Successful Use of Bortezomib in an Adolescent with Refractory TTP.

With increasing early and upfront use of rituximab and caplacizumab in the modern management of immune-mediated thrombotic thrombocytopenic purpura (iTTP), the risk of refractory disease is expected to decline. However, despite the use of adequate initial therapy, a small subset of patients develop a refractory disease which is difficult to manage. Bortezomib has come to be known as a safe and effective treatment option for refractory iTTP, but its use in children is limited. Here, we describe the case of an adolescent patient with refractory iTTP who had a satisfactory and sustained response to the use of bortezomib.

Impact of obesity on factor VIII and von Willebrand factor levels in patients with Type 1 von Willebrand disease and low von Willebrand factor: An analysis of the ATHNdataset.

INTRODUCTION: Obesity is associated with endothelial dysfunction, haemostatic and fibrinolytic disturbances, however the impact of obesity on von Willebrand factor (VWF) is unclear. AIM: The aim of this study was to test our hypothesis that the prevalence of obesity is higher among participants with low VWF (LVWF) compared to type 1 von Willebrand disease (T1VWD). METHODS: A retrospective review of the ATHNdataset as of March 2018 was performed. Participants were categorized as T1VWD if their VWF ristocetin cofactor activity was 30 IU/dL and LVWF if the values were 30-50 IU/dL, and by the NIH definitions for body mass index (BMI) for adult participants (≥ 18 years of age) or BMI z-score for paediatric participants (< 18 years). RESULTS: The prevalence of obesity was not significantly different between adults with T1VWD (n = 186) and LVWF (n = 362) (32% vs 36%; p = .345). The mean factor VIII (FVIII) increased with increasing BMIs in both groups. In the paediatric cohort (T1VWD, n = 583; LVWF, n = 1702), there was no difference in the prevalence of obesity, but BMI was positively correlated with mean FVIII (p < .001). Children < 10 years were 27.6% more likely to be diagnosed with T1VWD compared to > 10 years. CONCLUSION: Among participants in the ATHNdataset, the prevalence of obesity was similar among those with LVWF and T1VWD. However, higher BMI levels were associated with elevated FVIII. Further research is needed to evaluate the impact of obesity on bleeding phenotype and treatment practices.

Current practices in pediatric hospital-acquired thromboembolism: Survey of the Children's Hospital Acquired Thrombosis (CHAT) Consortium.

Background: A rise in hospital-acquired venous thromboembolism (HA-VTE) in children has led to increased awareness regarding VTE prophylaxis and risk assessment. Despite no consensus exists regarding these practices in pediatrics. Objective: To describe common practices in VTE prophylaxis, VTE risk assessment models, and anticoagulation dosing strategies in pediatric hospitals that are members of the Children's Hospital Acquired Thrombosis (CHAT) Consortium. Methods: An electronic survey of 44 questions evaluating practices surrounding pediatric HA-VTE risk assessment and prevention was distributed between August 9, 2021, and August 30, 2021, to the primary investigators from the 32 institutions within the CHAT Consortium. Results: The survey response rate was 100% (n = 32). In total, 85% (n = 27) of the institutions assess HA-VTE, but only 63% (n = 20) have formal hospital guidelines. Within the institutions with formal guidelines, 100% (n = 20) include acute systemic inflammation or infection and presence of a central venous catheter (CVC) as risk factors for VTE. Pharmacologic prophylaxis is prescribed at 87% (28) of institutions, with enoxaparin being the most frequent (96%, n = 27). Variability in responses persisted regarding risk factors, risk assessment, thromboprophylaxis, dosing of prophylactic anticoagulation or anticoagulant drug monitoring. A majority of providers were comfortable providing thromboprophylaxis across all age groups. In addition, the global coronavirus disease 2019 increased the providers' use of prophylactic anticoagulation 78% (n = 25). Conclusion: Practices among institutions are variable in regard to use of HA-VTE prophylaxis, risk assessment, or guideline implementation, highlighting the need for further research and a validated risk assessment model through groups like the CHAT Consortium.

Blockade of the Terminal Complement Cascade Using Ravulizumab in a Pediatric Patient With Anti-complement Factor H Autoantibody-Associated aHUS: A Case Report and Literature Review.

Atypical hemolytic uremic syndrome (aHUS) is a rare disease in pediatrics with 6-10% of cases associated with complement factor H autoantibodies. Ravulizumab is a new treatment option available for long-term management through blockage of the terminal complement cascade. We report a case of a previously healthy eight-year-old female who presented with hemolytic anemia, thrombocytopenia, and acute kidney injury. Low complement C3, normal ADAMTS13, and negative rheumatology and infectious disease panels suggested aHUS. A follow-up complement aHUS/TMA gene panel was negative for ADAMTS13, C3, CD46, CFB, CFD, CFH, CFHR1, CFHR3, CFHR5, CRI, DGKE, PLG, and THBD mutations and positive for MCP/CD46 haplotype and CFH-H3 haplotype. Further testing found decreased factor H (B1H) plasma level and increased factor H autoantibody, suggesting anti-factor H antibody-associated aHUS. She received hemodialysis (2 treatments) and eculizumab was initiated promptly. The patient had complete renal recovery after one month of therapy, and anemia, thrombocytopenia, and hemolysis resolved after two months of therapy. After five months of therapy, eculizumab was successfully switched to ravulizumab. After 12 months of initial diagnosis, complement C3 and factor H normalized, however, factor H autoantibody remained elevated. The case supports the notion that timely recognition of anti-FH-associated aHUS is important for disease management and that early specific therapy with immunosuppression results in favorable outcomes. It also illustrates that the blockade of the terminal complement cascade using eculizumab holds promise for pediatric cases. Finally, eculizumab can be safely switched to ravulizumab with an optimal longer duration between treatments in the context of aHUS.

Secretors of HBGA and Susceptibility to Norovirus and Rotavirus Diarrhea.

Histo-blood group antigen contains oligosaccharides that serve as receptors for norovirus (NoV) and rotavirus (RV). The receptors are only present on the surface of intestinal mucosal epithelial cells of secretors; therefore, secretors are susceptible to NoV and RV diarrhea and nonsecretors are resistant. The prevalence of secretors in different countries varies between 50% and 90%. Secretor rates evolved in response to environmental pressures such as infectious diseases.

COVID-19 associated Multisystem Inflammatory Syndrome in Children (MIS-C) guidelines; revisiting the Western New York approach as the pandemic evolves.

Multisystem inflammatory syndrome of children (MIS-C) continues to be a highly concerning diagnosis in those recently infected with SARS-CoV-2. The diagnosis of MIS-C cases will likely become even more challenging as vaccine uptake and natural immunity in previously infected persons leads to lower circulating rates of SARS-CoV-2 infection and will make cases sporadic. Febrile children presenting with cardiac dysfunction, symptoms overlapping Kawasaki disease or significant gastrointestinal complaints warrant a thorough screen in emergency departments, urgent care centers, and outpatient pediatric or family medicine practices. An increased index of suspicion and discussion regarding higher level of care (transferring to pediatric tertiary care centers or to intensive care) continues to be recommended. Herein we outline a broad approach with a multidisciplinary team for those meeting the case definition and believe such an approach is crucial for successful outcomes.

Retroperitoneal Sclerosing Lipogranuloma in an Adolescent With Congenital Atresia of the Inferior Vena Cava: Case Report and Literature Review.

Sclerosing lipogranuloma (SLG) in children is a rare, benign disease of unknown etiology suspected to be due to abnormal fatty tissue reaction. A 13-year-old girl presented with progressively worsening back pain. Cross-sectional imaging identified a retroperitoneal mass compressing the left ureter as well as infrarenal inferior vena cava atresia with extensive venous collaterals and chronic partially occlusive thromboses of the iliac veins. Surgical biopsy was consistent with SLG and it resolved spontaneously. SLG is typically a disease of adulthood but may be seen in children. The association between inferior vena cava atresia with venous thrombosis and development of SLG has not been reported previously.

Impact of exogenous antithrombin on low molecular weight heparin anti-Xa activity assays in a pediatric and young adult leukemia and lymphoma cohort with variable antithrombin levels.

BACKGROUND: Low molecular weight heparin (LMWH) remains the most commonly prescribed pediatric anticoagulant. There is debate whether LMWH anti-Xa assays with or without exogenous antithrombin (AT) best reflect anticoagulation effect, and how much discrepancy exists between assay types. OBJECTIVES: We assessed the effect of variable AT activity on LMWH anti-Xa levels in plasma samples from anticoagulated pediatric and young adult acute lymphoblastic leukemia and lymphoma (ALL/L) patients, using two instruments and their commercial kits with and without exogenous AT (ie, four platforms). METHODS: We analyzed LMWH anti-Xa levels on 60 plasma samples with known AT activity from 12 enoxaparin-treated ALL/L patients, using four commercial kits from Siemens and Stago containing AT or not, on Siemens BCS and Stago STA R Max, respectively. RESULTS: Of 236/240 samples with interpretable results, mean AT activity was 80% (46-138%). Correlation was acceptable for published kit ranges of LMWH anti-Xa levels when comparing kits containing AT (r = 0.82, P < .0001), or not (r = 0.93, P < .0001), and within a manufacturer (Berichrom to Innovance, r = 0.92, P < .0001; Stachrom to STA-Liquid Anti-Xa r = 0.98, P < .0001). LMWH anti-Xa levels were lower in platforms without added AT (P < .0001). For Stago kits, this effect increased when AT < 70% (P = .001, n = 19, mean 56%). Assay variability, measured as mean percent difference, was less pronounced with Stago kits (14.7%, n = 49) than Siemens (41.9%, n = 50). CONCLUSIONS: Although LMWH levels from anti-Xa assays with added AT trend higher than in those without, correlation was fairly good between platforms in pediatric ALL/L plasmas, even when AT activity was <70%.

Association of perioperative red blood cell transfusion with postoperative venous thromboembolism in pediatric patients: A propensity score matched analysis.

OBJECTIVE: To examine the association between perioperative red blood cell (RBC) transfusion and postoperative venous thromboembolism (VTE) in pediatric surgical patients. METHODS: Retrospective cohort study using the National Surgical Quality Improvement Project Pediatric, a validated registry of 118 United States children's hospitals. Patients under 19 years of age undergoing a surgical procedure between 2012 and 2017 were included, with the main exposure being RBC transfusion in the perioperative period (48 hours prior to operation to 72 hours after operation). The primary 30-day outcome of interest was a postoperative VTE requiring therapy. Risk-adjusted odds ratios (aOR) were calculated using multiple logistic regression. Subgroup analyses were performed across multiple surgical specialties. Sensitivity analyses were performed after (a) imputation for missing variables and (b) propensity score matching. RESULTS: During the study years, 482 867 pediatric patients (56.7% male; median age, 6 years [interquartile range, 1-12 years]) underwent an operation. Of these, 30 879 (6.4%) received at least one perioperative RBC transfusion. Postoperative VTE requiring therapy occurred in 618 patients (0.13%). After adjustment for multiple risk factors, perioperative RBC transfusion was associated with an increased risk of VTE (aOR 2.4; 95% CI, 1.9-3.0). The increased VTE risk persisted after imputation of missing demographic and clinical data as well as after 1:1 propensity score matching (29 811 matched pairs, aOR 2.2; 95% CI, 1.7-2.8). CONCLUSIONS: Perioperative RBC transfusion is associated with an increased, albeit still very low, risk of postoperative VTE in pediatric patients. Patients receiving blood in the perioperative period may benefit from additional monitoring or VTE prophylaxis.

Sickle cell screening in Uganda: High burden, human immunodeficiency virus comorbidity, and genetic modifiers.

BACKGROUND: The Uganda Sickle Surveillance Study provided evidence for a large sickle burden among HIV-exposed infants in Uganda. To date, however, no large scale screening program has been developed for Central or East Africa. METHODS: A 3-year targeted sickle cell screening project in Uganda was designed by the Ministry of Health to (1) determine sickle cell trait and disease prevalence within high-burden districts, (2) document the prevalence among HIV-exposed and nonexposed children, (3) confirm previously suggested HIV comorbidity, and (4) estimate the co-inheritance of known genetic modifiers of sickle cell disease. RESULTS: A total of 163 334 dried blood spot samples collected between April 2015 and March 2018 were analyzed, including 112 352 samples within the HIV Early Infant Diagnosis program. A high burden with >1% sickle cell disease was found within targeted East Central and Mid-Northern districts, in both HIV-exposed and nonexposed children. Based on crude birth-rate data, 236 905 sickle cell trait births and 16 695 sickle cell disease births will occur annually in Uganda. Compared to sickle cell disease without HIV, the odds ratio of having sickle cell disease plus HIV was 0.50 (95% confidence interval = 0.40-0.64, P < .0001). Alpha-thalassemia trait and G6PD deficiency were common with sickle cell disease, but with different geospatial distribution. CONCLUSIONS: High sickle cell burden and potential HIV comorbidity are confirmed in Uganda. Genetic modifiers are common and likely influence laboratory and clinical phenotypes. These prospective data document that targeted sickle cell screening is feasible and effective in Uganda, and support development of district-level comprehensive care programs.

Genetic ancestry and population differences in levels of inflammatory cytokines in women: Role for evolutionary selection and environmental factors.

Selection pressure due to exposure to infectious pathogens endemic to Africa may explain distinct genetic variations in immune response genes. However, the impact of those genetic variations on human immunity remains understudied, especially within the context of modern lifestyles and living environments, which are drastically different from early humans in sub Saharan Africa. There are few data on population differences in constitutional immune environment, where genetic ancestry and environment are likely two primary sources of variation. In a study integrating genetic, molecular and epidemiologic data, we examined population differences in plasma levels of 14 cytokines involved in innate and adaptive immunity, including those implicated in chronic inflammation, and possible contributing factors to such differences, in 914 AA and 855 EA women. We observed significant differences in 7 cytokines, including higher plasma levels of CCL2, CCL11, IL4 and IL10 in EAs and higher levels of IL1RA and IFNα2 in AAs. Analyses of a wide range of demographic and lifestyle factors showed significant impact, with age, education level, obesity, smoking, and alcohol intake, accounting for some, but not all, observed population differences for the cytokines examined. Levels of two pro-inflammatory chemokines, CCL2 and CCL11, were strongly associated with percent of African ancestry among AAs. Through admixture mapping, the signal was pinpointed to local ancestry at 1q23, with fine-mapping analysis refined to the Duffy-null allele of rs2814778. In AA women, this variant was a major determinant of systemic levels of CCL2 (p = 1.1e-58) and CCL11 (p = 2.2e-110), accounting for 19% and 40% of the phenotypic variance, respectively. Our data reveal strong ancestral footprints in inflammatory chemokine regulation. The Duffy-null allele may indicate a loss of the buffering function for chemokine levels. The substantial immune differences by ancestry may have broad implications to health disparities between AA and EA populations.

Risk factors for venous thromboembolic events in pediatric surgical patients: Defining indications for prophylaxis.

BACKGROUND: Venous thromboembolism (VTE) in pediatric surgical patients is a rare event. The risk factors for VTE in pediatric general surgery patients undergoing abdominopelvic procedures are unknown. STUDY DESIGN: The American College of Surgeon's National Surgical Quality Improvement Program-Pediatric (NSQIP-P) database (2012-2015) was queried for patients with VTE after abdominopelvic general surgery procedures. Patient and operative variables were assessed to identify risk factors associated with VTE and develop a pediatric risk score. RESULTS: From 2012-2015, 68 of 34,813 (0.20%) patients who underwent abdominopelvic general surgery procedures were diagnosed with VTE. On multivariate analysis, there was no increased risk of VTE based on concomitant malignancy, chemotherapy, inflammatory bowel disease, or laparoscopic surgical approach, while a higher rate of VTE was identified among female patients. The odds of experiencing VTE were increased on stepwise regression for patients older than 15 years and those with preexisting renal failure or a diagnosis of septic shock, patients with American Society of Anesthesia (ASA) classification ≥ 2, and for anesthesia time longer than 2 h. The combination of age > 15 years, ASA classification ≥ 2, anesthesia time > 2 h, renal failure, and septic shock was included in a model for predicting risk of VTE (AUC = 0.907, sensitivity 84.4%, specificity 88.2%). CONCLUSION: VTE is rare in pediatric patients, but prediction modeling may help identify those patients at heightened risk. Additional studies are needed to validate the factors identified in this study in a risk assessment model as well as to assess the efficacy and cost-effectiveness of prophylaxis methods. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

What Is Caring in Nursing?: Sorting Out Humanistic and Christian Perspectives.

Historically, some propose that organized nursing was founded on biblical principles and the caring behaviors and characteristics of Christ, and that caring originates with God. More recently, perceptions of caring have shifted to a humanistic, postmodern worldview, where the source of caring is within the person. This integrative literature review synthesized caring literature from humanistic, postmodern, and biblical, theological worldviews. Findings reveal that 95% of research and 85% of nonresearch publications were written from the humanistic perspective. The results lay a foundation for an alternative middle range theory on caring from a biblical worldview for nurses holding Christian beliefs.

TFE3-positive renal cell carcinoma occurring in three children with dysfunctional kidneys on immunosuppression.

Pediatric RCC is a rare pediatric neoplasm and is distinctly different compared to adult RCC, often demonstrating translocation morphology evidenced by unique histopathological features and TFE3 or TFEB nuclear expression. We report three cases of pediatric TFE3 positive RCC (TFE3-RCC) occurring in the setting of chronic kidney disease and long-term pharmacological immunosuppression, including two cases that developed in the native kidney following kidney transplantation. Together, these cases suggest that the kidney microenvironment in combination with immune dysregulation is likely contributing factors in the pathogenesis of some pediatric RCC, warranting further study. Long-term post-transplant surveillance may warrant screening for RCC.

Long-term outcome for kaposiform hemangioendothelioma: A report of two cases.

Kaposiform hemangioendothelioma (KHE) is a rare aggressive vascular tumor of skin and deep soft tissues that typically presents in infancy and may be associated with a potentially life-threatening coagulopathy known as Kasabach-Merrit phenomenon (KMP). Recent advances in medical therapy have successfully treated many patients. However, our knowledge regarding the natural history of these lesions and optimum surveillance strategies remains rudimentary. We report two young women who had KHE with KMP treated in infancy and presented in adolescence with comorbidities related to their KHE tumor. This presentation supports the need for long-term surveillance in these patients.

Knowledge insufficient: the management of haemoglobin SC disease.

Although haemoglobin SC (HbSC) accounts for 30% of sickle cell disease (SCD) in the United States and United Kingdom, evidence-based guidelines for genotype specific management are lacking. The unique pathology of HbSC disease is complex, characterized by erythrocyte dehydration, intracellular sickling and increased blood viscosity. The evaluation and treatment of patients with HbSC is largely inferred from studies of SCD consisting mostly of haemoglobin SS (HbSS) patients. These studies are underpowered to allow definitive conclusions about HbSC. We review the pathophysiology of HbSC disease, including known and potential differences between HbSS and HbSC, and highlight knowledge gaps in HbSC disease management. Clinical and translational research is needed to develop targeted treatments and to validate management recommendations for efficacy, safety and impact on quality of life for people with HbSC.

Genetic Modifiers of White Blood Cell Count, Albuminuria and Glomerular Filtration Rate in Children with Sickle Cell Anemia.

Discovery and validation of genetic variants that influence disease severity in children with sickle cell anemia (SCA) could lead to early identification of high-risk patients, better screening strategies, and intervention with targeted and preventive therapy. We hypothesized that newly identified genetic risk factors for the general African American population could also impact laboratory biomarkers known to contribute to the clinical disease expression of SCA, including variants influencing the white blood cell count and the development of albuminuria and abnormal glomerular filtration rate. We first investigated candidate genetic polymorphisms in well-characterized SCA pediatric cohorts from three prospective NHLBI-supported clinical trials: HUSTLE, SWiTCH, and TWiTCH. We also performed whole exome sequencing to identify novel genetic variants, using both a discovery and a validation cohort. Among candidate genes, DARC rs2814778 polymorphism regulating Duffy antigen expression had a clear influence with significantly increased WBC and neutrophil counts, but did not affect the maximum tolerated dose of hydroxyurea therapy. The APOL1 G1 polymorphism, an identified risk factor for non-diabetic renal disease, was associated with albuminuria. Whole exome sequencing discovered several novel variants that maintained significance in the validation cohorts, including ZFHX4 polymorphisms affecting both the leukocyte and neutrophil counts, as well as AGGF1, CYP4B1, CUBN, TOR2A, PKD1L2, and CD163 variants affecting the glomerular filtration rate. The identification of robust, reliable, and reproducible genetic markers for disease severity in SCA remains elusive, but new genetic variants provide avenues for further validation and investigation.

Characteristics of a rapid, point-of-care lateral flow immunoassay for the diagnosis of sickle cell disease.

Sickle cell disease (SCD) is a common and life-threatening hematological disorder, affecting approximately 400,000 newborns annually worldwide. Most SCD births occur in low-resource countries, particularly in sub-Saharan Africa, where limited access to accurate diagnostics results in early mortality. We evaluated a prototype immunoassay as a novel, rapid, and low-cost point-of-care (POC) diagnostic device (Sickle SCAN) designed to identify HbA, HbS, and HbC. A total of 139 blood samples were scored by three masked observers and compared to results using capillary zone electrophoresis. The sensitivity (98.3-100%) and specificity (92.5-100%) to detect the presence of HbA, HbS, and HbS were excellent. The test demonstrated 98.4% sensitivity and 98.6% specificity for the diagnosis of HbSS disease and 100% sensitivity and specificity for the diagnosis of HbSC disease. Most variant hemoglobins, including samples with high concentrations of HbF, did not interfere with the ability to detect HbS or HbC. Additionally, HbS and HbC were accurately detected at concentrations as low as 1-2%. Dried blood spot samples yielded clear positive bands, without loss of sensitivity or specificity, and devices stored at 37°C gave reliable results. These analyses indicate that the Sickle SCAN POC device is simple, rapid, and robust with high sensitivity and specificity for the detection of HbA, HbS, and HbC. The ability to obtain rapid and accurate results with both liquid blood and dried blood spots, including those with newborn high-HbF phenotypes, suggests that this POC device is suitable for large-scale screening and potentially for accurate diagnosis of SCD in limited resource settings.

Hemoglobin variants identified in the Uganda Sickle Surveillance Study.

The Uganda Sickle Surveillance Study analyzed dried blood spots that were collected from almost 100 000 infants and young children from all 10 regions and 112 districts in the Republic of Uganda, with the primary objective of determining the prevalence of sickle cell trait and disease. An overall prevalence of 13.3% sickle cell trait and 0.7% sickle cell disease was recently reported. The isoelectric focusing electrophoresis technique coincidentally revealed numerous hemoglobin (Hb) variants (defined as an electrophoresis band that was not Hb A, Hb F, Hb S, or Hb C) with an overall country-wide prevalence of 0.5%, but with considerable geographic variability, being highest in the northwest regions and districts. To elucidate these Hb variants, the original isoelectric focusing (IEF) gels were reviewed to identify and locate the variant samples; corresponding dried blood spots were retrieved for further testing. Subsequent DNA-based investigation of 5 predominant isoelectric focusing patterns identified 2 α-globin variants (Hb Stanleyville II, Asn78Lys; Hb G-Pest, Asp74Asn), 1 ß-globin variant (Hb O-Arab, Glu121Lys), and 2 fusion globin variants (Hb P-Nilotic, ß31-δ50; Hb Kenya, Aγ81Leu-ß86Ala). Compound heterozygotes containing an Hb variant plus Hb S were also identified, including both Hb S/O-Arab and HbS/Kenya. Regional differences in the types and prevalence of these hemoglobin variants likely reflect tribal ancestries and migration patterns. Algorithms are proposed to characterize these Hb variants, which will be helpful for emerging neonatal hemoglobinopathy screening programs that are under way in sub-Saharan Africa.