Standard management of sickle cell disease complications

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Available at www.sciencedirect.com

ScienceDirect journal homepage: www.elsevier.com/locate/hemonc

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REVIEW ARTICLE

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Standard management of sickle cell disease complications q

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Miguel R. Abboud

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Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon

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Received 21 November 2019; accepted 11 December 2019

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KEYWORDS Sickle cell disease; Acute chest syndrome; Hydroxyurea and transfusion

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Abstract Sickle cell disease remains a major public health concern in sub-Saharan Africa, Europe, and the United States. The survival rate of children and adolescents has increased immensely in developed countries, whereas the survival rate for adults lagged behind. The increase in the pediatric survival rate is attributable to the institution of hydroxyurea treatment as well as stroke prevention strategies. In this review, we discuss the management of the sickle disease major complications such as pain, stroke, and acute chest syndrome with the most current hydroxyurea use and transfusion therapy. Ó 2020 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acute clinical complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acute chest syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stroke. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chronic organ complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Transfusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Presented at the EBMT Pediatric Working Party Meeting, Regensburg Germany May 16–17, 2019. E-mail address: [email protected]

https://doi.org/10.1016/j.hemonc.2019.12.007 1658-3876/Ó 2020 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article as: M. R. Abboud, Standard management of sickle cell disease complications, Hematol Oncol Stem Cell Ther, https://doi. org/10.1016/j.hemonc.2019.12.007

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M.R. Abboud Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Transfusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hydroxyurea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . New therapeutic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Introduction

Pathophysiology

Sickle cell disease (SCD) refers to a number of inherited blood disorders that have in common the presence of sickle hemoglobin [1]. Sickled erythrocytes disrupt blood flow within the small vessels, and the resulting vaso-occlusion leads to distal tissue ischemia and inflammation, with acute symptoms, including painful events. Recurrent sickling leads to endothelial dysfunction and vasculopathy, which in turn results in chronic organ damage with substantial morbidity and early mortality. The survival of children with SCD in the developed world has improved significantly as a result of newborn screening programs, penicillin prophylaxis, pneumococcal immunization, and education of parents about disease complications (Fig. 1). Unfortunately, the projected life span of affected adults has not improved beyond the fifth decade of life [2]. The optimal use of existing therapies, such as hydroxyurea (HU) and transfusions, offers hope for decreased mortality and an improved quality of life, but these therapies are underutilized even in the developed world [3]. In the developing world, in particular sub-Saharan Africa, where most patients live, SCD is associated with high early childhood mortality and major morbidity. Better access to preventive strategies and drugs such as HU in the setting of both developed and developing countries is needed. Excellent reviews on SCD have been published recently [1,2]. In this brief review, we describe the pathophysiology of the disease, management of common problems including painful crises, acute chest syndrome (ACS), and stroke prevention, as well as the optimal use of existing therapeutic modalities such as HU and transfusions. We also discuss several novel therapies excluding gene therapy and stem cell transplantation, which are addressed elsewhere in the current issue.

SCD is caused by the inheritance of two abnormal beta-globin genes. The most common and severe form is homozygous HbSS, resulting from inheritance of the sickle mutation (HBB Glu6Val, bS) from both parents. Other forms of SCD include HbSC, HbS with beta-thalassemia (HbS/b0-thalassemia or HbS/b+-thalassemia), and HbS with other beta-globin variants that promote sickling such as HbSOArab or HbSD. The common feature of SCD is that erythrocytes undergo change of shape upon deoxygenation, because of the intracellular polymerization of sickle hemoglobin. These sickled erythrocytes cause vaso-occlusion. Repeated sickling leads to ischemia and inflammation, endothelial damage, as well as activation of adhesion molecules and the coagulation system [1].

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Acute clinical complications

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Pain Acute pain is the hallmark clinical feature of SCD, long supposed to be primarily caused by vaso-occlusion and impaired oxygen supply to distant bone and bone marrow. Pain is now thought to reflect hypoxia and ischemia–reperfusion injury. Pain in infants often present as dactylitis, but in older children and adults it affects the long bones in the extremities, as well as the chest and back. Non-steroidal antiinflammatory drugs and opioids are effective for the relief of acute pain, and guidelines exist to assist providers with the management of sickle pain [4]. Despite the recognition of chronic and acute pain in SCD for many years, access to care is not always easy for these patients. It has been recognized that patients with SCD suffering from acute pain experience longer waiting times in the setting of emergency departments [4], and that many physicians are not comfortable about managing sickle cell pain [5]. It is thus important that, short of dedicated facilities such as day hospitals for sickle cell care, institutions should have clear guidelines for the management of acute painful crises and trained staff that are familiar with the disease. This allows for more efficacious management of pain crises and decreases complications, such as ACS, that may develop after admission with painful VOC [6].

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Infections Bacterial infections remain frequent and serious complications of SCD. Sickling leads to functional asplenia that leaves affected children at risk for life-threatening infection, especially from encapsulated organisms such as Streptococcus pneumoniae, Neisseria meningitides, and Haemophilus influenzae type b. Immunization programs—including pneumococcal conjugate vaccines and the institution of prophylactic penicillin—have dramatically reduced

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Fig. 1

Please cite this article as: M. R. Abboud, Standard management of sickle cell disease complications, Hematol Oncol Stem Cell Ther, https://doi. org/10.1016/j.hemonc.2019.12.007

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the incidence of invasive pneumococcal disease in patients with SCD. These steps should be coupled with education of parents and other caregivers to seek immediate medical care and antibiotics for fever above 38.5 °C [1]. Acute chest syndrome A leading cause for death in adults [7], ACS is defined as the development of a new pulmonary infiltrate usually accompanied by fever, chest pain, tachypnea, wheezing, or cough. Antibiotics, oxygen, and blood transfusions are the mainstays of treatment [7,8]. The causes of ACS are multiple, ranging from infection, to hypoventilation secondary to over-sedation and chest pain, in addition to fat embolism from infarcted bones [7]. Studies to determine the etiology of ACS found that an infectious agent could be identified in 38% of cases [7]. Infections are more common in children than adults and are more common in winter. Mycoplasma pneumoniae and respiratory syncytial virus (RSV) are common in children, and chlamydia is most common in adults. Other bacterial and viral agents such as S. pneumoniae were also identified, and thus patients with ACS should be treated with antibiotic combinations that cover all of these organisms. A current recommendation includes ceftriaxone and a macrolide, but other combinations are also acceptable [9]. The role of blood transfusions has not been formally investigated in the setting of ACS, but there are significant data from observational and case–control studies that transfusions are effective in severe cases of ACS. Both simple and exchange transfusions have been used, and there are no clear guidelines as to when exchange is preferred, but most investigators use exchange transfusion for severe cases with rapid progression [9]. Preoperative transfusions, as part of a detailed protocol of management, may have a role in preventing the development of ACS postoperatively [10,11]. Other modalities such as a noninvasive high flow ventilation have recently been demonstrated to also be effective in the management of ACS and in decreasing the need to transfusions [12]. It is important to highlight here that institutional guidelines for the management of ACS should be developed, and providers familiar with the management of this complication should be involved in the care of these patients. Given the high risk of mortality and complications associated with ACS, such as stroke, acute kidney injury and posterior reversible encephalopathy [13], it seems obvious that we also need to focus on prevention as well as treatment of these complications. Treatment with HU has been demonstrated to be effective in preventing recurrent episodes of ACS in both adults and children [14,15] as well as chronic transfusion therapy and stem cell transplantation [10,11]. In this context, the implementation of standards of care, with attention to fluid balance, oxygenation, pain management, and incentive spirometry, has been demonstrated to prevent the development of ACS in patients admitted for painful crises [6]. Stroke Stroke is a leading cause of disability in SCD. Ischemic stroke occurs primarily in childhood, whereas cerebral hemorrhage occurs primarily in the third and fourth decades of life [16].

3 Natural history studies have shown that strokes will develop in 5–10% of children [10]. Once an acute stroke develops, an exchange transfusion should be performed without delay. After a stroke there is a high likelihood of recurrence, unless transfusion regimens are instituted to prevent recurrent strokes. Primary stroke prevention of ischemic strokes in children can be achieved using transcranial Doppler (TCD) screening and the institution of chronic transfusion for patients at high risk for stroke defined by elevated cerebral blood velocities. Transfusion therapy in this setting may be replaced by HU if TCD velocities normalize [17]. Despite the well-documented efficacy of TCD screening in controlled studies, however, recent data show that in TCD screening rates have fallen since the initial STOP and STOP II studies exposing an increasing number of children to this devastating complication [18].

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Chronic organ complications

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Compared to the management of acute events, relatively little is known about the pathogenesis of chronic organ damage. Most patients with SCD who survive into adulthood reach a stage when chronic organ complications become the main causes of morbidity and mortality. Organ damage develops in multiple systems through different mechanisms, and virtually every organ system can be affected. Complications such as retinopathy, avascular necrosis, leg ulcers, and priapism are all associated with significant morbidity and poor quality of life, but renal dysfunction and cardiopulmonary disease are mainly responsible for the increased mortality. Although cardiac iron overload is not usually seen in SCD, iron deposition caused by chronic or sporadic transfusion may be a factor in the development of sickle-related liver disease. Management of specific chronic organ damage is complicated, and for further information on the subject, the reader is referred to several recent reviews [1,19–21].

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Therapy

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Transfusions

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One of the mainstays of treatment for SCD is transfusions, and most of the affected adults are estimated to have received at least one transfusion. Transfusions can be given acutely to increase oxygen-carrying capacity and improve blood flow in the setting of severe anemia. This is usually accomplished using simple or top transfusions. By contrast, chronic blood transfusions are provided to prevent longterm complications and are done either by regular monthly simple or exchange transfusion (Table 1). The main clinical indications for an acute transfusion include correction of anemia, acute organ damage (such as ACS), and preoperatively. Other indications for transfusions are summarized in Tables 1 and 2. Despite their proven benefits, transfusions have complications that limit their long-term use. These include erythrocyte alloimmunization, which occurs because of discrepancies in blood group antigens between donors and recipients. In particular, life-threatening complications of alloimmunization include delayed hemolytic transfusion reactions [22]. Even serological matching for ABO, RhD, C,

Please cite this article as: M. R. Abboud, Standard management of sickle cell disease complications, Hematol Oncol Stem Cell Ther, https://doi. org/10.1016/j.hemonc.2019.12.007

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M.R. Abboud Table 1

Transfusion indications (Adapted from Ohene-Frempong,22 Stuart and Nagel,23 and Vichinsky24).

Indications for transfusion therapy in SCD Acute/episodic          

Long-term management       

Anemia Splenic sequestration Severe or long-lasting aplastic crises Malaria-associated severe hemolytic anemia Stroke Acute chest syndrome Preoperative (selected cases) Multiple-organ failure syndrome Acute multiple-organ failure syndrome Priapism

Prophylaxis against recurrent stroke Prevention of first episode of stroke in high-risk pediatric patients Heart failure Chronic pulmonary hypertension Chronic pain in hydroxyurea non-responders Previous splenic sequestration in children aged 2–3 years Short program: pregnancy

SCD = sickle cell disease.

Table 2 Benefits and Risks of Transfusions (Adapted from Pirenne and Yazdanbakhsh [22] and Balbuena-Merle and Hendrickson [26]). Transfusion therapy for prevention of complications in SCD Transfusions are effective for prevention of complications in SCD 1. Indications include: a. ACS b. Stroke c. Severe anemia d. Aplastic crises e. Sequestration f. Preoperative preparation 2. Associated risks are: a. Alloimmunization b. Delayed hemolytic reaction c. Transfusion reactions d. Hyperviscosity e. Iron overload ACS = acute chest syndrome; SCD = sickle cell disease.

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and E, and K antigens may not prevent a high rate of alloimmunization in SCD, which occurs mostly from RH gene variants with reduced antigenic expression [11–27]. Matching donors by race does not lower the incidence, as variant

RH alleles are common in persons with African ancestry [28]. However, targeting these individuals for donation will increase the available pool of suitable donors. Systematic, extended, and even molecular genotyping of blood group antigens are now being implemented in some centers. These techniques should be more widely used [27–29]. Worsening of anemia can be related to acute splenic sequestration crisis in children [30], transient red cell aplasia caused by parvovirus infection, or increased hemolysis in patients with pain or infection. In treating severe anemia, simple transfusion should correct the hemoglobin concentration only to the baseline, but not attempt to reach a normal level as this may be complicated by hyperviscosity [11].

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Hydroxyurea

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Higher levels of fetal hemoglobin (HbF) are clinically associated with reduced morbidity and mortality in patients with SCD since residual HbF is protective against intracellular HbS polymerization. Studies have shown significant positive effects of HU inducing increased HbF production and preventing vaso-occlusion in patients with SCD [14,15,31,32] since HU inhibits ribonucleotide reductase. HbF induction maybe also impacted through different pathways including guanylyl cyclase [32] and stress erythropoiesis resulting from its effect on the cell cycle [33].

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Table 3 BABY HUG

N Pain ACS Dactylitis Hospitalizationa Transfusionb

MSH

HU

PL

96 177 8 24 232 35

97 372 27 123 321 60

p

HU

PL

p

0.002 0.017 <0.001 0.050 0.033

152 2.5/y 25 – 1.0/y 48

147 4.5/y 51 – 2.4/y 73

<0.001 <0.001 – – 0.001

Data indicate number of episodes.ACS = acute chest syndrome; HU = hydroxyurea; MSH = ; PL = . Adapted from Charache et al. [14] and Wang et al. [15]. a In BABY HUG, all hospitalizations; in MSH, hospitalizations for pain only. b In BABY HUG, number of transfusions, in MSH, number of patients receiving transfusion. Please cite this article as: M. R. Abboud, Standard management of sickle cell disease complications, Hematol Oncol Stem Cell Ther, https://doi. org/10.1016/j.hemonc.2019.12.007

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Standard management of SCD complications Table 4

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Benefits of hydroxyurea [14].

Potential to increase HbF Have salutary effects on the adverse risk factors Phase 3 randomized trial 299 adults, 21 centers Decreased rate of painful crises by 50% Decreased rates of hospitalization for pain or ACS and decreased numbers transfusions Led to FDA approval of hydroxyurea ACS = acute chest Administration.

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syndrome;

FDA = US

Food

and

(95% confidence interval [CI], 135–142 cm/s) on the HU treatment arm compared to 143 cm/s (95% CI, 140– 146 cm/s on transfusions), noninferiority p = 8.82  10–19 [30]. In contrast to primary prevention, patients who had suffered a stroke need to remain on chronic transfusions and chelation, but selected patients may be converted to HU if they have mild vessel disease and/or cannot be maintained on chronic transfusions [35,36] (Table 5).

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New therapeutic agents

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Recently, L-glutamine was approved for the prevention of pain crises and vaso-occlusive events in patients with SCD based on a randomized phase III trial [38]. Patients who received L-glutamine experienced a reduction in the number of painful episodes and longer time to experience a painful crisis [38]. It is nonetheless unclear whether only the pharmacological grade glutamine used in the trial is effective, and there are other unanswered questions [39]. In conclusion, standard therapy has led to improved survival and decreased morbidity in patients with SCD. Significant effort should focus on improving access to these modalities. Recent advances in stem cell transplantation, the development of new therapeutic agents, and gene therapy will further improve the lives of patients with SCD.

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Drug

In children, it was shown through a phase I/II trial of 84 children with SCD that HU at a median 25.6 mg/kg/day was successful in reducing painful crisis and organ damage and was well tolerated [32] with sustained benefit and no long-term toxicity. In the BABY HUG multicenter randomized placebo-controlled phase III trial, which involved a total of 213 infants aged 9–18 months at enrolment, the results did not show preserved organ function, and no significant difference in qualitative splenic uptake or glomerular filtration rate (Table 3). However, other beneficial effects of HU treatment were significant including reduced rates of pain, dactylitis, transfusions, and hospitalizations (all p < .001) [15]. These results are in line with what had been previously reported in the adult randomized placebo-controlled phase III trial conducted on 299 adults [14], which showed that HU is well tolerated using once daily oral administration, with few short-term side effects (Table 4). A primary end point of 44% reduction in the median rate of painful crisis with HU treatment (2.5 vs. 4.5 events per year; p < .001). Secondary end points also showed significant differences in time to first and second crises, episodes of ACS, and number of transfusions and hospitalizations. Recently, the use of HU was shown to be safe and effective in children in sub-Saharan Africa. This study, which involved a total of 635 children, demonstrated that all complications caused by SCD were decreased, and there was a significant decrease in mortality among children with SCD on HU (15–20 mg/kg body weight/day for 6 months, followed by dose escalation) [34]. The TWiTCH multicenter randomized phase III trial compared HU with phlebotomy to transfusions with chelation for primary stroke prevention and management of iron overload. The noninferiority primary end point of the TWiTCH trial was met with an average TCD velocity of 138 cm/s

Table 5 Toxicity of hydroxyurea compared with standard care [37]. Toxicity

Outcome

Level of evidence

Leg ulcers Leukemia Other cancers Spermatogenesis Pregnancy

Comparable Comparable Comparable Defects Comparable

High Low Low Insufficient Insufficient

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Please cite this article as: M. R. Abboud, Standard management of sickle cell disease complications, Hematol Oncol Stem Cell Ther, https://doi. org/10.1016/j.hemonc.2019.12.007

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