Etiologies and Outcomes of Normocytic Anemia in Children.

OBJECTIVE: To characterize the evaluation and outcomes of children referred to pediatric hematology for normocytic anemia. STUDY DESIGN: Retrospective cohort study of children aged 0-21 years referred to a tertiary pediatric hematology clinic for normocytic anemia from 2019 through 2021. Normocytic anemia was defined as a low hemoglobin and normal mean corpuscular volume, per the referring laboratory reference range. RESULTS: Two-hundred seventy-one patients (48% female, median age 5.4 years) were included. The most common hematologic diagnoses included iron deficiency (n = 90, 33%), statistical anemia (n = 64, 24%), transient marrow suppression (n = 36, 13%), and transient erythroblastopenia of childhood (TEC, n = 19, 7%). There were 17 (6%) patients in whom anemia was thought to be secondary to a nonhematologic disorder and therefore were referred to another pediatric specialty. Sixteen patients (6%) had anemia which spontaneously resolved without an underlying etiology being identified. Aside from iron deficient patients, 35 (13%) had diagnoses requiring ongoing hematology care including transient erythroblastopenia of childhood, hemolytic anemia, Diamond Blackfan Anemia, and abnormal beta globin traits. Two-hundred fifty-one patients (93%) were discharged from hematology care after a median of 25 days (range 0-2124 days). CONCLUSION: Pediatric patients with normocytic anemia have diverse underlying etiologies with iron deficiency being most common. These data support initial management within the primary care setting including assessment of a serum ferritin, iron panel, and reticulocyte count, with only a subset of patients requiring ongoing subspecialty care.

Initial von Willebrand factor antigen values in adolescent females predict future values.

INTRODUCTION: Diagnosing von Willebrand Disease (VWD) in adolescent females is challenging as menstruation and physiologic stress elevate von Willebrand factor (VWF) laboratory values. AIM: To develop a VWF prediction model for adolescent females based on initial VWF results. METHODS: We identified female patients aged 9 to 21 years with any VWF laboratory test over a 5-year period (2017-2021) at any Texas Children's Hospital facility. Patient demographics, VWF testing, haemoglobin concentration, serum ferritin and site of clinical testing were collected (initial and subsequent laboratory evaluations). A Bayesian linear regression model was developed. Prediction intervals were analysed to identify thresholds for patients in whom repeat testing was unlikely to identify low VWF levels (< 50%), consistent with VWD. RESULTS: A total of 6125 adolescent females underwent VWF testing; 1204 (19.7%) had repeat testing. Based on the prediction model, initial VWF antigen values of 80%, 90% and ≥100% carried a 92.6%, 96.6% and ≥98.0% probability of having repeat normal repeat VWF values, respectively. Subjects assessed in outpatient adolescent medicine or gynaecology clinics were more likely to have low VWF values compared to those assessed in the acute care setting (p < .001). Median presenting haemoglobin and serum ferritin were 12.4 g/dL and 13 ng/mL, respectively and were similar in those with normal versus low VWF antigen values. CONCLUSION: Repeat testing in adolescent females whose initial VWF antigen values are ≥90% is unlikely to identify additional patients with VWD. Iron deficiency screening should be performed in all adolescent females.

The relationship between heavy menstrual bleeding, iron deficiency, and iron deficiency anemia.

For reproductive-aged women, the symptom of heavy menstrual bleeding is highly prevalent and a major contributor to iron deficiency and its most severe manifestation, iron deficiency anemia. It is recognized that these 2 clinical entities are not only highly prevalent, but their interrelationship is poorly appreciated and frequently normalized by society, healthcare providers, and affected girls and women themselves. Both heavy menstrual bleeding and iron deficiency, with or without anemia, adversely impact quality of life-heavy menstrual bleeding during the episodes of bleeding and iron deficiency on a daily basis. These combined issues adversely affect the lives of reproductive-aged girls and women of all ages, from menarche to menopause, and their often-insidious nature frequently leads to normalization. The effects on cognitive function and the related work and school absenteeism and presenteeism can undermine the efforts and function of women in all walks of life, be they students, educators, employers, or employees. There is also an increasing body of evidence that suggests that iron deficiency, even in early pregnancy, may adversely impact fetal neurodevelopment with enduring effects on a spectrum of cognitive and psychological disorders, critically important evidence that begs the normalization of iron stores in reproductive-aged women. The authors seek to raise individual, societal, and professional awareness of this underappreciated situation in a fashion that leads to meaningful and evidence-based changes in clinical guidance and healthcare policy directed at preventing, screening, diagnosing, and appropriately managing both disorders. This manuscript provides evidence supporting the need for action and describes the elements necessary to address this pervasive set of conditions that not only affect reproductive-aged girls and women but also the lives of children everywhere.

Diagnosis and management of isolated neutropenia: A survey of pediatric hematologist oncologists.

BACKGROUND: Isolated neutropenia is a common referral to pediatric hematology oncology (PHO) physicians. There are no established consensus guidelines in the diagnosis and management of patients with isolated, asymptomatic, and incidentally discovered neutropenia. METHODS: A survey was distributed to PHO physicians on the American Society of Pediatric Hematology Oncology member discussion page to determine the common diagnostic and management decisions regarding patients with isolated neutropenia and to explore beliefs regarding the term "benign ethnic neutropenia." RESULTS: One hundred twenty-six PHO attending physicians completed the survey. The most common tests reportedly ordered for this patient population included complete blood cell count (CBC) (98%), peripheral smear (75%), antineutrophil antibody testing (29%), and immunoglobulins (24%). Providers were more likely to order an antineutrophil antibody in toddlers (p = .0085), and antinuclear antibody (ANA) panels in adolescents (p < .001). Half of providers do not request additional CBCs prior to their initial consultation, and most suggest referring patients with mild neutropenia after confirming a declining absolute neutrophil count (ANC) (51%). The three most important factors influencing ongoing follow-up included: history of recurrent/severe infections (98%), family history of blood disorders (98%), and more severe/progressively worsening neutropenia (97%). Seventy percent of respondents have diagnosed patients with "benign ethnic neutropenia," and 75% support replacement of the term to "typical neutrophil count with Fy(a-/b-) status," if confirmed with red cell phenotyping. CONCLUSION: We identified practice patterns of PHO physicians for the diagnosis and management of patients referred for asymptomatic and isolated neutropenia. These data provide the framework to conduct cost-effectiveness studies.

Management of nutritional iron deficiency anemia for young children in the emergency department.

BACKGROUND: Guidelines for young children with nutritional iron deficiency anemia (IDA) presenting to the emergency department (ED) are lacking, leading to variability in care. We aimed to standardize management of these patients through the development and implementation of an evidence-based algorithm using quality improvement methodology. PROCEDURE: Baseline data of the target population (n = 42; 60% male; median age 22.5 months, median hemoglobin 5.3 g/dl) identified variability across four key measures of clinical management: laboratory evaluation, therapy choice, therapy administration, and patient disposition. Literature review and consensus from pediatric hematology providers informed a draft algorithm that was refined in an iterative multidisciplinary process. From September 2020 to June 2021, we aimed to increase IDA management per the algorithm by ≥20% relative to baseline for the four key outcome measures using sequential Plan-Do-Study-Act (PDSA) cycles. Process measures focusing on provider communication/documentation and balancing measures involving efficiency and therapy-related adverse events were assessed concurrently. RESULTS: Thirty-five patients were evaluated among four PDSA cycles and shared similar characteristics as the baseline population. Improvements of ≥20% above baseline adherence levels or 100% adherence were achieved for all outcome measure across four PDSA cycles. Adherence to recommended laboratory evaluation improved from 43 (baseline) to 71%, therapy choice from 78 to 100%, therapy administration from 50 to 83%, and disposition from 85 to 100%. ED length of stay remained stable. CONCLUSIONS: Implementation of a standardized algorithm for young children with nutritional IDA in the ED increased adherence to evidence-based patient care.

Poor efficacy of oral iron replacement therapy in pediatric patients with heart failure.

INTRODUCTION: Iron deficiency is associated with worse outcomes in children and adults with systolic heart failure. While oral iron replacement has been shown to be ineffective in adults with heart failure, its efficacy in children with heart failure is unknown. We hypothesised that oral iron would be ineffective in replenishing iron stores in ≥50% of children with heart failure. METHODS: We performed a single-centre retrospective cohort study of patients aged ≤21 years with systolic heart failure and iron deficiency who received oral iron between 01/2013 and 04/2019. Iron deficiency was defined as ≥2 of the following: serum iron <50 mcg/dL, serum ferritin <20 ng/mL, transferrin >300 ng/mL, transferrin saturation <15%. Iron studies and haematologic indices pre- and post-iron therapy were compared using paired-samples Wilcoxon test. RESULTS: Fifty-one children with systolic heart failure and iron deficiency (median age 11 years, 49% female) met inclusion criteria. Heart failure aetiologies included cardiomyopathy (51%), congenital heart disease (37%), and history of heart transplantation with graft dysfunction (12%). Median dose of oral iron therapy was 2.9 mg/kg/day of elemental iron, prescribed for a median duration of 96 days. Follow-up iron testing was available for 20 patients, of whom 55% (11/20) remained iron deficient despite oral iron therapy. CONCLUSIONS: This is the first report on the efficacy of oral iron therapy in children with heart failure. Over half of the children with heart failure did not respond to oral iron and remained iron deficient.

SLC25A38 congenital sideroblastic anemia: Phenotypes and genotypes of 31 individuals from 24 families, including 11 novel mutations, and a review of the literature.

The congenital sideroblastic anemias (CSAs) are a heterogeneous group of inherited disorders of erythropoiesis characterized by pathologic deposits of iron in the mitochondria of developing erythroblasts. Mutations in the mitochondrial glycine carrier SLC25A38 cause the most common recessive form of CSA. Nonetheless, the disease is still rare, there being fewer than 70 reported families. Here we describe the clinical phenotype and genotypes of 31 individuals from 24 families, including 11 novel mutations. We also review the spectrum of reported mutations and genotypes associated with the disease, describe the unique localization of missense mutations in transmembrane domains and account for the presence of several alleles in different populations.

Trends in Anemia, Iron, Therapy, and Transfusion in Hospitalized Pediatric Patients with Inflammatory Bowel Disease.

OBJECTIVE: To evaluate trends in diagnosis and management of iron deficiency anemia using a large national children's hospital database in pediatric patients admitted with inflammatory bowel disease (IBD). STUDY DESIGN: In this retrospective multicenter cohort study, we used the Pediatric Health Information System de-identified administrative database. Patients age <21 years with ≥2 admissions with International Classification of Disease, Ninth Revision and Tenth Revision codes for Crohn's disease or ulcerative colitis from 2012 to 2018 were included. We extracted data regarding diagnoses of anemia and/or iron deficiency, and receipt of oral iron, intravenous (IV) iron, and/or blood transfusion. Data were analyzed descriptively. RESULTS: We identified 8007 unique patients meeting study criteria for a total of 28 260 admissions. The median age at admission was 15.4 years. A diagnosis of anemia was documented in 29.8% of admissions and iron studies were performed in 12.6%. IV iron was given in 6.3% of admissions and blood transfusions in 7.4%. The prevalence of the diagnosis of anemia among IBD admissions increased from 24.6% in 2012 to 32.4% in 2018 (P < .0001). There was a steady increase in the proportion of IBD admissions that used IV iron, from 3.5% in 2012 to 10.4% in 2018 (P < .0001), and the proportion of admissions with red cell transfusions decreased over time from 9.4% to 4.4% (P < .0001). CONCLUSIONS: Iron deficiency anemia is prevalent among pediatric patients with IBD admitted to US children's hospitals. From 2012 to 2018, there was an increase in the use of inpatient IV iron for the treatment of iron deficiency anemia and a decrease in transfusions.

Barriers to and Facilitators of Iron Therapy in Children with Iron Deficiency Anemia.

OBJECTIVE: To characterize barriers to and facilitators of successful iron therapy in young children with iron deficiency anemia (IDA) from an in-depth parental perspective. STUDY DESIGN: Prospective, mixed methods study of children age 9 months to 4 years with a diagnosis of nutritional IDA by clinical history and laboratory criteria and their parents. Clinical data were obtained from the electronic health record. Semistructured interviews focused on knowledge of IDA, clinical effects, experience with iron therapies, and motivation were conducted with the parent who identified as the child's primary caregiver. RESULTS: Twenty patient-parent dyads completed the study; 80% (n = 16) identified as Hispanic/Latino (white). Patients' median age was 23 months (50% male); median initial hemoglobin concentration was 8.2 g/dL and duration of oral iron therapy was 3 months. Parents' median age was 29 years (85% female); 8 interviews (40%) were conducted in Spanish. Barriers included difficulty in administering oral iron owing to side effects and poor taste. Facilitators included provision of specific instructions; support from healthcare providers and additional caregivers at home; motivation to benefit child's health, which was strengthened by strong emotional reactions (ie, stress, anxiety) to therapy and follow-up; and an appreciation of child's improvement with successful completion of therapy. CONCLUSIONS: Our findings support the need for interventions designed to promote oral iron adherence in children with IDA. Rather than focusing on knowledge content related to IDA, interventions should aim to increase parental motivation by emphasizing the health benefits of adhering to iron therapy and avoiding more invasive interventions.

Iron Deficiency Is Associated with Adverse Outcomes in Pediatric Heart Failure.

OBJECTIVE: To evaluate the prevalence of iron deficiency and its association with outcomes in children with heart failure. STUDY DESIGN: A single-center retrospective cohort study of patients with heart failure aged 1-21 years from July 2012 to June 2017 with available serum iron studies was performed. Subjects were analyzed in 2 groups: biventricular systolic heart failure (BiV) and single-ventricle congenital heart disease with systolic heart failure (SV). Iron deficiency was defined as ≥2 of the following: serum iron <50 µg/dL, serum ferritin <20 ng/mL, transferrin >300 ng/mL, or transferrin saturation <15%. The primary outcome was a composite adverse event (CAE) of ventricular assist device implantation, heart transplantation, or death, at 3 and 6 months from time of iron studies. RESULTS: Of the 107 subjects (77 BiV, 30 SV) included in the study, 56% were iron deficient. Demographics, etiology of heart failure, and chronicity of heart failure symptoms were not associated with iron deficiency. On multivariable analysis, in group BiV, iron deficiency was associated with CAE at 3 months (79% iron deficiency in CAE group vs 37% iron deficiency in non-CAE, P = .001, OR 7, 95% CI 2-21) and 6 months (76% iron deficiency in CAE vs 35% iron deficiency in non-CAE, P = .002, OR 7, 95% CI 2-24). In group SV, iron deficiency was associated with CAE at 6 months (79% iron deficiency in CAE vs 29% iron deficiency in non-CAE, P = .014, OR 8, 95% CI 2-32). CONCLUSIONS: Iron deficiency was present in 56% of the pediatric patients with heart failure who were evaluated with iron studies. Iron deficiency was associated with greater risk of ventricular assist device implantation, heart transplantation, or death.

The cost of a "benign" condition: Healthcare utilization and infectious outcomes in young children with primary autoimmune neutropenia.

BACKGROUND: Autoimmune neutropenia (AIN) is a common cause of chronic neutropenia in childhood. Despite an expected benign clinical course, many patients undergo extensive evaluation. Data on healthcare utilization and rates of bloodstream infections in young patients with AIN are limited. METHODS: All patients with a diagnosis code of leukopenia, neutropenia, or AIN followed within the outpatient hematology clinic of a single institution from 2014 to 2016 were identified. Patients aged ≤5 years with absolute neutrophil count (ANC) ≤500/µL persisting for ≥3 months, a clinical diagnosis of AIN, and documented resolution of neutropenia were included. Data on clinical management, including infectious outcomes and emergency center (EC) encounters, were collected. RESULTS: Forty-three patients with AIN (18 male [42%], median age at diagnosis 12 months) met eligibility criteria. Children were followed by hematology for a median duration of 18 (range, 2-85) months. Diagnostic evaluations were variable. Thirty patients (70%) had ≥ 1 EC encounters for evaluation of isolated fever with a total of 113 EC encounters for the overall cohort. Patients with ANC < 500/µL and isolated fever were admitted for observation, which resulted in 24 hospitalizations in 16 patients. Of 138 blood cultures drawn, two were positive, both later determined to be contaminants. CONCLUSION: At a large tertiary care center, no bloodstream infections were identified in a cohort of 43 children with AIN presenting to the EC for assessment of fever. A less-intensive, more cost-effective management paradigm, which continues to prioritize patient safety, among young children with AIN is needed.

A Case of Sulfhemoglobinemia Secondary to a Urinary Tract Infection.

Sulfhemoglobinemia (SulfHb) is a rare dyshemoglobinemia that can present with cyanosis in the absence of respiratory distress. It has been reported secondary to drug ingestion and chronic constipation. We present a case of SulfHb in an adolescent female with spina bifida and neurogenic bladder in the setting of an Escherichia coli urinary tract infection. An arterial blood gas differentiated a dyshemoglobinemia from other causes of hypoxemia. The resolution was achieved with antibiotics and red cell transfusion. Here we review the pathophysiology of SulfHb and contribute a unique case report to the limited body of literature on this topic.

Management of Nonpregnant Women Presenting to the Emergency Department With Iron Deficiency Anemia Caused by Uterine Blood Loss: A Retrospective Cohort Study.

BACKGROUND: Women with abnormal uterine bleeding are commonly encountered in the emergency department (ED). Contemporary management of severe iron deficiency anemia (IDA) in this setting may be inadequate and expose patients to unnecessary blood transfusions. OBJECTIVE: We sought to describe the characteristics and management of women presenting to the ED with moderate to severe anemia caused by uterine bleeding. We hypothesized that blood transfusions were frequently administered to stable patients without severe symptoms or active bleeding. METHODS: This is a retrospective cohort study of women presenting to the ED from October 31, 2018 to March 31, 2019 with IDA from uterine bleeding. Eligible subjects were adult females with IDA caused by uterine blood loss, hemoglobin ≤10 g/dL, and who were discharged from the ED. RESULTS: One hundred twenty-seven encounters (117 unique patients, mean 40 years of age) met the eligibility criteria. No patients were hemodynamically unstable and clinically significant active bleeding was rare (6%). Blood transfusion was administered during 70 (55%) encounters, with ≥2 units given to more than half (53%) of those transfused. Subsequent ED visits (14%) and transfusions (16%) during the follow-up period were common. CONCLUSION: In this cohort of adult females with moderate to severe IDA caused by uterine bleeding, blood transfusion was often administered in the absence of hemodynamic instability or active hemorrhage, iron deficiency was inadequately treated, and a high rate of subsequent transfusions occurred. Future studies should investigate optimal indications for transfusion and emphasize adequate iron supplementation.

How I approach iron deficiency with and without anemia.

Iron deficiency anemia remains a common referral to the pediatric hematology-oncology subspecialist. Improved understanding of iron homeostasis, including the effects of the regulatory hormone hepcidin, recent adult and pediatric clinical trial data, as well as the availability of safer formulations of intravenous iron, have resulted in additional considerations when making treatment recommendations in such patients. Young children and adolescent females remain the most commonly affected groups, but children with complex medical or chronic inflammatory conditions including comorbid gastrointestinal disorders also require special consideration.

Addition of Vincristine and Irinotecan to Standard Therapy in a Patient With Refractory High-risk Hepatoblastoma Achieving Long-term Relapse-free Survival.

Children with metastatic hepatoblastoma have a poor prognosis, even with dose intensification of cisplatin and doxorubicin. Vincristine and irinotecan have demonstrated activity in high risk disease. This report describes a 3-year-old girl with metastatic hepatoblastoma with unresectable disease after 5 cycles of cisplatin, 5-fluorouracil, vincristine, and doxorubicin who had a complete response of her metastatic disease to vincristine and irinotecan (intravenous and oral forms), allowing surgical resection of her liver disease. She remains in remission 48 months since therapy completion.

Identification and Management of Iron Deficiency Anemia in the Emergency Department.

BACKGROUND: Iron deficiency anemia is the most common hematologic disorder in the United States and worldwide. Yet, clinical guidelines for the identification and management of this disorder in the emergency department are lacking. OBJECTIVE OF REVIEW: This clinical review examines strategies for identifying and treating iron deficiency anemia in the emergency department, with a focus on the role of oral iron therapy, intravenous iron therapy, as well as red blood cell transfusion. The article highlights both the available evidence on this topic and the need for future research. DISCUSSION: The diagnosis of iron deficiency anemia has important clinical implications and, although testing is generally straightforward, it may be under-recognized. The scant literature available describing emergency department practice patterns for iron deficiency anemia suggests there is room for improvement. In particular, intravenous iron may be underutilized and red blood cell transfusions administered too liberally. CONCLUSIONS: Iron deficiency anemia is common and many patients can be treated effectively with oral iron. For selected patients with moderate-to-severe iron deficiency anemia, intravenous iron is safe and more effective than oral iron. Red blood cell transfusions should be used rarely for hemodynamically stable patients with iron deficiency irrespective of hemoglobin levels.

Intravenous Ferric Carboxymaltose in Children with Iron Deficiency Anemia Who Respond Poorly to Oral Iron.

OBJECTIVE: To assess the benefits and risks of intravenous (IV) ferric carboxymaltose (FCM) in children with iron deficiency anemia (IDA). STUDY DESIGN: In a retrospective cohort study of patients seen at our center, we identified all FCM infusions in children with IDA over a 12-month period through a query of pharmacy records. Clinical data, including hematologic response and adverse effects, were extracted from the electronic medical record. RESULTS: A total of 116 IV FCM infusions were administered to 72 patients with IDA refractory to oral iron treatment (median age, 13.7 years; range, 9 months to 18 years). Median preinfusion and postinfusion hemoglobin values were 9.1 g/dL and 12.3 g/dL, respectively (at 4-12 weeks after the initial infusion; n = 53). Sixty-five patients (84%) experienced no adverse effects. Minor transient complications were encountered during or immediately after 7 infusions. CONCLUSION: FCM administered as a short IV infusion without a test dose proved to be safe and highly effective in a small yet diverse population of infants, children, and adolescents with IDA refractory to oral iron therapy.