Treatment Of Acute Chest Syndrome Research Articles

Acute chest syndrome in sickle cell disease.

Sickle cell disease (SCD) is an autosomal recessive disorder altering the shape of red blood cells, causing harmful obstructions in blood vessels, therefore altering normal blood flow. SCD can escalate quickly into acute chest syndrome (ACS), a life-threatening complication that requires immediate care. This article discusses the pathophysiology, assessment, diagnosis, and treatment of ACS, as well as nursing care and patient education.

Paediatric Association of Nigeria Guidelines on the Management of Acute Chest Syndrome in Children with Sickle Cell Disease (2023)

Acute Chest Syndrome (ACS) is a major cause of hospitalisation, a potentially life-threatening complication and a leading cause of mortality in children with Sickle Cell Disease (SCD). The affected child commonly presents with respiratory symptoms such as cough, breathlessness, chest pain, jitteriness, and confusion, with or without fever. The cause of this condition is multifactorial and sometimes unidentified, but the majority are due to infection, infarction, and fat embolism. ACS and its related complications may be minimised by prompt intervention and appropriate therapy, including the use of incentive spirometry and blood transfusion.
 
 Objective
 The development of a national guideline on the management of ACS in children with SCD under 18 years in Nigeria is meant to enhance early diagnosis and prompt treatment of ACS to improve the quality of care and clinical outcome and prevent death from ACS. It is intended to enhance the clinician's diagnostic capability and ensure that children with ACS receive the best available care.
 
 Methods
 This evidence-based guideline was adapted from the British Society of Haematology (BSH) and the American Society of Hematology (ASH) guidelines using the ADAPTE (Resource tool kit version 2.1) and AGREE II methods.
 
 Results
 The PAN Guideline Panel reached a consensus on 25 recommendations, three of which were modified and adapted for local use. The recommendations reflect a broad definition of ACS and a management approach, including blood transfusion and incentive spirometry, such as blowing latex balloons in the absence of a spirometer.
 
 Conclusions
 Most recommendations are conditional because of low-certainty evidence and closely balanced benefits and harms (benefits of therapy to patients and availability of such therapy). Patient preferences should drive clinical decisions. Randomised controlled trials and comparative-effectiveness studies are needed for optimal management of blood transfusion, fluid therapy, and use of oxygen.

Diagnostic Test Accuracy of Lung Ultrasound for Acute Chest Syndrome in Sickle Cell Disease: A Systematic Review and Meta-analysis

Acute chest syndrome (ACS) is a leading cause of death in patients with sickle cell disease. Lung ultrasound (LUS) is emerging as a point-of-care method to diagnose ACS, allowing for more rapid diagnosis in the ED setting and sparing patients from ionizing radiation exposure. What is the diagnostic accuracy of LUS for ACS diagnosis, using the current reference standard of chest radiography? Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed for this systematic review and meta-analysis. Embase, MEDLINE, Web of Science, and Google Scholar were used to compile all relevant studies. Two reviewers screened the studies for inclusion in this review. Cases of discrepancy were resolved by a third reviewer. Meta-analyses were conducted using both metadta and midas STATA software packages to retrieve summary receiver operating characteristic curves, sensitivities, and specificities. Three reviewers scored the studies with QUADAS-2 for risk of bias assessment. From a total of 713 unique studies retrieved, six studies were included in the final quantitative synthesis. Of these, five studies were in pediatric EDs. Two studies were conference abstracts and not published manuscripts. Data were available for 625 possible ACS cases (97%of cases in patients aged≤ 21 years) and 95 confirmed ACS diagnoses (pretest probability of 15.2%). The summary sensitivity was 0.92 (95%CI, 0.68-0.98) and the summary specificity was 0.89 (95%CI, 0.69-0.97) with an area under the curve of the summary receiver operating characteristic curve of 0.96 (95%CI, 0.94-0.97). LUS has excellent sensitivity and very good specificity for ACS diagnosis and may serve as an initial point-of-care test to facilitate rapid treatment of ACS and spare pediatric patients from ionizing radiation; however, further research is warranted to improve the generalizability to the adult sickle cell disease population.

Inhaled bronchodilators for acute chest syndrome in people with sickle cell disease.

Bronchodilators are used to treat bronchial hyper-responsiveness in asthma. Bronchial hyper-responsiveness may be a component of acute chest syndrome in people with sickle cell disease. Therefore, bronchodilators may be useful in the treatment of acute chest syndrome. This is an update of a previously published Cochrane Review. The aim of the review is to determine whether the use of inhaled, short-acting bronchodilators for acute chest syndrome reduces morbidity and mortality in people with sickle cell disease and to assess whether this treatment causes adverse effects. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. Additional searches were carried out on MEDLINE (1966 to 2004) and Embase (1981 to 2004) and ongoing trial registries (28 September 2022). Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 25 July 2022. Randomised or quasi-randomised controlled trials. Trials using quasi-randomisation methods will be included in future updates of this review if there is sufficient evidence that the treatment and control groups are similar at baseline. We found no trials investigating the use of bronchodilators for acute chest syndrome in people with sickle cell disease. We found no trials investigating the use of bronchodilators for acute chest syndrome in people with sickle cell disease. If bronchial hyper-responsiveness is an important component of some episodes of acute chest syndrome in people with sickle cell disease, the use of inhaled bronchodilators may be indicated. There is need for a well-designed, adequately-powered randomised controlled trial to assess the benefits and risks of the addition of inhaled bronchodilators to established therapies for acute chest syndrome in people with sickle cell disease.

A Phase II Study to Evaluate the Safety and Efficacy of Defibrotide in Sickle Cell Disease-Related Acute Chest Syndrome (IND 127812)

Background: Acute Chest Syndrome (ACS) is the greatest contributor to the morbidity and mortality of Sickle Cell Disease (SCD) patients with a rate of 12.8 cases per 100 patient-years. The mortality rates of ACS are 4 times higher in adults than in children (Children 1.1% vs Adults 4.3%) (Vichinsky et al, Blood, 1997). The root cause of ACS in SCD is related to endothelial dysfunction (Paul et all, European Journal of Hematology 2011). While existing therapies target infection, inflammation, and alveolar hypoxia, they do not work to repair loss of integrity within the endothelial barrier that ultimately causes ACS. Defibrotide is a polydisperse mixture of predominantly single stranded oligonucleotides derived from porcine intestinal mucosa. Several pre-clinical studies indicate that Defibrotide primarily protects endothelium, particularly in small vessels, and appears to reduce endothelial cell injury (Falanga et al, Leukemia, 2003). In a randomized, phase III study, a decrease in incidence of SOS/VOD was observed in pediatric hematopoietic stem cell transplantation patients who received prophylactic Defibrotide (Corbacioglu et al, 2012). We hypothesized that Defibrotide is safe and well tolerated in SCD-associated ACS. Primary Aims: To determine the safety and efficacy of defibrotide in the treatment of SCD-associated ACS. Design/Methods: Patients with SCD- (Homozygous Hemoglobin S disease, Hemoglobin SC Disease or Hemoglobin Sβ0/+ Thalassemia) associated ACS aged 2 to 40 years of age were enrolled. Defibrotide, generously supplied by Jazz Pharmaceuticals, was administered at 6.25 mg/kg IV Q6H (total daily dose 25 mg/kg/day) within 24 hours of consent and continued for 7 days or until the patient was discharged from hospital, whichever occurred first (IND 127812) (NCT 03805581). All patients were treated with current standard of care, including: antibiotics, analgesics, oxygen, intravenous fluids, and packed red blood cells (PRBC)/exchange transfusion. Complete blood counts and coagulation studies were performed at baseline, day 7 and day 30, while chest radiograph (CXR), CT chest angiogram (CTA), pulmonary function test (PFT), and transthoracic echocardiogram (ECHO) were performed at baseline and 30 days after Defibrotide was first given for disease assessment. Results: We have enrolled 20 patients (median age 9.5 years) with a gender ratio of M/F 8/12. Patients had hemoglobin SS (n=14), hemoglobin Sβ0/+ (n=2), or hemoglobin SC (n=4). The median doses of Defibrotide per patient was 18.5 (range 6-28) and the average hospital admission length was 6.1 days (range 3-13 days). There were no serious adverse events probably or directly related to Defibrotide, as judged by investigators. Two patients had a grade I/II epistaxis that did not disrupt Defibrotide's course. Pulmonary infiltrate on CXR and/or CTA was the most common finding at diagnosis, with 18/20 participants (90%) (Figure 1a). Thirteen patients had fever as a presenting symptom, and the average duration of the fever from diagnosis was 2.8 days (range 1-6 days) (Figure 1b). Nine patients required O2 supplementation, with an average duration of 4.1 days (range 2-7 days). Among patients who underwent Day 30 CXR or CTA, 87.5% and 92%, respectfully, showed improvement or resolution of pulmonary consolidation, only 4 patients had a day 30 ECHO, however, all of them had a resolution of previous findings. Thirteen patients were treated with blood transfusions with a median of 1.9 units (PRBC unit was defined as 15ml/kg) transfused per patient (range, 1-5 units) and 1 patient underwent an exchange transfusion. Conclusion: Our data suggests that Defibrotide is safe and well tolerated in SCD patients with ACS. No serious adverse events were observed. A randomized phase II/III multi-center clinical trial will need to be conducted to further investigate its efficacy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Complement Drives Acute Chest Syndrome in a Model of Sickle Cell Disease

Background: Despite being the first genetic disease described, sickle cell disease (SCD) continues to afflict millions of individuals worldwide. Patients with SCD can experience severe complications, including vasoocclusive crisis (VOC), which can progress to acute chest syndrome (ACS), a form of acute lung injury. While VOC can cause significant morbidity, ACS is the leading cause of mortality in patients with SCD. Despite the devastating consequences of ACS, no interventions exist that directly treat this complication. As a result, when patients present with ACS, options often remain limited to supportive care. The lack of optimal treatment options for patients with SCD experiencing ACS directly contributes to their morbidity and mortality. Using a combined approach of prospective observational studies in patients with SCD that experienced ACS and a novel preclinical model specifically designed to define the role of complement in SCD pathophysiology, we tested the hypothesis that complement plays a central role in the pathophysiology of ACS. Methods: Samples from patients with SCD experiencing ACS were compared to baseline measurements for the same patient obtained at outpatient follow up 4-6 weeks later. ELISA based assays were used to measure Ba, Bb, C3a, C5a, C5b-9 (membrane attack complex (MAC)) in each sample. SCD mice (HbSS) and control mice (HbAA) were injected with 7.5 units of cobra venom factor (CVF), a potent complement activator, followed by evaluation of hematocrit (Hct) measured by a Sysmex veterinary hematology analyzer, free heme by calorimetric assay, and complement deposition on red blood cells (RBCs) by flow cytometry or pulmonary endothelial cells by confocal analysis. Respiratory rate and O2 saturation were measured using a MouseOx pulse oximeter. HbSS or HbAA mice were crossed with complement component 3 (C3) knock out (KO) mice to generate HbSS x C3 KO and HbAA x C3 KO mice. Hemin (70 to 210 mmol/kg concentration) or CVF (7.5 units/mouse) were injected into HbSS, HbAA, HbSS x C3 KO or HbAA x C3 KO followed by evaluation of hemolysis, C3 deposition and pulmonary function. A one-way ANOVA with a Tukey's post hoc with a p value <0.05 was considered significant. Results: During ACS in patients, significant elevations in Ba and Bb, complement activation products unique to the alternative pathway, and downstream activation of complement, including C3a, C5a and MAC, were observed (p<0.0001). Changes in complement activation were accompanied by a drop in hemoglobin during ACS when compared to baseline (p<0.001), suggesting that complement activation results in hemolysis. To formally test this, the impact of complement activation in a preclinical model of SCD was defined. Injection of CVF or hemin resulted in rapid C3 deposition on RBCs and pulmonary endothelium in HbSS, but not HbAA, recipients. In addition, CVF or hemin injection was accompanied by increased hemolysis and ACS manifested by increased respiratory rate, drop in oxygen saturation and death within 2 hours in the majority of recipients (p<0.001). In contrast, control Hb AA mice were unaffected by CVF or hemin injection. Given the role of free heme in the development of ACS, we next defined the role of complement in hemin-induced lung injury. To accomplish this, SCD mice were crossed with C3 KO mice to generate HbSS x C3 KO. HbSS x C3 KO mice displayed a mild increase in Hb values at baseline (p<0.01), suggesting a role of C3 even in steady-state SCD-related hemolysis. Equally important, injection of HbSS x C3 KO mice with CVF or hemin failed to result in the same levels of C3 deposition, hemolysis, compromised pulmonary function, or mortality (p<0.001) as HbSS recipients. Discussion: These results demonstrate a critical role for C3 in the development of acute lung injury in SCD. The sensitivity of HbSS RBCs to complement-induced hemolysis and C3 deposition observed following hemin injection in SCD recipients suggests that C3 plays a key role in decreased hematocrits and pulmonary injury that accompanies ACS. As treatment of ACS largely relies on supportive care, these results suggest that approaches aimed at targeting complement activation may represent a useful prophylactic or treatment strategy for ACS. In doing so, these results hold promise in providing a more direct approach at reducing one of the most severe complications of patients with SCD.

Identification of the Pitfalls in the Attempted Use of Extracorporeal Membrane Oxygenation in an Adult Patient with Sickle Cell Disease and Severe Acute Chest Syndrome

BACKGROUNDAcute chest syndrome (ACS) is a life-threatening complication of sickle cell disease (SCD). Despite being the leading cause of death in adult patients with SCD, current recommendations for treatment of ACS remain largely supportive, consisting of pain management, aggressive fluid resuscitation, respiratory support, and transfusion therapy. Despite these measures, it is not uncommon for patients to require intubation due to progression to acute respiratory distress syndrome (ARDS). Recently, there have been a number of case reports that have successfully utilized extracorporeal membrane oxygenation (ECMO) for the management of ACS in those patients who fail to respond to conventional therapy [Kuo et al., 2013, Sewaralthahab et al, 2018]. However, the use of ECMO in this patient population remains uncommon, and further evaluation of this intervention is needed. This case report details an unsuccessful attempt at the use of ECMO in the case of ARDS secondary to ACS, in an attempt to identify critical pitfalls.CASE REPORTA 32-year-old African-American female with HbSS disease on hydroxyurea therapy was transferred from an outside hospital following 3 days of respiratory decompensation. Prior to arrival, patient coded once at the outside hospital and once on transfer. Veno-arterial ECMO was initiated with improving oxygen saturation and volume status with continuous renal replacement therapy. To maintain an ECMO-specific goal hemoglobin level of 10 g/dL, 1:1 manual exchange transfusions were performed due to an inability to access equipment for automated RBC exchange. Once stable enough for CT, patient was found to have gray-white inversion suggestive of irreversible severe brain damage. Following another 28 days of supportive care with no neurologic improvement, the family decided to withdraw care, and the patient expired.CONCLUSIONWhile unsuccessful, this patient's case revealed a need for defining parameters regarding the initiation of ECMO in SCD patients with severe ACS. A review of previously-published literature has shown that the use of ECMO for the management of ARDS in adults is more efficacious than conventional ventilation support [Peek et al., 2009]. In patients with SCD, this improvement in efficacy is not readily reproduced, likely due to unique challenges presented by the pathophysiology of the disease. Notably, patients with SCD face additional risks of venous thromboembolism and strokes while on prolonged bed rest due to a baseline prothrombotic state [Sewaralthahab et al., 2018]. A systematic review of available case reports is needed to develop a protocol for the management of severe ACS that takes SCD-specific risks into account.The present report also makes a case for the training of providers in the early recognition of severe ACS in SCD patients. SCD remains largely undertreated in the United States, likely due to a complex interplay of patient, physician, and institutional factors. Had this patient been transferred immediately to a facility better equipped to provide a higher level of care, her condition could have arguably taken a different course. Despite the aforementioned challenges, ECMO remains a feasible option for the management of severe ACS in patients with SCD, and efforts should be made to standardize current treatment protocols.REFERENCESKuo KW, Cornell TT, Shanley TP, Odetola FO, and Annich GM. The use of extracorporeal membrane oxygenation in pediatric patients with sickle cell disease. Perfusion. 2013 September; 28(5): 424-432.Peek GJ, Mugford M, Tiruvoipati R, Wilson A, Allen E, Thalanany M, et al. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. The Lancet. 2009 October; 374(9698): 1351-1363.Sewaralthahab SS, Menaker J, Law JY. Successful use of veno-venous extracorporeal membrane oxygenation in an adult patient with sickle cell anemia and severe acute chest syndrome. Hemoglobin. 2018 42(1): 65-67.DisclosuresNo relevant conflicts of interest to declare.

Successful Treatment of Acute Chest Syndrome with Manual Exchange Transfusion in a Patient with Sickle Beta&lt;sup&gt;+&lt;/sup&gt;-thalassemia

Acute chest syndrome (ACS), characterized by fever, respiratory symptoms, and new pulmonary infiltration, is a serious complication of sickle cell disease (SCD). Regardless of the etiology, the conventional treatment options for ACS include empirical antibiotic therapy, the administration of analgesics, and red cell transfusion. The indications and methods of red cell transfusion are critical. We herein report the case of a 26-year-old African-American man with SCD who developed ACS and who was successfully treated with manual exchange transfusion. Despite increasing globalization, SCD remains extremely rare in Japan. Manual exchange transfusion can be performed easily anywhere and should be considered for treating SCD patients presenting with ACS.

Inhaled bronchodilators for acute chest syndrome in people with sickle cell disease.

Bronchodilators are used to treat bronchial hyper-responsiveness in asthma. Bronchial hyper-responsiveness may be a component of acute chest syndrome in people with sickle cell disease. Therefore, bronchodilators may be useful in the treatment of acute chest syndrome. This is an update of a previously published Cochrane Review. To assess the benefits and risks associated with the use of bronchodilators in people with acute chest syndrome. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. Additional searches were carried out on MEDLINE (1966 to 2002) and Embase (1981 to 2002).Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 11 July 2016. Randomised or quasi-randomised controlled trials. Trials using quasi-randomisation methods will be included in future updates of this review if there is sufficient evidence that the treatment and control groups are similar at baseline. We found no trials investigating the use of bronchodilators for acute chest syndrome in people with sickle cell disease. We found no trials investigating the use of bronchodilators for acute chest syndrome in people with sickle cell disease. If bronchial hyper-responsiveness is an important component of some episodes of acute chest syndrome in people with sickle cell disease, the use of inhaled bronchodilators may be indicated. There is need for a well-designed, adequately-powered randomised controlled trial to assess the benefits and risks of the addition of inhaled bronchodilators to established therapies for acute chest syndrome in people with sickle cell disease.

The Pharmacologic Rationale Supporting the Potential Use of Vepoloxamer for the Treatment of Acute Chest Syndrome in Patients with Sickle Cell Disease

The Pharmacologic Rationale Supporting the Potential Use of Vepoloxamer for the Treatment of Acute Chest Syndrome in Patients with Sickle Cell Disease

Early Initiation of Inhaled Corticosteroids Does Not Decrease Acute Chest Syndrome Morbidity in Pediatric Patients with Sickle Cell Disease

Acute chest syndrome (ACS) is the leading cause of mortality in patients with sickle cell disease (SCD). Because the etiology of ACS is multifactorial, treatment approaches include broad spectrum antibiotics, intravenous fluids to prevent sickling, encouragement of ambulation, and incentive spirometry. Inflammation, airway hyper-reactivity, and ventilation/perfusion mismatch are also important in ACS etiology, but inhaled corticosteroids (ICS) are not universally initiated and efficacy still needs to be demonstrated in the treatment of ACS. Systemic corticosteroids have previously been investigated as part of the treatment for ACS. In these studies, patients who received systemic steroids had shorter hospital stays, but they were more likely to be readmitted with sickle cell painful vaso-occlusive crises (VOC). ICS may be a safe alternative to systemic steroids in patients with ACS. The current study aims to investigate the utility of initiating ICS at the time of hospital admission in reducing ACS morbidity (defined here as transfer to the pediatric intensive care unit (PICU), the need for BiPAP, intubation or pRBC transfusion) or hospital costs in SCD patients who were admitted to the hospital with VOC or ACS.A case control study was initiated to compare patients with a discharge diagnosis of ACS at a large, tertiary care children's hospital. Cases were those patients in whom ICS were initiated at the time of hospital admission for VOC or ACS. Controls were patients who did not receive ICS upon hospital admission. Outcome measures included rate of PICU transfer, transfusion requirements, need for intubation or BiPAP initiation, and hospital cost. Student t-tests were used to compare continuous variables between the cases and controls and Pearson chi-squared was used to compare categorical variables.A total of 120 patients with SCD admitted for ACS or VOC who later developed ACS were analyzed (55 controls vs. 65 cases). Eighty-one percent of the cases had HbSS, compared to 67% of the controls (p=0.07). Cases and controls were age matched (9.9±6.2 yrs vs. 8.7±5.5 yrs, respectively, p=0.28). A higher proportion of the cases had asthma (52.3% vs. 12.7%, p<0.001) and were followed in Pulmonology clinic (33.9% vs. 7.3%, p=0.001). Mean admission hemoglobin (Hb) and absolute reticulocyte counts (ARC) did not differ between the two groups (Case mean Hb 7.9±1.4 g/dL vs. Control mean Hb 8.5±1.8g/dL, p=0.05; Case mean ARC 308±155 K/µL vs. Control mean ARC 277±170K/µL, p=0.32). No statistically significant difference was seen in the proportion of cases who received pRBC transfusions when compared to the controls (56.9% vs. 41.8%, respectively, p=0.10). Twenty-one patients in the study cohort were transferred to the PICU [12 cases (18.5%) and 9 controls (16.3%), p=0.80]. Of those twenty-one patients who were transferred to the PICU, a lower proportion of cases required intubation (8.3% vs. 33.3% of controls, p=0.15), but more patients who began ICS at admission required BiPAP (15.3% vs. 5.4%, p=0.02). Hospital costs were slightly higher in the cases ($10,400 vs. $10,300 for the controls, p=0.40).Initiation of ICS in this case control study did not significantly decrease the rate of ACS morbidity. Patients who received ICS at admission were more likely to have HbSS and asthma, suggesting that the cases in this study may have had more severe ACS than the controls. This could explain why a higher proportion of the cases required PICU transfer and BiPAP initiation despite receiving ICS. Despite a plausible pathogenic mechanism for the use of ICS to reduce airway hyper-reactivity, we did not see a statistically significant benefit in the treatment of ACS. Prospective studies of the use of ICS to prevent ACS or decrease its morbidity are needed. DisclosuresNo relevant conflicts of interest to declare.

Inhaled bronchodilators for acute chest syndrome in people with sickle cell disease.

Bronchodilators are used to treat bronchial hyper-responsiveness in asthma. Bronchial hyper-responsiveness may be a component of acute chest syndrome in people with sickle cell disease. Therefore, bronchodilators may be useful in the treatment of acute chest syndrome. To assess the benefits and risks associated with the use of bronchodilators in people with acute chest syndrome. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. Additional searches were carried out on MEDLINE (1966 to 2002) and Embase (1981 to 2002).Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 17 March 2014. Randomised or quasi-randomised controlled trials. Trials using quasi-randomisation methods will be included in future updates of this review if there is sufficient evidence that the treatment and control groups are similar at baseline. We found no trials investigating the use of bronchodilators for acute chest syndrome in people with sickle cell disease. We found no trials investigating the use of bronchodilators for acute chest syndrome in people with sickle cell disease. If bronchial hyper-responsiveness is an important component of some episodes of acute chest syndrome in people with sickle cell disease, the use of inhaled bronchodilators may be indicated. There is need for a well-designed, adequately-powered randomised controlled trial to assess the benefits and risks of the addition of inhaled bronchodilators to established therapies for acute chest syndrome in people with sickle cell disease.

Sickle cell transgenic (HbSS) mice lungs produce greater inflammatory mediators with downregulation of dilator proteins (1175.10)

Sickle cell chronic lung disease is one of the notable causes of death in patients with sickle cell disease (SCD). Prevention and treatment of acute chest syndrome (ACS) constitutes a major concern in clinical management of SCD. Some lung complications in SCD result from direct or indirect effect of pulmonary microvascular occlusion by sickle erythrocytes and their adhesion to the vascular endothelium. Vasoactive eicosanoids are released resulting in inflammatory response. Studies with HbSS mice have enhanced knowledge of SCD pathology, but the biochemical mechanisms of initiation and progression of ACS is not well understood. We hypothesized that lungs of SCD patients are under greater inflammatory stress due to decreased expression of anti‐inflammatory proteins and metabolites, but greater inflammatory proteins and metabolites. We studied baseline expression of 5‐Lox, cysLT1 as well as PKA, COX1 and COX2 and CREB and measured Leukotrienes and PGI2 release by lungs of HbSS mice and transgenic HbAA mice. HbSS mice lungs expressed 40‐60% more 5‐Lox and CysLT1, but 40‐70% less COX1/COX2 and CREB proteins; produced 68% greater LTs, but PGI2 was not detected. Expression of PKA was not different. The data suggest that SCD lungs are under greater inflammatory stress which may trigger ACS and sustain sickle cell chronic lung disease in SCD patients.Grant Funding Source: LA Biomed Seed grant 520522

Targeted Treatment Of Acute Chest Syndrome In Transgenic Sickle Mice

Acute chest syndrome (ACS) is a major cause of morbidity and mortality in sickle cell disease (SCD). The diagnosis, prevention and treatment of ACS pose major clinical concerns in SCD partly because the mechanism underlying the pathogenesis of this syndrome remains elusive. Our group first reported that excess intravascular hemin causes a lethal acute lung injury (ALI) in transgenic SCD mice reminiscent of ACS (Ghosh and Ofori-Acquah, Blood 116 Suppl 1:944, 2010). Subsequently, large-scale genomics studies by Bean et al., (Blood 120:3822-8, 2012) and Galarneau et al., (Blood, 122:434-42, 2013) have implicated hemin catabolism and inflammation in the pathogenesis of ACS. In addition, we have reported recently that raised plasma free hemin increases the odds of ACS in children with SCD (Adisa et al., Br J Haematol. 2013). Collectively, these studies support a new theme of ACS pathogenesis involving extracellular hemin. In the current study, we validated the respiratory dysfunction of this ACS model, tested the hypothesis that toll-like receptor 4 (TLR4) mediates the associated lung injury, and examined the efficacy of two strategies to treat the condition in mice. Arterial blood gas analysis of SS mice with the ACS-like disease confirmed severe hypoxemia (PaO2; 40.23 ±3.85 mmHg, SO2; 58.72±6.6%, p<0.001), and revealed worsening hypercapnia (PaCO2; 56.08±3.64 mmHg) and acidosis (mean pH; 7.21), which are all typical of severe ALI. Blood gas parameters remained normal in control AA mice exposed to the same concentration of extracellular hemin. Next, we generated two types of sickle bone marrow chimeric mice that lack expression of TLR4 in non-hematopoietic cells (SSNHTLR4-/-) or express TLR4 on all cell types (SSTLR4+/+). Induction of extracellular hemin crisis with 70 micromoles/kg of hemin resulted in rapid oxygen desaturation, reduced breath rate, pulmonary infiltration, high lung wet/dry weight ratio and sudden death in the SSTLR4+/+ chimeras (n=6). Although all the SSNHTLR4-/- mice acquired a similar phenotype of hemin crisis as the SSTLR4+/+ mice, defined by acute intravascular hemolysis (∼1g/dl drop in Hb, ∼1g/dl increase in cell-free Hb), exhaustion of plasma hemopexin, ∼3-fold increase in plasma free hemin, they did not develop any respiratory symptoms (n=7). Next, we tested two potential therapies, recombinant human hemopexin and TAK-242 a small molecule inhibitor of TLR4. Both agents protected SS mice from developing ACS when they were administered immediately after the induction of hemin crisis. When SS mice were treated after developing respiratory distress evident by significant reductions in oxygen saturation and breath rate, only the recombinant human hemopexin was effective in preventing respiratory failure. In conclusion, we show that TLR4 expressed by the vessel wall, most likely the endothelium, mediates the inflammatory response to excess free hemin associated with severe ACS in mice. Pharmacological inhibition of TLR4 signaling and hemin sequestration may be effective in preventing the development of ACS. In addition, hemin sequestration offers a targeted approach that may halt the progression of ACS in those with more advanced disease. Disclosures:No relevant conflicts of interest to declare.

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.

Comparison of automated red cell exchange transfusion and simple transfusion for the treatment of children with sickle cell disease acute chest syndrome

Both simple transfusion (ST) of packed red blood cells and automated red cell exchange (RCE) are used in the treatment of acute chest syndrome (ACS). We report our experience using each of these modalities for the treatment of ACS. Retrospective chart review of patients with ACS treated with ST only (51 episodes, ST group) or RCE performed either at diagnosis (U-RCE group, 15 episodes) or after ST (ST + RCE group, 15 episodes). The mean clinical respiratory score (CRS) at diagnosis was significantly higher in the U-RCE group than in the ST group, but there were no significant differences among the other groups. The CRS and WBC each decreased significantly after simple transfusion in the ST group and after RCE in the U-RCE group, but both the CRS and WBC increased significantly, and the mean platelet count fell significantly, after simple transfusion in the ST + RCE group. Only patients in the ST + RCE group required mechanical ventilation. There were no significant differences in length of stay (LOS) or total hospital charges among any of the groups, probably due to the small sample size. We conclude that the CRS identifies the patients who are most severely affected with ACS, and that upfront RCE is a safe and effective treatment for these patients. Additional work is needed to develop a method to predict which of the apparently less severely affected patients will fail to improve after simple transfusion and should receive upfront RCE.

Considerations for Care: Management of Asthma in the Child with Sickle Cell Disease.

Asthma is difficult to diagnose in the child with sickle cell disease because symptoms and pulmonary function abnormalities are similar to the spectrum of pulmonary manifestations in sickle cell disease. There are no published reports of controlled trials of asthma medications in children with sickle cell disease. Thus, treatment decisions should be guided by the Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma (www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf). However, issues specific to children with sickle cell disease should be considered. Initial strategies should focus on control of environmental triggers, as effectiveness on asthma outcomes is proven and the cost for implementation can be low. Use of short- and long-acting β2-agonists may prolong QTc, particularly in this population of children who already have a higher prevalence of prolonged QTc than the general population. Long-acting β2-agonist use has been associated with life-threatening asthma exacerbations with potentially higher risks in African Americans. Montelukast has been reported to increase suicidal thinking and behavior, and persons with asthma and sickle cell disease are already at risk for these events. Oral corticosteroids in the treatment of acute chest syndrome may increase risk of readmission even in children with asthma. The lack of prospective controlled trials of asthma drug treatment in children with asthma and sickle cell disease compels us to move this issue forward.

Comprehensive healthcare for individuals with sickle cell disease

Comprehensive healthcare for individuals with sickle cell disease

Use of Transfusion to Treat Acute Chest In Sickle Cell Disease:California Hospital Practice Patterns

AbstractAbstract 253 Introduction:Acute chest syndrome (ACS) is a leading cause of morbidity and mortality in patients with Sickle Cell Disease (SCD). Although the NIH recommends transfusion as standard of care therapy for this diagnosis, practice patterns vary. In 2000, the National Acute Chest Study group found that 72% of patients with ACS were transfused. This study, which was perfomed at academic medical centers with sickle cell treatment programs, used specific diagnostic inclusion criteria. As ACS may be difficult to distinguish from pneumonia, recognition and treatment of the diagnosis may vary by hospital and by presence or absence of a sickle cell specialist. With access to hospital discharge data from all California hospitals seeing SCD patients, we aimed to describe transfusion practices in ACS. Methods:This retrospective cohort study uses 2005–2008 public data from the California Office of Statewide Health Planning and Development (OSHPD). Data included all inpatient and emergency department (ED) discharges from all non-federal California hospitals. Cases were selected based on discharge from or admission via an ED and the presence of a sickle cell disease ICD-9 code in the primary or a secondary diagnosis (282.60-282.69, 282.41–282.42). Further inclusion criteria included presence of ACS (517.3) or respiratory diagnoses including pneumonia, pulmonary edema, acute respiratory distress syndrome, hypoxia and respiratory failure in any primary or secondary diagnosis. Frequency of transfusion, intubation and mortality were described and chi-square tests were performed to determine the statistical significance of differences between groups of patients treated with or without transfusion as well as between groups of adults and children. Results:Between 2005–2008, 4306 ED visits by Californians with SCD were associated with either ACS or a related respiratory diagnosis and only 42.5% of these cases were associated with transfusion. Limiting the diagnosis to ACS only, 1399 cases were identified, and still only 50.4% of these cases were associated with transfusion. Among patients with ACS or a related diagnosis, the majority were admitted to the hospital (90.9%); only 59.2% of intubated cases (n=238) were transfused; and of the 92 deaths during this period, only 46.7% were associated with transfusion. Patients who were 18 and over were transfused more often than young children (43.2% vs. 35.7%; 2(1)=12.37, p<0.001). Conclusions:Despite transfusion being the standard of care for treatment of ACS as well as other sickle–related complications, many ACS cases in California are not being treated in this manner. Surprisingly, the most severely ill patients, those who were either intubated or died during the study period, had a lower transfusion frequency than the cohort as a whole. Although some mild pediatric cases may not be transfused, a minority of the total cohort was under 18 years old. Recent studies imply that patients transitioning out of pediatric SCD programs have an increased risk of dying due to ACS and other serious SCD complications. Our study suggests that underutilization of transfusion may play a role in these poor adult outcomes in SCD. These findings prompt further investigation into the role of transition to adult care and appropriate medical homes in access to quality SCD care. Disclosures:No relevant conflicts of interest to declare.

Current issues in blood transfusion for sickle cell disease

Although blood transfusion has been felt to be a beneficial therapy for sickle cell disease (SCD) since the 1950s, associated complications initially limited this therapy for these patients. With advances now reducing the side effects of transfusion and several landmark studies over the last decade clearly defining the efficacy for decreasing sickle cell morbidity, the indications for transfusion have increased. This review will discuss the indications, methods and goals of transfusion as well as complications and recent changes in transfusion therapy for SCD. Recently studies have established the efficacy of transfusion for prevention of stroke, treatment of acute chest syndrome and perioperative transfusion management of SCD. Pulmonary hypertension is increasingly recognized as a significant source of morbidity and mortality and is an evolving indication for transfusion therapy. Phenotypically matching transfused blood has been shown to decrease alloimmunization, and genotyping for antigen matching may help match donors to patients in the future. The increased use of transfusions may ultimately be balanced by hydroxyurea and other newer therapies developed as the complex pathophysiology of SCD is better understood; however, red cell transfusion is currently the most studied and accepted therapy for most acute and many chronic complications of SCD. Physicians caring for patients with sickle cell disease should be aware of the unique complications and transfusion requirements in this population.