The Gut Microbiome Regulates Psychological-Stress-Induced Inflammation.

Psychological stress has adverse effects on various human diseases, including those of the cardiovascular system. However, the mechanisms by which stress influences disease activity remain unclear. Here, using vaso-occlusive episodes (VOEs) of sickle cell disease as a vascular disease model, we show that stress promotes VOEs by eliciting a glucocorticoid hormonal response that augments gut permeability, leading to microbiota-dependent interleukin-17A (IL-17A) secretion from T helper 17 (Th17) cells of the lamina propria, followed by the expansion of the circulating pool of aged neutrophils that trigger VOEs. We identify segmented filamentous bacteria as the commensal essential for the stress-induced expansion of aged neutrophils that enhance VOEs in mice. Importantly, the inhibition of glucocorticoids synthesis, blockade of IL-17A, or depletion of the Th17 cell-inducing gut microbiota markedly reduces stress-induced VOEs. These results offer potential therapeutic targets to limit the impact of psychological stress on acute vascular occlusion.

Neutrophils as drivers of vascular injury in sickle cell disease.

While neutrophils are the main effectors of protective innate immune responses, they are also key players in inflammatory pathologies. Sickle cell disease (SCD) is a genetic blood disorder in which red blood cells (RBCs) are constantly destroyed in the circulation which generates a highly inflammatory environment that culminates in vascular occlusions. Vaso-occlusion is the hallmark of SCD and a predictor of disease severity. Neutrophils initiate and propagate SCD-related vaso-occlusion through adhesive interactions with the activated and dysfunctional endothelium, sickle RBCs, and platelets, leading to acute and chronic complications that progress to irreversible organ damage and ultimately death. The use of SCD humanized mouse models, in combination with in vivo imaging techniques, has emerged as a fundamental tool to understand the dynamics of neutrophils under complex inflammatory contexts and their contribution to vascular injury in SCD. In this review, we discuss the various mechanisms by which circulating neutrophils sense and respond to the wide range of stimuli present in the blood of SCD patients and mice. We argue that the central role of neutrophils in SCD can be rationalized to develop targets for the management of clinical complications in SCD patients.

Endothelial VWF is critical for the pathogenesis of vaso-occlusive episode in a mouse model of sickle cell disease.

Vaso-occlusive episode (VOE) is a common and critical complication of sickle cell disease (SCD). Its pathogenesis is incompletely understood. von Willebrand factor (VWF), a multimeric plasma hemostatic protein synthesized and secreted by endothelial cells and platelets, is increased during a VOE. However, whether and how VWF contributes to the pathogenesis of VOE is not fully understood. In this study, we found increased VWF levels during tumor necrosis factor (TNF)-induced VOE in a humanized mouse model of SCD. Deletion of endothelial VWF decreased hemolysis, vascular occlusion, and organ damage caused by TNF-induced VOE in SCD mice. Moreover, administering ADAMTS13, the VWF-cleaving plasma protease, reduced plasma VWF levels, decreased inflammation and vaso-occlusion, and alleviated organ damage during VOE. These data suggest that promoting VWF cleavage via ADAMTS13 may be an effective treatment for reducing hemolysis, inflammation, and vaso-occlusion during VOE.

Sex-disaggregated analysis of acute kidney injury in hospitalized children with sickle cell anemia in Uganda.

A growing body of research is categorizing sex differences in both sickle cell anemia (SCA) and acute kidney injury (AKI); however, most of this work is being conducted in high-resource settings. Here, we evaluated risk factors and clinical parameters associated with AKI and AKI severity, stratified by sex, in a cohort of children hospitalized with SCA and vaso-occlusive pain crisis (VOC). The purpose of this study was to explore sex disparities in a high-risk, vulnerable population. This study was a secondary analysis of data collected from a cohort of Ugandan children between 2 and 18 yr of age prospectively enrolled. A total of 185 children were enrolled in the primary study; 41.6% were female and 58.4% were male, with a median age of 8.9 yr. Incident or worsening AKI (P = 0.026) occurred more frequently in female compared with male children, despite no differences in AKI on admission. Female children also had altered markers of renal function including higher creatinine levels at admission (P = 0.03), higher peak creatinine (P = 0.006), and higher urine neutrophil gelatinase-associated lipocalin (NGAL) at admission (P = 0.003) compared with male children. Female children had elevated total (P = 0.045) and conjugated bilirubin at admission (P = 0.02) compared with male children and higher rates of hematuria at admission (P = 0.004). Here, we report sex differences in AKI in children with SCA and VOC, including increased incidence and worsening of AKI in female pediatric patients, in association with an increase in biological indicators of poor renal function including creatinine, estimated glomerular filtration rate, and NGAL.NEW & NOTEWORTHY In this study, we report an increased risk of developing acute kidney injury (AKI) during hospitalization, worsening AKI, and death among females with sickle cell anemia (SCA) hospitalized with an acute pain crisis compared with males. The sex differences in AKI were not explained by socioeconomic differences, severity of pain, or disease severity among females compared with males. Together, these data suggest that female children with SCA may be at increased risk of AKI.

Exploring the role of viscosity-vaso-occlusion and haemolysis-endothelial dysfunction in pain sensitization among Jamaicans with sickle cell disease.

Viscosity-vaso-occlusion (VVO) and haemolysis-endothelial dysfunction (HED) are pathophysiological mechanisms and clinical subphenotypes of sickle cell disease (SCD). Recurrent vaso-occlusive crises (VOC) may lead to neuroplastic changes and pain sensitization. Among 257 SCD participants, we assessed the relationship of subphenotypes with pain sensitivity using quantitative sensory testing to identify heat pain thresholds (HPT) and pressure pain thresholds (PPT). VOC history and sleep, social and emotional functioning were assessed using the Adult Sickle Cell Quality of Life Measurement Information System. The 'elbow method' determined the optimal number of clusters as three. Clustering was performed using K-prototypes. Among clusters 2 and 3, VOC frequency and severity were higher. Clusters 1 and 3 had lower haemoglobin, higher reticulocytes and lactate dehydrogenase and more leg ulcers. In multivariate regression, cluster 3 was associated with approximately 13.6% lower PPT compared to cluster 1, and female sex was associated with decreases in PPT and HPT at the hands and feet (p < 0.001). Hydroxyurea use and unit increases in sleep functioning and age were associated with approximately 20.1% higher foot-PPT, 6.8% higher hand-PPT and 2.5% higher hand-HPT and foot-HPT respectively. Findings suggest that a third subphenotype with mixed VVO and HED features and worse pain sensitization may exist.

Sickle cell disease in India: Not just a mild condition.

Sickle cell disease (SCD) is a common and life-threatening global health problem, with more than 500 000 affected infants born annually. The burden of SCD in sub-Saharan Africa is well established, but the comparably high prevalence in India is not well recognized and many consider SCD in India to be less severe. In their paper, a national study in India demonstrated the significant impact of SCD for patients, families and the healthcare system, supporting a call to action to recognize and address SCD as a serious and common health condition in India. Commentary on: Seth et al. Burden of vaso-occlusive crisis, its management, and impact on quality of life of Indian sickle cell disease patients. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19829.

Burden of vaso-occlusive crisis, its management and impact on quality of life of Indian sickle cell disease patients.

Sickle cell disease (SCD) with vaso-occlusive pain crisis (VOC) significantly impacts patient well-being and often results in extensive healthcare resource utilization. This study assessed the VOC burden, its management and its impact on patients' quality of life (QoL). A cross-sectional observational study was conducted between November 2021 and June 2022, including 1000 SCD patients from high-prevalence states in India. Data on demographics, clinical characteristics, VOC severity, management and QoL were collected. The study revealed that 33.5% of patients reported at least one VOC episode during the study period. In the year prior to their enrolment, 836 (83.60%) patients reported at least one VOC episode, with an equal proportion of 407/487 (83.6%) adults and 429/513 (83.6%) paediatric patients, reducing their QoL across all domains compared to patients without VOC. Of these, 469/1000 patients (46.9%) experienced ≥3 VOC episodes. Additionally, 764/1000 (76.40%) patients managed their VOCs at healthcare facilities, with 501/1000 (50.1%) requiring inpatient admissions. Further, 71.80% of patients received Hydroxyurea (HU) therapy. The study depicts the severity of the Arab-Indian haplotype in Indian SCD patients visiting healthcare settings based on high VOC burden. This highlights the urgent need for better management strategies and resource allocation for these patients.

On the optimization of 3D inflow-based vascular-space-occupancy (iVASO) MRI for the quantification of arterial cerebral blood volume (CBVa).

PURPOSE: The inflow-based vascular-space-occupancy (iVASO) MRI was originally developed in a single-slice mode to measure arterial cerebral blood volume (CBVa). When vascular crushers are applied in iVASO, the signals can be sensitized predominantly to small pial arteries and arterioles. The purpose of this study is to perform a systematic optimization and evaluation of a 3D iVASO sequence on both 3 T and 7 T for the quantification of CBVa values in the human brain. METHODS: Three sets of experiments were performed in three separate cohorts. (1) 3D iVASO MRI protocols were compared to single-slice iVASO, and the reproducibility of whole-brain 3D iVASO MRI was evaluated. (2) The effects from different vascular crushers in iVASO were assessed. (3) 3D iVASO MRI results were evaluated in arterial and venous blood vessels identified using ultrasmall-superparamagnetic-iron-oxides-enhanced MRI to validate its arterial origin. RESULTS: 3D iVASO scans showed signal-to-noise ratio (SNR) and CBVa measures consistent with single-slice iVASO with reasonable intrasubject reproducibility. Among the iVASO scans performed with different vascular crushers, the whole-brain 3D iVASO scan with a motion-sensitized-driven-equilibrium preparation with two binomial refocusing pulses and an effective TE of 50 ms showed the best suppression of macrovascular signals, with a relatively low specific absorption rate. When no vascular crusher was applied, the CBVa maps from 3D iVASO scans showed large CBVa values in arterial vessels but well-suppressed signals in venous vessels. CONCLUSION: A whole-brain 3D iVASO MRI scan was optimized for CBVa measurement in the human brain. When only microvascular signals are desired, a motion-sensitized-driven-equilibrium-based vascular crusher with binomial refocusing pulses can be applied in 3D iVASO.

Expert consensus on the management of infusion-related reactions (IRRs) in patients with sickle cell disease (SCD) receiving crizanlizumab: a RAND/UCLA modified Delphi panel.

Crizanlizumab, a monoclonal antibody against P-selectin, has been shown to reduce vaso-occlusive crises (VOCs) compared to placebo in patients ≥ 16 years with sickle cell disease (SCD). However, there have been rare reports of patients experiencing severe pain and subsequent complications within 24 hours of crizanlizumab infusions. These events are defined as infusion-related reactions (IRRs). Informed by current literature and clinical experience, a group of content experts developed clinical guidelines for the management of IRRs in patients with SCD. We used the RAND/University of California, Los Angeles (UCLA) modified Delphi panel method, a valid, reproducible technique for achieving consensus. We present our recommendations for managing IRRs, which depend on patient characteristics including: prior history of IRRs to other monoclonal antibodies or medications, changes to crizanlizumab infusion rate and patient monitoring, pain severity relative to patient's typical SCD crises, and severe allergic symptoms. These recommendations outline how to evaluate and manage IRRs in patients receiving crizanlizumab. Future research should validate this guidance using clinical data and identify patients at risk for these IRRs.

Safety and efficacy of L-Glutamine in reducing the frequency of acute complications among patients with sickle cell disease: A randomized controlled study.

To evaluate the safety and efficacy of L-glutamine in reducing vaso-occlusive crisis (VOC) and improving cerebral arterial blood flow in children with sickle cell disease (SCD). This is an interventional randomized controlled trial that recruited sixty SCD patients, aged 9.2 ± 3.7 years, who had at least two VOCs during the last 12 months and on a stable dose of hydroxyurea. They were randomly assigned in a 1:1 ratio to receive glutamine (0.3 gm/kg/dose/12h) orally for 24 weeks or the standard of care (SOC). All patients had VOCs in the last year > 3, those on glutamine had a higher number of VOCs and hospitalization for VOC in the last year. There was a decreasing trend in the number, severity, and hospitalization of VOC and a significantly lower cumulative number of VOCs and hospitalizations in the glutamine group than in SOC (p = 0.008, p < 0.001 respectively). Time-averaged mean maximum velocity for the glutamine group had a marginal increase in both middle cerebral arteries, all values remained normal within a normal range, and in both internal carotid arteries, values increased from abnormally low to normal ranges at week 24. Glutamine reduced the number of VOCs and severity and may have a potentially favorable impact on the cerebral arterial flow velocities.

Nitric oxide: A potential etiological agent for vaso-occlusive crises in sickle cell disease.

Nitric oxide (NO), a vasodilator contributes to the vaso-occlusive crisis associated with the sickle cell disease (SCD). Vascular nitric oxide helps in vasodilation, controlled platelet aggregation, and preventing adhesion of sickled red blood cells to the endothelium. It decreases the expression of pro-inflammatory genes responsible for atherogenesis associated with SCD. Haemolysis and activated endothelium in SCD patients reduce the bioavailability of NO which promotes the severity of sickle cell disease mainly causes vaso-occlusive crises. Additionally, NO depletion can also contribute to the formation of thrombus, which can cause serious complications such as stroke, pulmonary embolism etc. Understanding the multifaceted role of NO provides valuable insights into its therapeutic potential for managing SCD and preventing associated complications. Various clinical trials and studies suggested the importance of artificially induced nitric oxide and its supplements in the reduction of severity. Further research on the mechanisms of NO depletion in SCD is needed to develop more effective treatment strategies and improve the management of this debilitating disease.

Society for Maternal-Fetal Medicine Consult Series #68: Sickle cell disease in pregnancy.

Pregnant individuals with sickle cell disease have an increased risk of maternal and perinatal morbidity and mortality. However, prepregnancy counseling and multidisciplinary care can lead to favorable maternal and neonatal outcomes. In this consult series, we summarize what is known about sickle cell disease and provide guidance for sickle cell disease management during pregnancy. The following are Society for Maternal-Fetal Medicine recommendations.

Real-World Evidence of Crizanlizumab Showing Reductions in Vaso-Occlusive Crises and Opioid Usage in Sickle Cell Disease.

OBJECTIVE: Access to crizanlizumab, a disease-modifying therapy for sickle cell disease (SCD), was provided through a managed access program (MAP, NCT03720626). The present analysis evaluated the impact of 12 months of crizanlizumab treatment on vaso-occlusive crises (VOCs), and on the use of opioids for VOC-related pain relief, in patients with SCD from the MAP. METHODS: From June 2018 to January 2023, 112 patients with a history of recurrent VOCs completed 12 months of crizanlizumab (5 mg/kg) treatment and were monitored for adverse events (AEs). RESULTS: Crizanlizumab led to reductions of 18.0% and 36.2% in the proportions of patients having ≥ 1 home- and ≥ 1 healthcare-managed VOCs. Median absolute changes (interquartile range) from baseline in the rates of home- and healthcare-managed VOCs were -3.0 (-6.0, -1.0) and -2.0 (-4.0, 0), respectively. Data stratified by genotype and prior hydroxyurea use showed similar reductions in VOC rates. A 35.5% reduction in the proportion of patients requiring opioids was noted. AEs were consistent with earlier reports, and no new safety concerns were identified. CONCLUSIONS: Crizanlizumab demonstrated potential benefits in attenuating VOC episodes, irrespective of SCD genotype and prior hydroxyurea use, and in lowering opioid usage. The safety of crizanlizumab was consistent with earlier reports. TRIAL REGISTRATION: The MAP has been registered at ClinicalTrials.gov with the ID, NCT03720626.

Targeting ICAM1 to Ameliorate Vaso-Occlusion and Inflammation in Sickle Cell Disease.

Sickle cell disease (SCD) is a hereditary disorder characterized by vaso-occlusion, inflammation, and tissue damage. Intercellular adhesion molecule 1 (ICAM-1) plays a crucial role in the pathophysiology of SCD by promoting the adhesion of sickle cells to the endothelium, contributing to vaso-occlusion and tissue damage. The ICAM-1 gene encodes a glycoprotein that interacts with lymphocyte function-associated antigen 1 (LFA-1) and macrophage 1-antigen (Mac-1) receptors, perpetuating inflammation, and oxidative stress. The NF-κB signaling pathway regulates ICAM-1 expression, which is elevated in patients with SCD, leading to increased endothelial cell activation and damage. Targeting ICAM-1 and its interactions with sickle cells and the endothelium has emerged as a potential therapeutic strategy for managing SCD. This review highlights the complex interplay between ICAM-1, sickle cells, and the endothelium, and discusses the potential of ICAM-1-targeted therapies for mitigating VOC and improving the quality of life for patients with SCD.

Biomarkers to Differentiate Acute Chest Syndrome From Vaso-Occlusive Crisis in Children With Sickle Cell Disease.

BACKGROUND: Acute Chest Syndrome (ACS) is the leading cause of death in children with sickle cell disease (SCD) in the US-about half of the children who develop ACS present initially with pain. METHODS: Here, we studied biomarkers to differentiate ACS from vaso-occlusive crises (VOC) in children with SCD who presented with pain to the emergency department (ED). We conducted a prospective cohort study of consecutive patients who presented to the ED with pain and were discharged with ACS or VOC between March, 2017 and February, 2020. RESULTS: We identified 7 patients with ACS and 19 patients with VOC. The two groups were comparable in age and sex. All patients with ACS had asthma versus 42% of the VOC group. The ACS group had lower weight and BMI z-scores. Patients with ACS compared to VOC had significantly higher respiratory rates, lower O2 saturation, and longer hospital stays. They also had higher white blood cell count, glucose level (> 99 mg/dL), anion gap (> 9 mEq/L), sPLA2 (> 7 pg/mL), IFN-γ (> 17.8 pg/mL), IL-10 (1.54 pg/mL), and IL-12 (> 0.5 pg/mL) levels. CONCLUSIONS: We identified biomarkers associated with ACS development in children with SCD presenting with pain that allow for earlier ACS interventions to reduce mortality and morbidity.

Intravenous fluid therapy and hospital outcomes for vaso-occlusive episodes in children, adolescents, and young adults with sickle cell disease.

BACKGROUND: While intravenous fluid (IVF) therapy in patients with sickle cell disease (SCD) admitted for a vaso-occlusive episode (VOE) can help reduce red blood cell sickling, clinical practice varies across institutions. We examined the relationship between IVF therapy and hospital length of stay (HLOS), as well as adverse events, such as acute chest syndrome (ACS), pediatric intensive care unit (PICU) transfer, and 28-day re-admission. METHODS: This is a single-center retrospective analysis of SCD VOE hospitalizations between January 2015 and April 2020. Patients with SCD, age 0-30, with consecutive hospitalizations for VOE were included. For the first 3 days of each admission, an "IVF ratio" was calculated by dividing actual IVF rate administered by weight-based maintenance IVF (mIVF) rate. RESULTS: A total of 617 hospitalizations for 161 patients were included. Mean HLOS was 5.7 days, (SD 3.9), and mean IVF volume over the first 3 days of admission was 139.6 mL/kg/day (SD 57.8). Multivariate analysis showed that for each additional 0.5 times the mIVF rate, HLOS increased by 0.53 day (p < .001; 95% confidence interval [CI]: 0.609-0.989), but there was no significant association between IVF therapy and adverse events. History of chronic pain was associated with increased odds of re-admission (OR 6.4; 95% CI: 3.93-10.52). CONCLUSIONS: Despite the theoretical potential for IVF therapy to slow down the sickling process, our findings suggest that increased IVF therapy was associated with prolonged HLOS, which places a burden on patients, families, and the health system.

Inflammatory and vaso-occlusive ulcers: Part I - clinical presentation and diagnosis.

In this CME, we review two specific categories of ulcers: inflammatory (where inflammation is the primary pathologic process leading to ulceration) and vaso-occlusive (where occlusion is the primary process). Inflammatory ulcers include pyoderma gangrenosum and vasculitides, whereas livedoid vasculopathy, calciphylaxis and Martorell ulcers are vaso-occlusive ulcers. Determining the causes of ulcers in these conditions may require laboratory evaluation, biopsy and imaging.

Inflammatory and vaso-occlusive ulcers: Part II - Management.

In the second part of this CME, we present an approach for the management of inflammatory and vaso-occlusive ulcers and highlight the need for further research in this field. The three overarching principles for management are etiology-specific treatment, ulcer care, and consideration of patient comorbidities and risk factors for poor healing. Both etiology-specific treatment and management of patient comorbidities and risk factors often require collaboration with providers from other specialties. Ulcer care is governed by TIME, or tissue debridement, infection control, management of moisture imbalance and epithelial edge advancement. As wound healing is a dynamic process, management should be adapted to changes in the status of the ulcer.

Simultaneous bilateral purtscher like retinopathy with systemic lupus erythematosus: a case.

BACKGROUD: Systemic lupus erythematosus is an unexplained autoimmune disease involving multiple systems throughout the body, and its ocular changes include dry eye, monocular or binocular visual field defects, vaso-occlusive diseases, or ischemic optic neuropathy. CASE PRESENTATION: This article reports a patient with SLE complicated with bilateral Purtscher like retinopathy, who had a sudden decrease in ocular vision as the first symptom, the autoantibodies related to phospholipid syndrome showed no abnormality, and both anti-dsDNA antibodies and anti-SM antibodies were significantly positive, indicating that anti-dsDNA antibodies and anti-SM antibodies were also important factors in the pathogenesis of Purtscher like retinopathy. CONCLUSION: The close relationship between SLE retinopathy and systemic inflammatory activities and emphasize the importance of systemic immunotherapy.

Trends and hospital practice variation for analgesia for children with sickle cell disease with vaso-occlusive pain episodes: An 11-year analysis.

This cross-sectional analysis of 86,111 visits for sickle cell disease and vaso-occlusive episodes (VOE) in U.S. pediatric emergency departments between 2013 and 2023 shows increased use of NSAIDs, ketamine, and acetaminophen, with unchanged opioid use. Hospitals with a higher volume of VOE visits more frequently administered opioids. BACKGROUND: Vaso-occlusive episodes (VOEs) are a hallmark of sickle cell disease (SCD), leading to frequent emergency department (ED) visits. Effective pain management is crucial, with guidelines recommending routine use of non-steroidal anti-inflammatory drugs (NSAIDs) with opioids, and emerging evidence supporting ketamine use. However, these recommendations are based on low-certainty evidence, and the impact of these guidelines on analgesia use over time remains unclear. OBJECTIVE: This study aimed to analyze trends in analgesia use over an 11-year period in pediatric SCD patients presenting to U.S. EDs with VOE and assess variations in treatment across hospitals. METHODS: A cross-sectional study was conducted using data from the Pediatric Health Information System covering 34 U.S. children's hospitals from January 1, 2013, to December 31, 2023. The primary outcomes were the proportions of visits where opioids, NSAIDs, acetaminophen, and/or ketamine were administered on the first calendar day of the initial visit. Secondary outcomes included the co-administration of NSAIDs with opioids. Logistic and linear regression models were used to assess trends and hospital-level variations. RESULTS: A total of 86,111 ED visits for VOE were analyzed. Opioids were administered in 82 % of encounters, NSAIDs in 72 %, acetaminophen in 17 %, and ketamine in 1 %. Co-administration of NSAIDs with opioids occurred in 59 % of the visits. Among discharged patients, there was a positive trend for NSAID use (slope: 1.68 %/year, 95 % CI: 0.91 %, 2.45 %) and NSAID-opioid co-administration (slope: 1.03 %/year, 95 % CI: 0.37 %, 1.69 %) over time. Acetaminophen use also increased over the study period (slope: 0.99 %/year, 95 % CI: 0.80 %, 1.17 %). In hospitalized patients, there was a significant upward trend for acetaminophen (slope: 1.29 %/year, 95 % CI: 0.69 %, 1.89 %) and ketamine (slope: 0.36 %/year, 95 % CI: 0.27 %, 0.45 %), while opioid use remained unchanged. Significant hospital-level variations were observed, with larger hospitals more likely to administer opioids but less likely to co-administer NSAIDs with opioids compared to medium-volume hospitals. CONCLUSION: Over the past decade, the use of NSAIDs, acetaminophen, and ketamine has increased in the management of VOE in pediatric SCD patients, while opioid use remains consistent. The co-administration of NSAIDs and opioids has also increased, reflecting guideline adherence. Variations in analgesia practices across hospitals underscore the need for standardizing pain management strategies in this population.