SNAP: Supportive non-invasive ventilation for acute chest syndrome prevention for hospitalized children with sickle cell disease: Perspectives of patients, parents, and the healthcare team.

RATIONALE: Acute chest syndrome (ACS) often develops during hospitalizations for sickle cell disease (SCD) vaso-occlusive episodes and may be triggered by a combination of chest wall splinting, opioid use, hypoventilation, and atelectasis. In 2017, Boston Medical Center's general pediatric inpatient unit instituted the novel use of bi-level positive airway pressure (BiPAP) as "supportive non-invasive ventilation for ACS prevention" (SNAP) to prevent ACS and respiratory decompensation. OBJECTIVE: The goals of this qualitative study were to identify perceived benefits, harms, facilitators, and barriers to use of SNAP. METHODS: We conducted semi-structured key informant interviews at three sites with different levels of SNAP implementation (Site 1: extensive implementation; Site 2: limited implementation; Site 3: not yet implemented) regarding experiences with and/or perceptions of SNAP. Interviews and coding were guided by the Promoting Action on Research Implementation in Health Services (PARiHS) framework. RESULTS: Thirty-four participants (physicians, nurses, respiratory therapists, child life specialists, psychologists, youth with SCD, and parents) completed interviews. Major themes included: (i) participants perceive BiPAP as effective at preventing ACS, and for those with medically stable ACS, for preventing respiratory decompensation. (ii) BiPAP use is appropriate on the general pediatric inpatient unit for medically stable patients with SCD. (iii) Improving the patient experience is the most important factor to optimize acceptance of BiPAP by patients and families. CONCLUSION/FUTURE DIRECTIONS: SNAP is perceived as effective and appropriate for hospitalized pediatric patients with SCD. Improving the patient experience is the biggest challenge. These data will inform a future protocol for a multicenter hybrid effectiveness/implementation trial of SNAP.

Indications for transfusion in the management of sickle cell disease.

The transfusion of red blood cells (RBCs) is a crucial treatment for sickle cell disease (SCD). While often beneficial, the frequent use of transfusions is associated with numerous complications. Transfusions should be offered with specific guidelines in mind. Here we present updates to the indications for transfusion of RBCs in SCD. We review recent publications and include expert perspectives from hematology and transfusion medicine. For some clinical indications, such as ischemic stroke, the role of transfusion has been well studied and can be applied almost universally. For many other clinical scenarios, the use of transfusion therapy has less conclusive data and therefore must be tailored to individual needs. We highlight the roles of RBC transfusions in preventing or mitigating neurological disease, in reducing perioperative complications, in managing acute chest syndrome, and in optimizing pregnancy outcomes in SCD. We further highlight various transfusion techniques and when each might be considered. Potential complications of transfusion are also briefly discussed.

SNAP: Supportive noninvasive ventilation for acute chest syndrome prevention in children with sickle cell disease.

BACKGROUND: Acute chest syndrome (ACS) is a leading cause of morbidity and mortality among children with sickle cell disease (SCD). Preventing hypoxemia by optimizing lung aeration during sleep remains a challenge. OBJECTIVES: To explore safety, feasibility, and tolerability of noninvasive, bi-level positive airway pressure ventilation (BiPAP) as preventative, supportive care for hospitalized, medically stable children with SCD on a general pediatric inpatient unit. METHODS: Retrospective chart review of patients ≤22 years of age with SCD admitted to the general pediatric inpatient unit from February 1, 2017 to March 1, 2020 for whom BiPAP was recommended as supportive care. Hospitalizations were excluded if patients were admitted to the pediatric intensive care unit (PICU), required BiPAP for respiratory failure, or used BiPAP at home for obstructive sleep apnea. RESULTS: Twenty-three patients had 53 hospitalizations in which BiPAP was recommended. Fifty-two (98%) hospitalizations included acute SCD pain. Indications for BiPAP included prior ACS (94%), chest or back pain (79%), and/or oxygen desaturation (66%). On 17 occasions, patients already had mild to moderate ACS but were stable when BiPAP was recommended. BiPAP was used successfully during 75% of hospitalizations for a median of two nights. There were no adverse effects associated with BiPAP. PICU transfer for respiratory support occurred during three hospitalizations. In 26 hospitalizations of children at risk for ACS who tolerated BiPAP, 23 (88%) did not develop ACS. CONCLUSIONS: BiPAP is safe, feasible, and well tolerated as supportive care for hospitalized children with SCD. Next steps include an intervention trial to further assess the efficacy of BiPAP on ACS prevention.

Augmented NRF2 activation protects adult sickle mice from lethal acute chest syndrome.

Acute chest syndrome (ACS) mortality in sickle cell disease (SCD) rises sharply in young adult patients and mechanism-based prophylaxis is lacking. In SCD, haem oxygenase-1 (HO-1) declines with age and ACS is associated with low HO-1. To test if enhanced HO-1 can reduce ACS mortality, young SCD mice were treated with D3T (3H-1,2-dithiole-3-thione), an activator of nuclear-factor erythroid 2 like 2, which controls HO-1 expression, for 3 months. Following haem-induced ACS, all vehicle-treated mice succumbed to severe lung injury, while D3T-treated mice had significantly improved survival. Blocking HO-1 activity abrogated the D3T effect. Thus HO-1 may be targeted to reduce ACS severity in adult patients.

Randomized phase 2 trial of monthly vitamin D to prevent respiratory complications in children with sickle cell disease.

In sickle cell disease, respiratory infection and asthma may lead to respiratory complications that are a leading cause of morbidity and mortality. Vitamin D has anti-infective and immunomodulatory effects that may decrease the risk for respiratory infections, asthma, and acute chest syndrome. We conducted a randomized double-blind active-controlled clinical trial to determine whether monthly oral vitamin D3 can reduce the rate of respiratory events in children with sickle cell disease. Seventy sickle cell subjects, ages 3-20 years, with baseline records of respiratory events over 1 year before randomization, underwent screening. Sixty-two subjects with 25-hydroxyvitamin D levels of 5-60 ng/mL were randomly assigned to oral vitamin D3 (100 000 IU or 12 000 IU, n = 31 each) under observed administration once monthly for 2 years. The primary outcome was the annual rate of respiratory events (respiratory infection, asthma exacerbation, or acute chest syndrome) ascertained by the use of a validated questionnaire administered biweekly. Analysis included 62 children (mean age of 9.9 years, 52% female, and predominantly with homozygous HbS disease [87%]) with mean baseline 25-hydroxyvitamin D of 14.3 ng/mL. The annual rates of respiratory events at baseline and intervention years 1 and 2 were 4.34 ± 0.35, 4.28 ± 0.36, and 1.49 ± 0.37 (high dose) and 3.91 ± 0.35, 3.34 ± 0.37, and 1.54 ± 0.37 (standard dose), respectively. In pediatric patients with sickle cell disease, 2-year monthly oral vitamin D3 was associated with a >50% reduction in the rate of respiratory illness during the second year (P = .0005), with similar decreases associated with high- and standard-dose treatment. This trial was registered at www.clinicaltrials.gov as #NCT01443728.

Acute chest syndrome in sickle cell disease.

Acute chest syndrome (ACS) is a leading complication of sickle cell disease (SCD) with significant morbidity and mortality. ACS is the most common cause of death and the second most common cause of hospitalization in patients with SCD. Delineating the specific cause of ACS is often difficult, and multiple risk factors that precipitate ACS frequently coexist. The prominent risk factors include infection, hypoxia, bronchial hyperresponsiveness, the SCD genotype, and opioid use. The key to the successful treatment of ACS is early recognition and initiation of treatment without delay. The main goal is to prevent and treat acute respiratory failure and, thus, minimize irreversible lung damage. This review focuses on the risk factors, pathogenesis, clinical presentation, and management of ACS.

Lung vaso-occlusion in sickle cell disease mediated by arteriolar neutrophil-platelet microemboli.

In patients with sickle cell disease (SCD), the polymerization of intraerythrocytic hemoglobin S promotes downstream vaso-occlusive events in the microvasculature. While vaso-occlusion is known to occur in the lung, often in the context of systemic vaso-occlusive crisis and the acute chest syndrome, the pathophysiological mechanisms that incite lung injury are unknown. We used intravital microscopy of the lung in transgenic humanized SCD mice to monitor acute vaso-occlusive events following an acute dose of systemic lipopolysaccharide sufficient to trigger events in SCD but not control mice. We observed cellular microembolism of precapillary pulmonary arteriolar bottlenecks by neutrophil-platelet aggregates. Blood from SCD patients was next studied under flow in an in vitro microfluidic system. Similar to the pulmonary circulation, circulating platelets nucleated around arrested neutrophils, translating to a greater number and duration of neutrophil-platelet interactions compared with normal human blood. Inhibition of platelet P-selectin with function-blocking antibody attenuated the neutrophil-platelet interactions in SCD patient blood in vitro and resolved pulmonary arteriole microembolism in SCD mice in vivo. These results establish the relevance of neutrophil-platelet aggregate formation in lung arterioles in promoting lung vaso-occlusion in SCD and highlight the therapeutic potential of targeting platelet adhesion molecules to prevent acute chest syndrome.

The intersection between asthma and acute chest syndrome in children with sickle-cell anaemia.

Acute chest syndrome is a frequent cause of acute lung disease in children with sickle-cell disease. Asthma is common in children with sickle-cell disease and is associated with increased incidence of vaso-occlusive pain events, acute chest syndrome episodes, and earlier death. Risk factors for asthma exacerbation and an acute chest syndrome episode are similar, and both can present with shortness of breath, chest pain, cough, and wheezing. Despite overlapping risk factors and symptoms, an acute exacerbation of asthma or an episode of acute chest syndrome are two distinct entities that need disease-specific management strategies. Although understanding has increased about asthma as a comorbidity in sickle-cell disease and its effects on morbidity, substantial gaps remain in knowledge about best management.

A Multinational Trial of Prasugrel for Sickle Cell Vaso-Occlusive Events.

BACKGROUND: Sickle cell anemia is an inherited blood disorder that is characterized by painful vaso-occlusive crises, for which there are few treatment options. Platelets mediate intercellular adhesion and thrombosis during vaso-occlusion in sickle cell anemia, which suggests a role for antiplatelet agents in modifying disease events. METHODS: Children and adolescents 2 through 17 years of age with sickle cell anemia were randomly assigned to receive oral prasugrel or placebo for 9 to 24 months. The primary end point was the rate of vaso-occlusive crisis, a composite of painful crisis or acute chest syndrome. The secondary end points were the rate of sickle cell-related pain and the intensity of pain, which were assessed daily with the use of pain diaries. RESULTS: A total of 341 patients underwent randomization at 51 sites in 13 countries across the Americas, Europe, Asia, and Africa. The rate of vaso-occlusive crisis events per person-year was 2.30 in the prasugrel group and 2.77 in the placebo group (rate ratio, 0.83; 95% confidence interval, 0.66 to 1.05; P=0.12). There were no significant differences between the groups in the secondary end points of diary-reported events. The safety end points, including the frequency of bleeding events requiring medical intervention, of hemorrhagic and nonhemorrhagic adverse events that occurred while patients were taking prasugrel or placebo, and of discontinuations due to prasugrel or placebo, did not differ significantly between the groups. CONCLUSIONS: Among children and adolescents with sickle cell anemia, the rate of vaso-occlusive crisis was not significantly lower among those who received prasugrel than among those who received placebo. There were no significant between-group differences in the safety findings. (Funded by Daiichi Sankyo and Eli Lilly; ClinicalTrials.gov number, NCT01794000.).

Transfusion therapy for sickle cell disease: a balancing act.

Transfusion therapy is a key intervention in decreasing morbidity and mortality in patients with sickle cell disease (SCD). Current indications for acute and chronic transfusion therapy have significantly increased the number of RBC units transfused to patients with SCD worldwide. This review summarizes transfusion management for the treatment or prevention of neurologic and perioperative complications, acute chest syndrome, and acute anemia associated with SCD. Despite the recognized benefits of transfusion therapy, it is not without the risks of iron overload, alloimmunization, and delayed hemolytic transfusion reactions. Transfusional iron overload management includes automated RBC exchange, noninvasive imaging to monitor iron burden, and iron chelation with parenteral or oral agents. Although limited and extended RBC antigen matching reduces antibody formation, the prevalence of RBC alloimmunization in patients with SCD remains high. Recent studies demonstrate that RH genetic diversity in patients with SCD contributes to Rh alloimmunization, suggesting that even more refined RBC matching strategies are needed. Advances in molecular blood group typing offer new opportunities to improve RBC matching of donors and recipients and can be of particular benefit to patients with SCD.

Extracellular hemin crisis triggers acute chest syndrome in sickle mice.

The prevention and treatment of acute chest syndrome (ACS) is a major clinical concern in sickle cell disease (SCD). However, the mechanism underlying the pathogenesis of ACS remains elusive. We tested the hypothesis that the hemolysis byproduct hemin elicits events that induce ACS. Infusion of a low dose of hemin caused acute intravascular hemolysis and autoamplification of extracellular hemin in transgenic sickle mice, but not in sickle-trait littermates. The sickle mice developed multiple symptoms typical of ACS and succumbed rapidly. Pharmacologic inhibition of TLR4 and hemopexin replacement therapy prior to hemin infusion protected sickle mice from developing ACS. Replication of the ACS-like phenotype in nonsickle mice revealed that the mechanism of lung injury due to extracellular hemin is independent of SCD. Using genetic and bone marrow chimeric tools, we confirmed that TLR4 expressed in nonhematopoietic vascular tissues mediated this lethal type of acute lung injury. Respiratory failure was averted after the onset of ACS-like symptoms in sickle mice by treating them with recombinant hemopexin. Our results reveal a mechanism that helps to explain the pathogenesis of ACS, and we provide proof of principle for therapeutic strategies to prevent and treat this condition in mice.

La drepanocitosis y el asma bronquial / Sickle cell disease and bronchial asthma

El diagnóstico del asma en niños y adultos con drepanocitosis se ha asociado a un aumento de las crisis de dolor y del síndrome torácico agudo, así como a un mayor riesgo de muerte y una menor expectativa de vida. No está bien definido el mecanismo por el cual el asma influye en la drepanocitosis y su prevalencia en esta entidad es muy variable. Ambas son enfermedades inflamatorias y sus mediadores, así como las alteraciones en la vía del óxido nítrico contribuyen a su fisiopatología. La hipovitaminosis D que ocurre en la drepanocitosis se relaciona con la severidad del asma, con una respuesta disminuida a los esteroides y pudiera contribuir a la elevada morbilidad en estos pacientes. La hiperreactividad de las vías aéreas es frecuente en la drepanocitosis, así como las alteraciones de las pruebas funcionales respiratorias. El patrón obstructivo pulmonar está asociado con un mayor número de hospitalizaciones por síndrome torácico agudo y crisis vasoclusivas dolorosas, y a un mayor riesgo de muerte. Por otra parte, el acetaminofén se asocia a un aumento del riesgo de asma y se utiliza con frecuencia en los episodios dolorosos en la drepanocitosis, por lo tanto debe investigarse si existe alguna relación entre su uso en la drepanocitosis y la prevalencia del asma. El diagnóstico y tratamiento adecuado del asma puede disminuir su impacto en la drepanocitosis(AU)

The diagnosis of asthma in children and adults with sickle cell disease has been associated with increased painful crises and acute chest syndrome, as well as an increased risk of death and a lower life expectancy. The mechanism by which asthma affects patients with sickle cell disease is not well defined and its prevalence in this condition is highly variable. Both are inflammatory diseases and their mediators and alterations in the nitric oxide pathway contribute to its pathophysiology. Hypovitaminosis D occurs in sickle cell disease and is related to the severity of asthma with a diminished response to steroids and may contribute to the high morbidity in these patients. The airway hyperresponsiveness and the abnormalities of lung function tests are common in sickle cell disease. The pulmonary obstructive pattern is associated to an increased risk of death and hospitalizations for acute chest syndrome and painful vaso-occlusive crises. On the other hand, acetaminophen is associated to an increased risk of asthma and is frequently used in painful episodes in sickle cell disease; therefore, it should be investigated whether there is any relationship between its use in sickle cell disease and asthma prevalence. An adequate diagnosis and treatment of asthma can reduce its impact on sickle cell disease(AU)

Pain and other non-neurological adverse events in children with sickle cell anemia and previous stroke who received hydroxyurea and phlebotomy or chronic transfusions and chelation: results from the SWiTCH clinical trial.

To compare the non-neurological events in children with sickle cell anemia (SCA) and previous stroke enrolled in SWiTCH. The NHLBI-sponsored Phase III multicenter randomized clinical trial stroke with transfusions changing to hydroxyurea (SWiTCH) (ClinicalTrials.gov NCT00122980) compared continuation of chronic blood transfusion/iron chelation to switching to hydroxyurea/phlebotomy for secondary stroke prevention and management of iron overload. All randomized children were included in the analysis (intention to treat). The Fisher's Exact test was used to compare the frequency of subjects who experienced at least one SCA-related adverse event (AE) or serious adverse event (SAE) in each arm and to compare event rates. One hundred and thirty three subjects, mean age 13 ± 3.9 years (range 5.2-19.0 years) and mean time of 7 years on chronic transfusion at study entry, were randomized and treated. Numbers of subjects experiencing non-neurological AEs were similar in the two treatment arms, including SCA-related events, SCA pain events, and low rates of acute chest syndrome and infection. However, fewer children continuing transfusion/chelation experienced SAEs (P = 0.012), SCA-related SAEs (P = 0.003), and SCA pain SAEs (P = 0.016) as compared to children on the hydroxyurea/phlebotomy arm. The timing of phlebotomy did not influence SAEs. Older age at baseline predicted having at least 1 SCA pain event. Patients with recurrent neurological events during SWiTCH were not more likely to experience pain. In children with SCA and prior stroke, monthly transfusions and daily iron chelation provided superior protection against acute vaso-occlusive pain SAEs when compared to hydroxyurea and monthly phlebotomy.

The Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) study: a randomised, controlled, multicentre clinical trial.

BACKGROUND: No consensus exists on whether preoperative blood transfusions are beneficial in patients with sickle-cell disease. We assessed whether perioperative complication rates would be altered by preoperative transfusion. METHODS: We did a multicentre, randomised trial. Eligible patients were aged at least 1 year, had haemoglobin SS or Sß(0)thalassaemia sickle-cell-disease subtypes, and were scheduled for low-risk or medium-risk operations. Patients were randomly assigned no transfusion or transfusion no more than 10 days before surgery. The primary outcome was the proportion of clinically important complications between randomisation and 30 days after surgery. Analysis was by intention to treat. FINDINGS: 67 (96%) of 70 enrolled patients-33 no preoperative transfusion and 34 preoperative transfusion-were assessed. 65 (97%) of 67 patients had the haemoglobin SS subtype and 54 (81%) were scheduled to undergo medium-risk surgery. 13 (39%) of 33 patients in the no-preoperative-transfusion group had clinically important complications, compared with five (15%) in the preoperative-transfusion group (p=0.023). Of these, 10 (30%) and one (3%), respectively, had serious adverse events. The unadjusted odds ratio of clinically important complications was 3.8 (95% CI 1.2-12.2, p=0.027). 10 (91%) of 11 serious adverse events were acute chest syndrome (nine in the no-preoperative-transfusion group and one in the preoperative-transfusion group). Duration of hospital stay and readmission rates did not differ between study groups. INTERPRETATION: Preoperative transfusion was associated with decreased perioperative complications in patients with sickle-cell disease in this trial. This approach could, therefore, be beneficial for patients with the haemoglobin SS subtype who are scheduled to undergo low-risk and medium-risk surgeries. FUNDING: NHS Blood and Transplant.