A case of autopsy discovery of acute chest syndrome triggered by pulmonary embolism in a sickle cell patient.

This is a case report about a 7-year-old male child with sickle cell anemia (S/ß+) who died unexpectedly during hospitalization, justifying the performance of a forensic autopsy completed by histological examination of organ fragments and toxicological analyses of biological fluids. The diagnosis retained was pulmonary thromboembolism as the cause of death occurring in the context of an acute chest syndrome (ACS). The mechanism of occurrence of this pulmonary embolism was vascular stasis caused by sickle cell disease. The search for etiologies of ACS complicating sickle cell disease should not exclude pulmonary embolism with red cell dense fibrin clot..

Pulmonary Blastomycosis: A Rare Cause of Acute Chest Syndrome and Prolonged Fevers in a Pediatric Patient With Sickle Cell Disease.

Blastomyces is a fungus found in the soil of regions of North America including the Mississippi and Ohio River Valleys. It can be inhaled into the lungs and cause pneumonia and disseminated disease. Although blastomycosis is not widely reported in the sickle cell literature, sickle cell patients may be at increased risk of complications from blastomycosis pneumonia due to their immune compromise and risk of developing acute chest syndrome. We describe the case of a 13-year-old female with homozygous sickle cell disease who presented with pneumonia and acute chest syndrome and was found to have pulmonary blastomycosis.

The burden of respiratory syncytial virus infections among children with sickle cell disease.

BACKGROUND: Although respiratory syncytial virus (RSV) is the leading cause of pediatric lower respiratory tract infections, the burden of RSV in children with sickle cell disease (SCD) is unknown. METHODS: We conducted a retrospective, nested, case-control study of children with SCD <18 years who had respiratory viral panels (RVPs) performed at Children's Healthcare of Atlanta from 2012 to 2019. We abstracted the medical records to describe the demographics, clinical features, and outcomes of children who tested positive for RSV (cases) versus children who tested negative (controls). We calculated the annual incidence of RSV and related hospitalization rates with 95% confidence intervals (CIs) and used multivariate logistic regression to evaluate associations. RESULTS: We identified 3676 RVP tests performed on 2636 patients over seven respiratory seasons resulting in 219/3676 (6.0%) RSV-positive tests among 160/2636 (6.1%) patients. The average annual incidence of laboratory-confirmed RSV infection among children with SCD was 34.3 (95% CI 18.7-49.8) and 3.8 (95% CI 0.5-7.0) cases per 1000 person-years for those <5 years and 5-18 years, respectively. The RSV-related hospitalization rate for children <5 years was 20.7 (95% CI 8.5-32.8) per 1000 person-years. RSV-positive cases were significantly younger than RSV-negative patients (3.8 years vs 7.6 years, P < .001). Of RSV-positive cases, 22 (13.8%) developed acute chest syndrome and nine (5.6%) required intensive care, which was not significantly different from RSV-negative children with SCD. CONCLUSION: RSV infections are common in children with SCD with higher burden in younger patients. RSV is associated with considerable morbidity, including higher rates of hospitalization compared to the general population.

Gap Junctions between Endothelial Cells Are Disrupted by Circulating Extracellular Vesicles from Sickle Cell Patients with Acute Chest Syndrome.

Intercellular junctions maintain the integrity of the endothelium. We previously found that the adherens and tight junctions between endothelial cells are disrupted by plasma extracellular vesicles from patients with sickle cell disease (especially those with Acute Chest Syndrome). In the current study, we evaluated the effects of these vesicles on endothelial gap junctions. The vesicles from sickle cell patients (isolated during episodes of Acute Chest Syndrome) disrupted gap junction structures earlier and more severely than the other classes of intercellular junctions (as detected by immunofluorescence). These vesicles were much more potent than those isolated at baseline from the same subject. The treatment of endothelial cells with these vesicles led to reduced levels of connexin43 mRNA and protein. These vesicles severely reduced intercellular communication (transfer of microinjected Neurobiotin). Our data suggest a hierarchy of progressive disruption of different intercellular connections between endothelial cells by circulating extracellular vesicles that may contribute to the pathophysiology of the endothelial disturbances in sickle cell disease.

Sickle cell disease as a vascular disorder.

INTRODUCTION: In sickle cell disease (SCD), hemoglobin S (HbS) red blood cells (RBCs) are characteristically deformed and inflexible. Often breaking down in the circulation, they exhibit increased adhesive properties with the endothelium and activated neutrophils and platelets, increasing the risk of occlusion of the microcirculation. SCD is categorized into two sub-phenotypes: hyperhemolytic, associated with priapism, leg ulcers, pulmonary hypertension, and stroke, and high hemoglobin/viscosity, which may promote vaso-occlusion-associated pain, acute chest syndrome, and osteonecrosis. AREAS COVERED: The sub-phenotypes are not completely distinct. Hemolysis may trigger vaso-occlusion, contributing to vascular complications. Targeting P-selectin, a key mediator of cross-talk between hyperhemolysis and vaso-occlusion, may be beneficial for vascular and vaso-occlusion-associated complications. English-language articles from PubMed on the topic of SCD and vaso-occlusive crises (VOCs) were reviewed from 1 January 2000 to 1 January 2019 using the search terms 'sickle cell disease,' 'vaso-occlusive crises,' and 'selectin.' EXPERT OPINION: Besides targeting P-selectin, other strategies to counter VOCs and RBC sickling are being pursued. These include platelet inhibition to counter aggregation, intercellular adhesion, and thrombosis during VOCs; gene therapy to correct the homozygous missense mutation in the ß-globin gene, causing polymerization of HbS; L-glutamine, possibly reducing oxidative stress in sickled RBCs; and fetal hemoglobin inducers.

Veno-Venous Extracorporeal Membrane Oxygenation in Adult Patients with Sickle Cell Disease and Acute Chest Syndrome: a Single-Center Experience.

Acute chest syndrome (ACS) in adult patients with sickle cell disease represents a leading cause of death. It is characterized by a new density on chest X-ray accompanied by fever and/or respiratory symptoms. Currently, 49 adult patients with sickle cell disease are registered at our department. By now, 12 patients (24.5%) suffered from ACS and two patients showed multiple/recurrent (>2) episodes. Death in one patient was related to acute respiratory failure secondary to ACS. In three patients with ACS, invasive mechanical ventilation and subsequent veno-venous extracorporeal membrane oxygenation (VV-ECMO) was mandatory. Veno-venous ECMO was applied within 24 hours upon arrival to the intensive care unit (ICU). All patients were treated aggressively for ACS including exchange transfusions [packed red blood cell (pRBC) units 5-16] maintaining a Hb S threshold of <30.0% in addition to broad-spectrum antibiotics, resulting in a successful outcome following decannulation from VV-ECMO (49 hours, 251 hours, 30 min., and 98 hours, respectively). Limited information is presently available on the use of VV-ECMO in adult patients with sickle cell disease in the context of acute respiratory failure secondary to ACS. The adequate timing of the decision to place ECMO in critically ill adults with sickle cell disease, incapable of being treated by conventional mechanical ventilation secondary to very severe vaso-occlusive crisis (VOC), might further reduce mortality rates while treating the underlying condition.

Nucleated Red Blood Cells in Children With Sickle Cell Disease Hospitalized for Pain.

Acute chest syndrome (ACS) and transfusion requirements are common and difficult to predict during hospitalizations for acute vaso-occlusive episodes (VOE) among individuals with sickle cell disease (SCD). This study examined the relationship between nucleated red blood cell (NRBC) counts during hospitalization for VOE and development of ACS or transfusion requirement among children with SCD. Retrospective chart review was performed for 264 encounters of patients with SCD hospitalized for uncomplicated VOE who had NRBC count data at admission during a 5-year period. Multivariable logistic regression analysis was conducted to determine the relationship of admission and change in NRBC ([INCREMENT]NRBC) to ACS/transfusion requirement. Overall, 44 of 264 (16.7%) encounters resulted in ACS, transfusion, or both. Admission NRBC was not associated with development of ACS/transfusion requirement. Among 125 of 264 (47.3%) encounters in which a subsequent CBC was obtained, greater increases in NRBCs and greater decrease in hemoglobin were significantly associated with ACS/transfusion requirement (OR, 2.72; 95% CI, 1.16, 6.35; P=0.02 and OR, 2.52; 95% CI, 1.08, 5.89; P=0.03, respectively). Our finding that an increase in NRBC counts was associated with development of ACS/transfusion requirement suggests that [INCREMENT]NRBCs may represent a useful biomarker for predicting complications in children with SCD hospitalized for VOE.

Maternal sickle cell disease and twin pregnancy: a case series and review of the literature.

OBJECTIVES: Maternal sickle cell disease (SCD) and multiple gestations are well known separately as causes of high-risk pregnancies, however, there is sparse information available on maternal and perinatal outcome when both conditions occur together. This case series describes the outcomes of women with maternal SCD and twin pregnancy in the largest single-center case series to date. METHODS: Retrospective identification of all twin pregnancies in maternal SCD patients between 2006 and 2016 at Guy's and St. Thomas' Hospital, United Kingdom Results: Eight women were included: seven with HbSS and one with HbSC. Our cohort experienced common SCD-related and pregnancy-related complications such as painful vaso-occlusive crises (VOC), acute chest syndrome (ACS), and pre-eclampsia and less common complications such as peri-partum cardiomyopathy and delayed hemolytic transfusion reaction. Only two out of eight women had relatively uncomplicated pregnancies. Seven out of eight women required transfusion antenatally and there was no maternal or perinatal mortality. A review of the available literature highlighted the lack of available information on this uncommon cohort. It was evident that outcomes have improved over the years, where historical studies demonstrate higher rates of maternal and perinatal mortality. DISCUSSION: The antenatal and postnatal complications described in our study and literature review highlights the significant morbidity and mortality associated with these high-risk pregnancies. CONCLUSION: Our case series highlights the advantage of closer monitoring and comprehensive multidisciplinary care in delivering improved clinical outcomes.

Acute chest syndrome in sickle cell anaemia: higher serum levels of interleukin-8 and highly sensitive C-reactive proteins are associated with impaired lung function.

BACKGROUND: Sickle cell anaemia (SCA) is a chronic inflammatory disorder with multiple organ manifestations including acute and long-term pulmonary dysfunction. AIMS/OBJECTIVES: To assess lung function of children with SCA and determine the possible role of acute chest syndrome (ACS), serum inflammatory cytokines, highly sensitive C-reactive protein (hs-CRP), leucocytes and 25-hydroxyvitamin D on the development of impaired lung function. SUBJECTS AND METHODS: Lung function of 76 children with SCA was determined by spirometer and classified into normal or impaired. Sociodemographic, clinical, haematological, biochemical and immunological data of the two groups were compared by univariate and multivariate analyses. RESULTS: Fifty (65.8%) patients had impaired lung function, comprising of 30.3%, 3.9% and 31.6% with restrictive, obstructive and mixed disease patterns, respectively. Children with previous ACS were 3.6 times more likely to have impaired lung function than those without ACS (82.1% vs 56.3%, p = 0.02, OR 3.6, 95% CI 1.2-10.8). Interleukin (IL)-8 and hs-CRP were significantly higher in patients with impaired lung function (p = 0.02 and <0.001, respectively). Using logistic regression, previous ACS (OR 5.8, 95% CI 1.1-5.8, p = 0.03) and higher serum IL-8 levels (OR 3.0, 95% CI 1.0-8.0, p = 0.02) independently predicted the presence of abnormal lung function. CONCLUSIONS: Lung dysfunction, predominantly restrictive pattern, is common in SCA and is associated with previous ACS and alterations in immunological markers, especially serum IL-8 and hs-CRP. ABBREVIATIONS: ACS: acute chest syndrome; CBT: chronic blood transfusion; ELISA: enzyme-linked immunosorbent assay; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; HPLC: high-density liquid chromatography; hs-CRP: highly sensitive C-reactive proteins; HU: hydroxyurea; IL: Interleukin; PEFR: peak expiratory flow rate; SEM: standard error of the mean; TLC: total lung capacity; 25-OHD: 25-hydroxyvitamin D; VOC: vaso-occlusive crisis; WGH: Wesley Guild Hospital.

The McConnell Sign is Seen in Patients With Acute Chest Syndrome.

Bedside ultrasound is often used as a part of the evaluation of patients who are critically ill. The McConnell sign is an important echocardiographic finding in some critically ill patients with pulmonary embolism and an acute right ventricular infarct. We present 3 critically ill patients with confirmed acute chest syndrome who showed the McConnell sign on echocardiography. In patients with sickle cell disease presenting with chest pain and shortness of breath, the presence of the McConnell sign does not narrow the differential diagnosis between pulmonary embolism, an acute right ventricular infarct, and acute chest syndrome.

Perinatal Maternal Mortality in Sickle Cell Anemia: Two Case Reports and Review of the Literature.

As outcomes of patients with sickle cell anemia improve and survival into adulthood with good quality of life and expectation of long-term survival becomes more common, challenges have developed, including issues related to reproduction. Pregnancy is frequently complicated in patients with sickle cell anemia with mortality up to 4.0%. Here we report maternal perinatal mortality in two women with sickle cell anemia who died post-partum due to acute chest syndrome (ACS), caused by bone marrow fat embolism and review the literature pertinent to this subject. Patient A was a 28-year-old woman with sickle cell anemia with multiple complications. At 30 weeks' gestation she developed hemolysis associated with poor placental function necessitating delivery by C-section. The fetus was delivered successfully but she died due to multi organ failure after delivery. Autopsy showed pulmonary and amniotic fluid embolization. Patient B was a 37-year-old woman with uncomplicated sickle cell anemia who presented with pre term labor and crisis, then ACS and fetal distress. The infant was delivered successfully but the patient died after cardiovascular collapse. Autopsy results showed fat and bone marrow embolization as the cause of death. Pregnancy continues to be high risk for patients with sickle cell anemia including those with mild disease. Maternal perinatal mortality could be unpredictable due to serious complications of sickle cell disease. More studies to assess maternal perinatal mortality are needed.

A multiscale analytical model of bronchial airway acoustics.

Sound transmission and resulting airway wall vibration in a complex multiscale viscoelastic model of the subglottal bronchial tree was calculated using a modified one-dimensional (1D) branching acoustic waveguide approach. This is an extension of previous work to enable use of complex airway trees that are partially derived from subject-specific medical images, without the need for self-similarity in the geometric structure. The approach was validated numerically for simplified airway geometries, as well as experimentally by comparison to previous studies. A comprehensive conducting airway tree with about 60 000 branches was then modified to create fibrotic, bronchoconstrictive, and pulmonary infiltrate conditions. The fibrotic case-systemic increase in soft tissue stiffness-increased the Helmholtz resonance frequency due to the increased acoustic impedance. Bronchoconstriction, with geometric changes in small conducting airways, decreased acoustic energy transmission to the peripheral airways due in part to the increased impedance mismatch between airway orders. Pulmonary infiltrate significantly altered the local acoustic field in the affected lobe. Calculation of acoustic differences between healthy versus pathologic cases can be used to enhance the understanding of vibro-acoustic changes correlated to pathology, and potentially provide improved tools for the diagnosis of pulmonary diseases that uniquely alter the acoustics of the airways.

Alpha-thalassaemia promotes frequent vaso-occlusive crises in children with sickle cell anaemia through haemorheological changes.

BACKGROUND: Sickle cell anaemia (SCA) is a severe hereditary haemoglobinopathy characterised by haemorheological abnormalities, which play a role in the occurrence of several acute and chronic clinical complications. While ßS -haplotypes and alpha-thalassaemia modulate SCA clinical severity, their effects on blood rheology have been incompletely described. The aim of this study was to test the effects of these genetic modifiers on the haemorheological properties and clinical complication of children with SCA. PROCEDURE: Steady-state haemorheological profile, biological parameters, ßS -haplotypes, alpha-globin status, vaso-occlusive crisis (VOC) and acute chest syndrome frequencies were analysed in 128 children (aged 5 to 18 years) with SCA. RESULTS: Patients with alpha-thalassaemia showed increased red blood cell (RBC) deformability and aggregation compared to those without. Median VOC rate was higher in patients with homozygous alpha-thalassaemia compared to those with a normal alpha genotype. Conversely, the haemorheological profile and clinical complications were not influenced by the ßS -haplotypes in our study. CONCLUSION: Our results demonstrate that alpha-thalassaemia is associated with higher risk for VOC events in children with SCA, which may be due in part to its effects on RBC deformability and aggregation.

Pulmonary platelet thrombi and vascular pathology in acute chest syndrome in patients with sickle cell disease.

A growing body of evidence suggests a role for platelets in sickle cell disease (SCD). Despite the proinflammatory, occlusive nature of platelets, a role for platelets in acute chest syndrome (ACS), however, remains understudied. To provide evidence and potentially describe contributory factors for a putative link between ACS and platelets, we performed an autopsy study of 20 SCD cases-10 of whom died from ACS and 10 whose deaths were not ACS-related. Pulmonary histopathology and case history were collected. We discovered that disseminated pulmonary platelet thrombi were present in 3 out of 10 of cases with ACS, but none of the matched cases without ACS. Those cases with detected thrombi were associated with significant deposition of endothelial vWF and detection of large vWF aggregates adhered to endothelium. Potential clinical risk factors were younger age and higher platelet count at presentation. However, we also noted a sharp and significant decline in platelet count prior to death in each case with platelet thrombi in the lungs. In this study, neither hydroxyurea use nor perimortem transfusion was associated with platelet thrombi. Surprisingly, in all cases, there was profound pulmonary artery remodeling with both thrombotic and proliferative pulmonary plexiform lesions. The severity of remodeling was not associated with a severe history of ACS, or hydroxyurea use, but was inversely correlated with age. We thus provide evidence of undocumented presence of platelet thrombi in cases of fatal ACS and describe clinical correlates. We also provide novel correlates of pulmonary remodeling in SCD.

Golden tracheal secretions and bronchoalveolar fluid during acute chest syndrome in sickle cell disease.

Acute chest syndrome (ACS) is the leading cause of ICU admission in patients with sickle cell disease and is characterized by golden sputum, which is commonly attributed to the presence of bilirubin. Three young consecutive patients with homozygous sickle cell disease were admitted for severe acute respiratory syndrome due to ACS. In all 3 patients, tracheal secretions and bronchoalveolar lavage fluid (BALF) showed a yellowish plasma-like stain. After normalization for the plasma-to-BAL urea ratio, BALF protein and lactate dehydrogenase levels were consistent with an exudative process. BALF bilirubin concentrations were very low, implying that the yellowish stain was not related to bilirubin content. The yellowish coloration of tracheal secretions and BALF observed during ACS appears to be related to an intense exudative process rather than to the presence of bilirubin.