很小或无影响，RR为0.70（95%CI 0.23至2.13）（1项试验，196名参与者，低质量证据）。两项试验均未报告死亡情况。长期红细胞输血可能降低以下发生率：急性胸综合征，RR为0.24（95%CI 0.12至0.49）（2项试验，326名参与者，低质量证据）；以及疼痛性危机，RR为0.63（9%CI 0.42至0.95）（2项试验，326名参与者，低质量证据）；并且可能降低临床中风的发生率，RR为0.12（95%CI 0.03至0.49）（2项试验，326名参与者，中等质量证据）。长期红细胞输血可能改善有既往无症状脑梗死儿童的生活质量（差异估计值 -0.54；95%置信区间 -0.92至 -0.17；1项试验；166名参与者），但可能对认知功能无影响（最小二乘均值：1.7，95%CI -1.1至4.4）（1项试验，166名参与者，低质量证据）。输血持续与输血停止：TCD速度已恢复正常的儿童和青少年（79名参与者；1项试验） 继续进行红细胞输血可能降低无症状脑梗死的发生率，RR为0.29（95%CI 0.09至0.97）（低质量证据）。我们非常不确定继续进行红细胞输血对全因死亡率是否有任何影响，Peto比值比（OR）为8.00（95%CI 0.16至404.12）；或对临床中风是否有影响，RR为0.22（95%CI 0.01至4.35）（极低质量证据）。该试验未报告：SCD相关不良事件的比较数据；生活质量；或认知功能。羟基脲和放血疗法与输血和螯合疗法 一级预防，儿童（121名参与者；1项试验） 我们非常不确定改用羟基脲和放血疗法对以下方面是否有任何影响：无症状脑梗死（无梗死）；全因死亡率（无死亡）；中风风险（无中风）；或SCD相关并发症，RR为1.52（95%CI 0.58至4.02）（极低质量证据）。二级预防，有中风病史的儿童和青少年（133名参与者；1项试验） 我们非常不确定改用羟基脲和放血疗法对以下方面是否有任何影响：无症状脑梗死，Peto OR为7.28（95%CI 0.14至366.91）；全因死亡率，Peto OR为1.02（95%CI 0.06至16.41）；或临床中风，RR为14.78（95%CI 0.86至253.66）（极低质量证据）。改用羟基脲和放血疗法可能增加SCD相关并发症的风险，RR为3.10（95%CI 1.42至6.75）（低质量证据）。两项试验均未报告生活质量或认知功能。
我们未找到预防成人或非HbSS型SCD儿童无症状脑梗死的试验。长期红细胞输血可能降低TCD速度异常儿童无症状脑梗死的发生率，但对TCD速度正常的儿童可能影响很小或无影响。在中风风险较高且此前未进行长期输血的儿童中，长期红细胞输血可能降低中风风险以及其他SCD相关并发症（急性胸综合征和疼痛性危机）的风险。在中风风险较高且TCD速度已恢复正常的儿童和青少年中，继续进行红细胞输血可能降低无症状脑梗死的风险。尚未确定停止输血的治疗持续时间阈值。在二级中风预防中改用羟基脲加放血疗法可能增加无症状脑梗死和SCD相关严重不良事件的风险。本综述中的所有其他证据质量都非常低。
