Early Death In Children Research Articles

Predictive model for early death risk in pediatric hemophagocytic lymphohistiocytosis patients based on machine learning

BackgroundHemophagocytic Lymphohistiocytosis (HLH) is a rare and life-threatening disease in children, with a high early mortality rate. This study aimed to construct machine learning model to predict the risk of early death using clinical indicators at the time of HLH diagnosis. MethodsThis observational cohort study was conducted at the National Clinical Research Center for Child Health and Disease. Data was collected from pediatric HLH patients diagnosed by the HLH-2004 protocol between January 2006 and December 2022. Six machine learning models were constructed using the Least Absolute Shrinkage and Selection Operator (LASSO) to select key clinical indicators for model construction. ResultsThe study included 587 pediatric HLH patients, and the early mortality rate was 28.45 %. The logistic and XGBoost model with the best performance after feature screening were selected to predict early death of HLH patients. The logistic model had an AUC of 0.915 and an accuracy of 0.863, while the XGBoost model had an AUC of 0.889 and an accuracy of 0.829. The risk factors most associated with early death were the absence of immunochemotherapy, decreased TC levels, increased BUN and total bilirubin, and prolonged TT. We developed an online calculator tool for predicting the probability of early death in children with HLH. ConclusionsWe developed the first web-based early mortality prediction tool for pediatric HLH to assist clinicians in risk stratification at diagnosis and in developing personalized treatment protocols. This study is registered on the China Clinical Trials Registry platform (ChiCTR2200061315).

Low total cholesterol predicts early death in children with hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rapidly progressive and potentially life-threatening disorder. Identifying risk factors and timely adjustment of the given treatment regimens is critical to reducing the early mortality in HLH patients. Hypocholesterolemia has been reported to be associated with poor prognosis in a variety of critical illnesses. However, serum cholesterol is rarely studied in HLH patients, and its prognostic value is unclear. We conducted a retrospective cohort study in National Clinical Research Center for Child Health and Disorders (Chongqing), identifying pediatric HLH patients (including genetically confirmed pHLH and not genetically confirmed pHLH) diagnosed with the HLH-2004 protocol and treated with immunochemotherapy between January 2008 and December 2020. The patients' blood lipid levels at initial diagnosis of HLH, including triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), were reviewed based on electronic medical records. Both Cox and logistic regression models were used to estimate the effects of blood lipid indicators on early death (within 30 days after diagnosis). A total of 353 patients were enrolled in the study, with a median age at diagnosis of 45 months. The observed 30-day mortality rate was 19.05% (64/336, 17 were lost to follow-up) and Kaplan-Meier-estimated 3-year survival rate was 61.67% (95% CI, 56.27%-67.59%). DNA-targeted sequencing of HLH-related genes was performed in 173 (49.0%, 173/353) patients (not all patients with suspected pHLH underwent genetic testing), and 29 patients were diagnosed with genetically confirmed pHLH. Lipid panel was performed in 349 patients: 91.98% (321/349) had TG ≥ 1.80 mmol/L, 62.75%(219/349) had TG ≥ 3.00 mmol/L, 92.84% (324/349) had HDL-C ≤ 1.04 mmol/L, 58.74% (205/349) had LDL-C ≤ 1.30 mmol/L and 24.64% (86/349) had TC ≤ 3.11 mmol/L. TC ≤ 3.11 mmol/L and BUN ≥ 7.14 mmol/L were the independent risk factors for 30-day mortality [HR(95%CI): 2.85(1.46, 5.57) and 2.90(1.48, 5.68), respectively]. The presence of one of these risk factors increased the 30-day mortality rate by 6-fold [HR = 6.24, 95%CI: (3.18, 12.22)] and the presence of two risk factors by nearly 10-fold [HR = 9.98, 95%CI: (4.23, 23.56)] compared with the patients with no risk factors. Severe derangement of lipoproteins is common in children with HLH, and decreased TC is an independent risk factor for early death. Hypocholesterolemia should be included as a biomarker during the diagnosis and management of HLH patients.

Stroke in Pediatric Sickle Cell Disease in Sub-Saharan Africa: Systematic Review and Estimated Prevalence

Background: Most people with sickle cell disease (SCD) live in Sub-Saharan Africa (SSA); many do not survive to adulthood (Grosse et al. Am J Prev Med 2011). Stroke is a common complication of SCD in the region (Ohene-Frempong et al.Blood 1998), yet the region's burden of pediatric SCD stroke is unknown. This systematic review aims to describe what is known, and to estimate the number of children affected by SCD stroke in SSA.Methods: Systematic reviews using Pubmed, Embase, and Web of Science were performed for all studies reporting pediatric SCD stroke prevalence data. Keyword search strategy included these or related terms: “stroke” or “brain” and “sickle cell” and “Africa” or each country in SSA available in English or French. Publication dates were selected between 1980 and December 13, 2016. Using pre-selected inclusion criteria, titles and abstracts were screened and full-text articles were reviewed. For publications meeting inclusion criteria, extracted data included: study and participant characteristics, number of patients with stroke, diagnostic criteria, imaging, management, recurrence. The number of children affected by SCD stroke in SSA was estimated based on current estimates of national population and S allele frequency (Piel et al. Lancet 2013) and the stroke prevalence in the extracted studies. The stroke prevalence in SSA was estimated based on both fixed-effect analysis and random-effect analysis.Results: After duplicates were removed, 133 individual articles remained. Ten full text articles met review selection criteria, including one in French. In all, papers reported data from seven countries in the region, including four reports from Nigeria. Cross-sectional SCD clinic-based data, with a sample size of 6,289 patients, reported pediatric stroke prevalence of 2.9-16.9%. Diagnostic criteria of stroke varied by site and were limited by access to brain imaging, which was reported in only half of the included studies. Treatment for stroke included packed red blood cell transfusion, exchange transfusion, or hyperhydration. Secondary stroke prevention with chronic blood transfusion or hydroxyurea was offered at two of 10 sites. Recurrence data was limited by variable study follow-up and limited reporting times. Using available sickle gene frequencies by country, estimated births affected by SCD per country in SSA, and a linear- or random-effects model, pediatric stroke prevalence in SSA was projected as 279,908 (95% CI: 240,335-319,481) and 561,746 (347,472-775,056), respectively. Estimates do not include stroke- or disease-associated mortality.Conclusion: This meta-analysis estimates prevalence of pediatric SCD stroke in SSA, underscoring the region's high stroke burden. Multiple clinic-based cross-sectional studies reported stroke prevalence comparable to data from high income countries prior to implementation of standardized prevention strategies. Accuracy is limited by different approaches to stroke diagnosis, paucity of population-based data on disease prevalence and mortality, regional variation in disease prevalence and severity, and overall high rates of early death in children with SCD. Available data would skew towards surviving patients, leading to possible underreporting of people at risk for SCD stroke. Improved diagnostic specificity with standardized criteria and imaging would be useful for identification of strokes. Understanding the large numbers affected by SCD stroke is critical for focusing public health efforts to introduce preventive measures to reduce stroke risk and to implement rehabilitative strategies. Adopting standardized primary and secondary stroke prevention measures in SSA may decrease the burden of SCD-associated stroke.This work was supported by funding from the National Institutes of Health (5R21HD089791, PIs Idro, Green). DisclosuresNo relevant conflicts of interest to declare.

Early Deaths after Arterial Ischemic Stroke in Pediatric Patients: Incidence and Risk Factors.

In developed countries, cerebrovascular diseases are among the 10 most common causes of death in both the pediatric and adult population. The prevalence of fatal outcomes following arterial ischemic stroke (AIS) in various groups of pediatric patients ranges from 1% to almost 32%. However, a constant improvement in stroke mortality among children has been observed. The extent of the decline differs among studies (from nearly tenfold to twofold decline), as it depends on the study population. While a portion of this variability might be explained by factors such as health care access, population age, diseases related to ethnicity, and different etiologies of stroke in studied populations, the understanding of such differences is still insufficient. Risk factors for death in the early stages of the disease are poorly understood and are usually based on the clinical presentations of relatively small groups of pediatric patients. Familiarity with these factors may be of significant importance for prognosis, but also for the early selection of patients requiring careful supervision. The present study aimed to analyze and discuss the current literature data on the incidence of early death and risk factors for early death in children suffering from stroke.

Targeted genome editing for the correction or alleviation of primary Immunodeficiencies.

Primary immunodeficiencies (PID) are a growing list of unique disorders that result in a failure of the innate/adaptive immune systems to fully respond to disease or infection. PIDs are classified into five broad categories; B cell disorders, combined B and T cell disorders, phagocytic disorders, complement disorders, and disorders with recurrent fevers and inflammation. Many of these disorders, such as X-SCID, WAS, and CGD lead to early death in children if intervention is not implemented. At present, the predominant method of curative therapy remains an allogeneic transplant from a healthy donor, however many complications and limitations exist with his therapy such as availability of donors, graft vs host disease, graft rejection, and infection. More recently, gene therapy using viral based complementation vectors have successfully been implemented to functionally correct patient cells in an autologous transplant, but these methods carry significant risks, including insertional mutagenesis, and provide non-physiological gene expression. For these reasons, gene-editing reagents such as targeted nucleases, base editors (BE), and prime editors (PE) are being explored. The BE and PE tools, sometimes referred to as digital editors, are of very high interest as they provide both enhanced molecular specificity and do not rely on DNA repair pathways after DSBs to change individual base pairs or directly replace DNA sequences responsible for pathogenic phenotypes. With this in mind the purpose of this chapter is to highlight some of the most common PIDs found within the human population, discuss successes and shortcomings of previous intervention strategies, and highlight how the next generation of gene-editing tools may be deployed to directly repair the underlying genetic causes of this class of disease.

Prognostic factors of early death in children with hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis is a rapidly progressing and fatal disease. Early identification of early death for HLH patients based on the laboratory findings at the time of diagnosis could improve the overall survival. A retrospective study was performed on 95 Chinese pediatric patients with HLH. Patients’ data including clinical features and laboratory findings at diagnosis were collected. In a multivariate Cox proportional hazard regression model analysis, albumin≤27.75g/L (hazard ratio (HR)=11.82, 95% confidence interval (CI) 2.58–54.23; P=0.001), LDH≥3707.5 U/L (HR=4.15, 95%CI 1.43–12.01; P=0.009), and IL-10≥456pg/ml (HR=12.39, 95%CI 1.59–96.79; P=0.016) at diagnosis were independent prognostic factors of early death. The risk of early death was 33-fold increase in patients with three risk factors (HR=33.33; 95%CI 8.40–125.00; P<0.001), and 12-fold increase in patients with two risk factors (HR=12.80; 95%CI 2.34–69.80; P=0.002) when compared to it in patients with zero to one risk factor. Our results reveal that HLH patients with the risk of early death can be identified by laboratory findings at diagnosis, which may help guide the treatment decision making for this disease.

Timing of the loss of Pten protein determines disease severity in a mouse model of myeloid malignancy

AbstractJuvenile myelomonocytic leukemia (JMML) is an aggressive pediatric mixed myelodysplastic/myeloproliferative neoplasm (MDS/MPN). JMML leukemogenesis is linked to a hyperactivated RAS pathway, with driver mutations in the KRAS, NRAS, NF1, PTPN11, or CBL genes. Previous murine models demonstrated how those genes contributed to the selective hypersensitivity of JMML cells to granulocyte macrophage–colony-stimulating factor (GM-CSF), a unifying characteristic in the disease. However, it is unclear what causes the early death in children with JMML, because transformation to acute leukemia is rare. Here, we demonstrate that loss of Pten (phosphatase and tensin homolog) protein at postnatal day 8 in mice harboring Nf1 haploinsufficiency results in an aggressive MPN with death at a murine prepubertal age of 20 to 35 days (equivalent to an early juvenile age in JMML patients). The death in the mice was due to organ infiltration with monocytes/macrophages. There were elevated activities of protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) in cells at physiological concentrations of GM-CSF. These were more pronounced in mice with Nf1 haploinsufficiency than in littermates with wild-type Nf1, but this model is insufficient to cause cells to be GM-CSF hypersensitive. This new model represents a murine MPN model with features of a pediatric unclassifiable mixed MDS/MPN and mimics many clinical manifestations of JMML in terms of age of onset, aggressiveness, and organ infiltration with monocytes/macrophages. Our data suggest that the timing of the loss of PTEN protein plays a critical role in determining the disease severity in myeloid malignancies. This model may be useful for studying the pathogenesis of pediatric diseases with alterations in the Ras pathway.

C-11. An Update on Gene Therapy for the Treatment of Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency

Aromatic L-amino acid decarboxylase (AADC) is an enzyme responsible for the final step of the synthesis of neurotransmitters dopamine and serotonin. AADC deficiency is a rare genetic disorder causing motor and autonomic dysfunction and early death in children. Taiwanese carry a high prevalence of AADC deficiency due to a founder mutation (IVS6+4A>T) in the AADC gene. A gene therapy with recombinant adeno-associated virus (AAV) serotype 2 CMV promoter-driven human AADC (AAV2-hAADC) was conducted in children with AADC deficiency since 2010. Clinical grade vector was manufactured. Two target points were determined in each putamen and a total of 1.7×1011 vg vector was injected. Eight patients have been treated at a mean age of 4.9 years (2-8 years), and the mean follow up period was 3.8 years (3-4.5 years). All patients, except one, had homozygous IVS6+4A>T mutations. Before gene therapy, these patients didn't have head control, and could not sit or stand, and they all had regular and severe oculogyric crisis (OGC) attacks. The stereotaxic surgeries were performed smoothly and there was no intracerebral bleeding. At the most recently follow-up visits after gene therapy, one patient was learning walking, two stood with support, one sat without assist, and three had better head control. The severity of OGC decreased and emotion stabilized in all patients.[18F]fluoro-dopa positron emission tomography (PET) signal intensity over putamen increased and cerebrospinal fluid neurotransmitter levels rose in all treated patients. Post gene therapy transient (orofacial) dyskinesia was the main adverse event of the treatment, and one patient experienced a hypovolemic shock due to dyskinesia and he remained bed-ridden. There is no virus-associated side effect, and currently no patient reveals a loss of treatment effect.

Treatment Adherence and Quality of Life of Thalassemic Children

Thalassemia is a genetic disease in which a defect occurs in the rate of synthesis of α or β chains of hemoglobin leading to premature death of RBCs. Children suffering from thalassemia major may become pale and listless and have poor appetite, unexplained fever within first months after birth. For survival, these children have to undergo blood transfusions every 2–4 weeks depending on the severity of illness combined with iron chelation therapy to remove excess iron from their body due to frequent blood transfusions. These children do not always adhere to the treatment regimen which not only affects their physical health but the overall quality of life and may lead to early death in children. Thalassemia can be cured completely using bone marrow transplantation and cord blood stem cell transplantation. However, this treatment is possible only for a small number of children because of suitable donor and cost of treatment. Care of thalassaemia has been included in 12th Five year Plan of the Government of India. Nurses play a major role in improving the quality of life of children by providing the awareness to parents and children and motivate them to follow the treatment regimen.

Risk factors for early death in children with haemophagocytic lymphohistiocytosis

Haemophagocytic lymphohistiocytosis (HLH) is a life-threatening disturbance of immunoregulation. HLH comprises primary and acquired forms with different disease severity. A large proportion of deaths occur early into treatment. We investigated association with early death for laboratory and clinical parameters before the start of and 2 weeks into therapy. A total of 232 children from Scandinavia, Germany or Italy, fulfilling diagnostic criteria and/or with familial disease and/or HLH-causing mutations, receiving HLH treatment 1994-2008 were included. The relation between clinical findings and early pre-transplant death was examined using the Cox proportional hazards model, with a 4-month right-truncation of the outcome. Patients were censored at last follow-up or transplant. Statistically significant predictors were adjusted for sex, age and each other. The following features were significantly associated with adverse outcome: hyperbilirubinaemia (>50 μmol/L; adjusted hazard ratio (aHR) 3.2; 95% confidence interval 1.3-8.1, p = 0.011), hyperferritinaemia (>2000 μg/L; aHR 3.2; 1.2-8.6, p = 0.019), cerebrospinal fluid pleocytosis (>100 × 10(6) /L; aHR 5.1; 1.4-18.5, p = 0.012) at diagnosis, and thrombocytopenia (<40 × 10(9) /L; aHR 3.4; 1.1-10.7, p = 0.033), and hyperferritinaemia (>2000 μg/L; aHR 10.6; 1.2-96.4, p = 0.037) 2 weeks into therapy. Non-improvement of fever, anaemia and/or thrombocytopenia also had adverse impact. There seem to be easily available clinical predictors of early mortality in HLH patients, which may help guide treatment decisions.

EARLY DEATH IN CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA: DOES MALNUTRITION PLAY A ROLE?

The study aim was to correlate malnutrition and early death in children with acute lymphoblastic leukemia (ALL). A study was conducted in 100 consecutive children with ALL. An analysis included clinical and laboratory parameters as well as co-morbidity factors. Forty patients were standard risk and 60 high risk. Multivariate analysis showed variables of statistical importance, including female gender (p 010), ALL high-risk (p 04), and infection (p 036). Malnutrition (p 1.0) and poverty (p 0.5) did not influence. Early mortality was documented in 15/100 (15%) patients. The study shows that high-risk ALL and infection represent the leading causes of early mortality.

Hemorrhagic Complications in Pediatric Hematologic Malignancies

Hematologic malignancies account for almost 40% of all cancers in children. Hemorrhage is the most common cause of early death in children with leukemia. Furthermore, major bleeding episodes lead to shorter survival and increased resource use. Potential risk factors for bleeding include hyperleukocytosis, immunophenotype of leukemia (especially acute promyelocytic leukemia), thrombocytopenia, and associated infections. Successful management of a bleeding episode is dependent on prompt identification of a child at high risk for bleeding, and should be directed at the replacement of blood products as well as to the aggressive therapy for underlying risk factors. Although in recent years there is a favorable decline in the hemorrhage-related mortality, the overall prevalence and the extent of morbidity posed by this potentially fatal complication, including disease outcome in children with hematologic malignancy, is largely unknown. In addition, there are no evidence-based guidelines for prophylactic blood or blood product transfusions. Prospective studies are required to define the epidemiology and risk factors predisposing children with hematologic malignancy to bleeding and to develop management guidelines.

Hepatic artery resistance index can predict early death in children with biliary atresia

Hepatic artery resistance index has been measured by ultrasonography Doppler and has been found to predict rapid deterioration and death in children with biliary atresia. Clinical, biochemical, ultrasonographic, and outcome data were collected prospectively and retrieved on 32 patients with resistance index of > or = 1.0 (group A). These were compared with the same data for 32 age- and sex-matched patients with biliary atresia and a resistance index of ≤ 1.0 (group B). Group A was found to have significantly worse liver function tests than group B. In group A, all patients died (n = 11) or underwent transplantation (n = 21; of whom 4 died) compared with only 2 patients who died in group B and 4 patients who underwent transplantation without fatality. Survival at 2 years was 52% in group A v 94% in group B. It is suggested that regular ultrasonography Doppler examination in patients with biliary atresia can detect a group with a resistance index of > 1.0 who have a very high risk of early mortality. Such patients require early evaluation and listing for transplantation. Those listed for liver transplantation on other grounds require ultrasonography examinations every 2 to 3 months with immediate upgrading of the priority of those patients found to have a resistance index of ≤ or = 1.0. (Liver Transpl Surg 1997 Nov;3(6):604-10)

Hepatic artery resistance index can predict early death in children with biliary atresia.

Hepatic artery resistance index has been measured by ultrasonography Doppler and has been found to predict rapid deterioration and death in children with biliary atresia. Clinical, biochemical, ultrasonographic, and outcome data were collected prospectively and retrieved on 32 patients with resistance index of > or = 1.0 (group A). These were compared with the same data for 32 age- and sex-matched patients with biliary atresia and a resistance index of < 1.0 (group B). Group A was found to have significantly worse liver function tests than group B. In group A, all patients died (n = 11) or underwent transplantation (n = 21; of whom 4 died) compared with only 2 patients who died in group B and 4 patients who underwent transplantation without fatality. Survival at 2 years was 52% in group A v 94% in group B. It is suggested that regular ultrasonography Doppler examination in patients with biliary atresia can detect a group with a resistance index of > 1.0 who have a very high risk of early mortality. Such patients require early evaluation and listing for transplantation. Those listed for liver transplantation on other grounds require ultrasonography examinations every 2 to 3 months with immediate upgrading of the priority of those patients found to have a resistance index of > or = 1.0.

Hepatic artery resistance index predicts early death in children with biliary atersia: [formula omitted]. Dept. of Child Health, Liver Transplantation Unit, King's College Hospital, London

Hepatic artery resistance index predicts early death in children with biliary atersia: [formula omitted]. Dept. of Child Health, Liver Transplantation Unit, King's College Hospital, London

Frequency of early death in children with acute leukemia presenting with hyperleukocytosis

The relationship of hyperleukocytosis, early death, and intracerebral hemmorahage was determined in 547 pediatric patients with acute leukemia. Hyperleukocytosis occurred in 7.3% of patients with acute leukemia. The early mortality rate was significantly increased in hyperleukocytic patients when compared to the nonhyperleukocytic group. Hyperleukocytic patients with ANLL had a significantly greater risk of early death than nonhyperleukocytic patients with ANLL. The difference in the incidence of early death between hyperleukocytic and nonhyperleukocytic patients with ALL/AUL was not statistically significant. In the hyperleukocytic patients intracerebral hemorrhage was the universal cause of early death but this entity did not occur in any of the nonhyperleukocytic patients. There was no correlation of intracerebral hemorrhage to thrombocytopenia or coagulation abnormalities. Autopsies confirmed intracerebral hemorrhage and leukostasis with leukemic infiltration of the brain tissue.