Evans syndrome: Disease awareness and clinical management in a nation-wide ITP-NET survey.

Evans syndrome (ES) is rare and mostly treated on a "case-by-case" basis and no guidelines are available. With the aim of assessing disease awareness and current management of adult ES, a structured survey was administered to 64 clinicians from 50 Italian participating centers. Clinicians had to be involved in the management of autoimmune cytopenias and were enrolled into the ITP-NET initiative. The survey included domains on epidemiology, diagnosis, and therapy of ES and was designed to capture current practice and suggested work-up and management. Thirty clinicians who had followed a median of 5 patients (1-45)/15 years responded. The combination of AIHA plus ITP was more common than the ITP/AIHA with neutropenia (p < .001) and 25% of patients had an associated condition, including lymphoproliferative syndromes, autoimmune diseases, or primary immunodeficiencies. The agreement of clinicians for each diagnostic test is depicted (i.e., 100% for blood count and DAT; only 40% for anti-platelets and anti-neutrophils; 77% for bone marrow evaluation). Most clinicians reported that ES requires a specific approach compared to isolated autoimmune cytopenias, due to either a more complex pathogenesis and a higher risk of relapse and thrombotic and infectious complications. The heterogeneity of treatment choices among different physicians suggests the need for broader harmonization.

Chronic neutropenia in childhood: experience of a tertiary center

Abstract Objective: To assess the prevalence of chronic neutropenia (CN) and the clinical profile of patients with CN aged up to 18 years, followed in the pediatric hematology, rheumatology, or immunology outpatient clinic of a tertiary medical center from May 1, 2018, to 30 April 2019. Methods: Retrospective observational study carried out by collecting data from the patient's medical charts. CN was defined as absolute neutrophil count (ANC) below 1.5 × 109/L lasting over three months. Autoimmune neutropenia (AIN) was defined by clinical criteria and an over twofold increase in ANC after glucocorticoid stimulation. AIN was considered secondary when associated with autoimmune or immunoregulatory disorders. Wilcoxon and Fisher's exact tests were used to compare variables; the significance level was 5 %. Results: A total of 1,039 patients were evaluated; 217 (20 %) presented CN. Twenty-one (2 %) had AIN, classified as primary in 57 % of the cases. The average age at the onset of symptoms was 38.6 months. During follow-up, patients had 4.2 infections on average; frequency was higher among patients with secondary AIN (p = 003). Isolated neutropenia occurred in 43 % of the patients with AIN. Neutropenia resolved in eight (38 %) of the 21 patients with AIN within 19.6 months on average. Eight patients with secondary AIN met the criteria for Inborn Errors of Immunity. Conclusion: AIN prevalence was 2 %. Most cases were first evaluated by a pediatric immunologist or rheumatologist rather than a pediatric hematologist. This study highlights the need for a multidisciplinary approach involving a pediatric immunologist, rheumatologist, and hematologist.

A Case of Omphalitis Revealing Alloimmune Neonatal Neutropenia.

Neutropenia, characterized by a decrease in peripheral blood neutrophil count less than 1500/µL, poses significant clinical challenges due to its association with recurrent infections. This paper presents a rare and intriguing case of alloimmune neonatal neutropenia (ANN), an uncommon variant of neutropenia instigated by the transplacental transfer of maternal anti-neutrophil antibodies that consequently induce opsonization and phagocytosis of the neonate's neutrophils within the reticuloendothelial system. The patient, an 18-day-old boy, was born at 36 weeks five days of gestation and weighed 2465 g, an attribute considered appropriate for gestational age (AGA). He experienced multiple episodes of skin and respiratory infections, coupled with delayed umbilical cord separation and demonstrated a significant reduction in neutrophil count. Despite these symptoms, the patient did not develop bacteremia and his condition improved with antibiotic therapy, leading to his discharge from the hospital. Crucially, both the patient and his mother tested positive for anti-HNA (human neutrophil alloantigen)-1a and anti-HNA-1b antibodies, indicative of a diagnosis of ANN. ANN is intriguing in its clinical course, where despite neutropenia, severe infections are relatively uncommon, and the majority of cases resolve spontaneously within several months post-birth as the maternal antibodies diminish. Nevertheless, there have been reports of moderate to severe infections, demanding clinical intervention and close patient monitoring. The patient in our case was treated with prophylactic antibiotics for six weeks, until a rise in neutrophil count was confirmed, stemming from the severity and recurrence of infections. The issue of using antibiotics and granulocyte colony-stimulating factor (G-CSF) agents in the treatment of ANN remains contentious, with contrasting reports regarding their efficacy and safety. The balance between the prospective therapeutic advantages, potential risks such as antibiotic resistance, and the possibility of inducing leukemia with long-term administration of G-CSF agents necessitates meticulous deliberation. This case underscores the crucial role of early recognition of ANN in neonates presenting with neutropenia. Prompt diagnosis enables a more targeted approach to treatment, reduction in unnecessary antibiotic administration, and specific testing, thus impacting the overall patient management and potentially improving outcomes. Furthermore, in the event of delayed umbilical cord separation in neonates, healthcare providers should consider ANN and other immunodeficiencies related to neutrophil functional abnormalities as potential diagnoses. This patient's story accentuates the need for further investigations to elucidate the precise etiology and pathogenesis of ANN, paving the way for improved diagnostic tools and effective therapeutic strategies.

An adult case of refractory autoimmune neutropenia after liver transplantation.

Autoimmune neutropenia (AIN) is an exceptionally rare condition that occurs after liver transplantation. Here, we report an adult case of refractory AIN 3.5 years after liver transplantation. A 59-year-old man who underwent brain-dead donor liver transplantation in August 2018 developed rapid neutropenia (0.07 × 109/L) in December 2021. The patient was diagnosed with AIN based on positivity for anti-human neutrophil antigen-1a antibody. There was no response to granulocyte colony-stimulating factor (G-CSF), prednisolone, or rituximab, and intravenous immunoglobulin (IVIg) therapy induced only a temporary recovery in neutrophil count. The patient continued to have a low neutrophil count for several months. However, the response to IVIg and G-CSF improved after the post-transplant immunosuppressant was changed from tacrolimus to cyclosporine. Post-transplant AIN has many unknown aspects. Tacrolimus-induced immunomodulation and graft-associated alloimmunity may be involved in its pathogenesis. Further studies are needed to elucidate the underlying mechanisms and explore new treatment options.

A high prevalence of neutrophil-specific antibodies in ELANE-mutated severe congenital neutropenia.

An assay for neutrophil-specific antibodies is frequently used in the workup of chronic severe neutropenia and is suggestive of autoimmune, or sporadically alloimmune neutropenia, rather than severe congenital neutropenia (SCN). We analyzed a neutropenia consortium database for the outcomes of antibody testing initiated before receiving genetic diagnosis in Polish SCN cohort. Test results, performed in a single reference laboratory, were available for 14 patients with ELANE-mutated SCN or cyclic neutropenia, and were frequently positive (36%). We note that the trigger for genetic studies in severe neutropenia should not be affected by antibody-positivity and should be clinically driven.

Autoimmune Neutropenia and Immune-Dysregulation in a Patient Carrying a TINF2 Variant.

In recent years, the knowledge about the immune-mediated impairment of bone marrow precursors in immune-dysregulation and autoimmune disorders has increased. In addition, immune-dysregulation, secondary to marrow failure, has been reported as being, in some cases, the most evident and early sign of the disease and making the diagnosis of both groups of disorders challenging. Dyskeratosis congenita is a disorder characterized by premature telomere erosion, typically showing marrow failure, nail dystrophy and leukoplakia, although incomplete genetic penetrance and phenotypes with immune-dysregulation features have been described. We report on a previously healthy 17-year-old girl, with a cousin successfully treated for acute lymphoblastic leukemia, who presented with leukopenia and neutropenia. The diagnostic work-up showed positive anti-neutrophil antibodies, leading to the diagnosis of autoimmune neutropenia, a slightly low NK count and high TCR-αß+-double-negative T-cells. A next-generation sequencing (NGS) analysis showed the 734C>A variant on exon 6 of the TINF2 gene, leading to the p.Ser245Tyr. The telomere length was short on the lymphocytes and granulocytes, suggesting the diagnosis of an atypical telomeropathy showing with immune-dysregulation. This case underlines the importance of an accurate diagnostic work-up of patients with immune-dysregulation, who should undergo NGS or whole exome sequencing to identify specific disorders that deserve targeted follow-up and treatment.

Evans Syndrome in the Context of Incomplete Systemic Lupus Erythematosus.

Evans syndrome is an autoimmune disorder characterized by the simultaneous or sequential occurrence of autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura (ITP) with or without neutropenia. It can occur idiopathically or secondary to autoimmune or malignant processes. We are presenting a case of ITP with concurrent chronic hemolytic anemia and positive markers for systemic lupus erythematosus with no prior diagnosis of any rheumatological disorder.

Underlying Inborn Errors of Immunity in Patients With Evans Syndrome and Multilineage Cytopenias: A Single-Centre Analysis.

Background: Evans syndrome (ES) is a rare disorder classically defined as the simultaneous or sequential presence of autoimmune haemolytic anaemia and immune thrombocytopenia, but it has also been described as the presence of at least two autoimmune cytopenias. Recent reports have shown that ES is often a manifestation of an underlying inborn error of immunity (IEI) that can benefit from specific treatments. Aims: The aim of this study is to investigate the clinical and immunological characteristics and the underlying genetic background of a single-centre cohort of patients with ES. Methods: Data were obtained from a retrospective chart review of patients with a diagnosis of ES followed in our centre. Genetic studies were performed with NGS analysis of 315 genes related to both haematological and immunological disorders, in particular IEI. Results: Between 1985 and 2020, 40 patients (23 men, 17 women) with a median age at onset of 6 years (range 0-16) were studied. ES was concomitant and sequential in 18 (45%) and 22 (55%) patients, respectively. Nine of the 40 (8%) patients had a positive family history of autoimmunity. Other abnormal immunological features and signs of lymphoproliferation were present in 24/40 (60%) and 27/40 (67%) of cases, respectively. Seventeen out of 40 (42%) children fit the ALPS diagnostic criteria. The remaining 21 (42%) and 2 (5%) were classified as having an ALPS-like and an idiopathic disease, respectively. Eighteen patients (45%) were found to have an underlying genetic defect on genes FAS, CASP10, TNFSF13B, LRBA, CTLA4, STAT3, IKBGK, CARD11, ADA2, and LIG4. No significant differences were noted between patients with or without variant and between subjects with classical ES and the ones with other forms of multilineage cytopenias. Conclusions: This study shows that nearly half of patients with ES have a genetic background being in most cases secondary to IEI, and therefore, a molecular evaluation should be offered to all patients.

Phagocytosis of Mature Granulocytes by Bone Marrow Macrophages in an Elderly Man with Adult-Onset Primary Autoimmune Neutropenia.

Adult-onset primary autoimmune neutropenia (AIN) is an extremely rare but sometimes life-threatening disease. Its pathophysiology is still to be clarified. We describe a case with adult-onset primary AIN with phagocytosis of mature granulocytes by macrophages in bone marrow. A 77-year-old male was referred to our hospital with severe neutropenia. Based on the normal cellular bone marrow without morphological dysplasia and the positivity of anti-neutrophil antibodies in the serum, adult-onset primary AIN was diagnosed. After five years from the initiation of granulocyte colony-stimulating-factor therapy, neutropenia had progressed. At that time, the second bone marrow examination revealed segmented neutrophils phagocytosed by macrophages. Continuous low dose prednisolone succeeded to increase the neutrophil count. An impressive morphological feature of AIN indicated the destruction of mature granulocytes in bone marrow by antibody-dependent cellular phagocytosis mediated by granulocyte-specific antibodies. More cases should be accumulated to elucidate the precise mechanism and establish the optimal therapy.

Autoimmune Cytopenias Post Hematopoietic Stem Cell Transplantation in Pediatric Patients With Osteopetrosis and Other Nonmalignant Diseases.

Autoimmune cytopenia (AIC) is a rare complication post hematopoietic stem cell transplantation (HSCT), with a higher incidence in nonmalignant diseases. The etiology of post-HSCT AIC is poorly understood, and in many cases, the cytopenia is prolonged and refractory to treatment. Diagnosis of post-HSCT AIC may be challenging, and there is no consensus for a standard of care. In this retrospective study, we summarize our experience over the past five years with post-HSCT AIC in pediatric patients with osteopetrosis and other nonmalignant diseases. All pediatric patients who underwent HSCT for nonmalignant diseases at Hadassah Medical Center over the past five years were screened for post-HSCT AIC, and data were collected from the patient's medical records. From January 2017 through December 2021, 140 pediatric patients underwent HSCT for osteopetrosis (n=40), and a variety of other nonmalignant diseases. Thirteen patients (9.3%) presented with post-HSCT AIC. Of these, 7 had osteopetrosis (17.5%), and 6 had other underlying nonmalignant diseases. Factors associated with developing AIC included unrelated or non-sibling family donors (n=10), mixed chimerism (n=6), and chronic GvHD (n=5). Treatment modalities included steroids, IVIG, rituximab, bortezomib, daratumumab, eltrombopag, plasmapheresis, and repeated HSCT. Response to treatment was variable; Seven patients (54%) recovered completely, and three patients (23%) recovered partially, still suffering from mild-moderate thrombocytopenia. Three patients died (23%), two following progressive lung disease and one from sepsis and multi-organ failure after a 3rd HSCT. In our experience, post-HSCT AICs in pediatric patients with nonmalignant diseases may pose a challenging post-transplant complication with a variable presentation and a wide spectrum of severity. A relatively high prevalence is seen in patients with osteopetrosis, possibly due to difficult engraftment and high rates of mixed chimerism. There is a dire need for novel treatment modalities for better management of the more severe and refractory cases.

Autoimmune Neutropenia Associated With HHV-6 Virus Infection: A Case Report.

Background: Autoimmune neutropenia (AIN) is divided into primary and secondary forms. The former is more prevalent in children and is usually a self-limiting disease. Secondary AIN is more common in adults and often occurs in the setting of another autoimmune disorder or secondary to infections, malignancies or medications. Several viral and bacterial pathogens were described to trigger AIN. Here we report a case of AIN in an adult woman associated with human herpesvirus-6 (HHV-6) infection. Case Presentation: We report a case of AIN in an adult woman associated with HHV-6 infection. The patient presented to the emergency department with fever and painful genital ulcers. Upon arrival, her laboratory workup demonstrated severe neutropenia and elevated inflammatory markers. She was hospitalized and underwent a thorough infectious, hematological, autoimmune and inflammatory workup. Malignancy was also excluded using an advanced whole body radiological scan. Serological tests confirmed the presence of both acute and chronic types of HHV-6 antibodies, at very high titers. Polymerase chain reaction demonstrated a numerous copies of the virus in the patient's blood. Specific immunofluorescence test confirmed the diagnosis of autoimmune neutropenia. Conclusion: Secondary AIN is a rare disease that may affect all range of ages. The adult type is a challenging disorder that has different etiologies and may be triggered by a variable infectious pathogen. The finding of HHV-6 as a possible culprit pathogen may warrant physicians into widening the evaluation and include HHV-6 in the analysis.

Adult Evans' Syndrome.

Evans syndrome (ES) is a rare immune disorder defined as the simultaneous or sequential occurrence in a single patient of immune thrombocytopenia (ITP) and warm autoimmune hemolytic anemia (wAIHA) ± autoimmune neutropenia (AIN). ES represents approximately 5% to 10% of all wAIHA and 2%-5% of all ITP cases in adults and its mortality rate is high. When ITP and wAIHA occurred concomitantly, other differential diagnoses must be ruled out. ES can be primary or secondary and isolated or associated with another underlying disorder and secondary ES. The management of ES is mostly empirical with a low level of evidence. This review reports some new insights on this rare disease and provides some practical tools for the diagnosis and management of adult ES.

Alemtuzumab-induced red cell aplasia and other immune cytopenias: not so 'pure'.

We report on the presentation and outcome of a 28-year-old female who developed red cell aplasia following alemtuzumab therapy for relapsing remitting multiple sclerosis. The patient also developed synchronous immune thrombocytopenia and immune neutropenia, but not aplastic anemia. This patient received high dose steroids, intravenous immunoglobulin (iv.Ig), rituximab, red cell transfusions, vincristine, G-CSF, cyclosporin and mycophenolate to treat the combination of cytopenias over a period of 6 months with subsequent improvement in bone marrow function. While alemtuzumab has several recognized autoimmune complications, little is known about the potential hematological side effects. The combination of red cell aplasia, immune thrombocytic purpura and autoimmune neutropenia has not previously been described in the literature following alemtuzumab immunotherapy and highlights the importance of monthly blood monitoring post alemtuzumab administration.

Lay abstract We report a case of 28-year-old women with relapsing remitting multiple sclerosis who was treated with alemtuzumab and subsequently developed a series of autoimmune complications. Several months after completing her second course of alemtuzumab the patient became breathless and noticed bruising on her legs. On investigation she was found to be anemic and had a low platelet level (which predisposed her to bruising). In addition, her immune system was also impaired meaning she was more prone to developing opportunistic infections. The patient was treated with a variety of different medications and required blood transfusions for several months before she recovered. Despite the multiple complications the patient developed from alemtuzumab her multiple sclerosis remains stable with no new relapses 3 years following treatment.

The ASH-ASPHO Choosing Wisely Campaign: 5 hematologic tests and treatments to question.

Choosing Wisely is a medical stewardship and quality-improvement initiative led by the American Board of Internal Medicine Foundation in collaboration with leading medical societies in the United States. The American Society of Hematology (ASH) has been an active participant in the Choosing Wisely project. In 2019, ASH and the American Society of Pediatric Hematology/Oncology (ASPHO) formed a joint task force to solicit, evaluate, and select items for a pediatric-focused Choosing Wisely list. By using an iterative process and an evidence-based method, the ASH-ASPHO Task Force identified 5 hematologic tests and treatments that health care providers and patients should question because they are not supported by evidence, and/or they involve risks of medical and financial costs with low likelihood of benefit. The ASH-ASPHO Choosing Wisely recommendations are as follows: (1) avoid routine preoperative hemostatic testing in an otherwise healthy child with no previous personal or family history of bleeding, (2) avoid platelet transfusion in asymptomatic children with a platelet count 10 × 103 /µL unless an invasive procedure is planned, (3) avoid thrombophilia testing in children with venous access-associated thrombosis and no positive family history, (4) avoid packed red blood cells transfusion for asymptomatic children with iron deficiency anemia and no active bleeding, and (5) avoid routine administration of granulocyte colony-stimulating factor for prophylaxis of children with asymptomatic autoimmune neutropenia and no history of recurrent or severe infections. We recommend that health care providers carefully consider the anticipated risks and benefits of these identified tests and treatments before performing them.

Immune cytopenias as a continuum in inborn errors of immunity: An in-depth clinical and immunological exploration.

BACKGROUND: Immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and autoimmune neutropenia (AIN) are disorders characterized by immune-mediated destruction of hematopoietic cell lineages. A link between pediatric immune cytopenias and inborn errors of immunity (IEI) was established in particular in the combined and chronic forms. OBJECTIVE: Aim of this study is to provide clinical-immunological parameters to hematologists useful for a prompt identification of children with immune cytopenias deserving a deeper immunological and genetic evaluation. METHODS: We retrospectively collected 47 pediatric patients with at least one hematological disorder among which persistent/chronic ITP, AIHA, and AIN, aged 0-18 years at onset of immune cytopenias and/or immune-dysregulation. The cohort was divided into two groups (IEI+ and IEI-), based on the presence/absence of underlying IEI diagnosis. IEI+ group, formed by 19/47 individuals, included: common variable immune deficiency (CVID; 9/19), autoimmune lymphoproliferative syndrome (ALPS; 4/19), DiGeorge syndrome (1/19), and unclassified IEI (5/19). RESULTS: IEI prevalence among patients with ITP, AIHA, AIN, and Evans Syndrome was respectively of 42%, 64%, 36%, and 62%. In IEI+ group the extended immunophenotyping identified the presence of statistically significant (p < .05) specific characteristics, namely T/B lymphopenia, decrease in naїve T-cells%, switched memory B-cells%, plasmablasts%, and/or immunoglobulins, increase in effector/central memory T-cells% and CD21low B-cells%. Except for DiGeorge and three ALPS patients, only 2/9 CVID patients had a molecular diagnosis for IEI: one carrying the pathogenic variant CR2:c.826delT, the likely pathogenic variant PRF1:c.272C> and the compound heterozygous TNFRSF13B variants p.Ser144Ter (pathogenic) and p.Cys193Arg (variant of uncertain significance), the other one carrying the likely pathogenic monoallelic variant TNFRSF13B:p.Ile87Asn. CONCLUSION: The synergy between hematologists and immunologists can improve and fasten diagnosis and management of patients with immune cytopenias through a wide focused clinical/immunophenotypical characterization, which identifies children worthy of IEI-related molecular analysis, favouring a genetic IEI diagnosis and potentially unveiling new targeted-gene variants responsible for IEI phenotype.

Autoimmune Cytopenias and Dysregulated Immunophenotype Act as Warning Signs of Inborn Errors of Immunity: Results From a Prospective Study.

Inborn errors of immunity (IEI) are genetic disorders characterized by a wide spectrum of clinical manifestations, ranging from increased susceptibility to infections to significant immune dysregulation. Among these, primary immune regulatory disorders (PIRDs) are mainly presenting with autoimmune manifestations, and autoimmune cytopenias (AICs) can be the first clinical sign. Significantly, AICs in patients with IEI often fail to respond to first-line therapy. In pediatric patients, autoimmune cytopenias can be red flags for IEI. However, for these cases precise indicators or parameters useful to suspect and screen for a hidden congenital immune defect are lacking. Therefore, we focused on chronic/refractory AIC patients to perform an extensive clinical evaluation and multiparametric flow cytometry analysis to select patients in whom PIRD was strongly suspected as candidates for genetic analysis. Key IEI-associated alterations causative of STAT3 GOF disease, IKAROS haploinsufficiency, activated PI3Kδ syndrome (APDS), Kabuki syndrome and autoimmune lymphoproliferative syndrome (ALPS) were identified. In this scenario, a dysregulated immunophenotype acted as a potential screening tool for an early IEI diagnosis, pivotal for appropriate clinical management and for the identification of new therapeutic targets.

Autoimmune hematologic complications of umbilical cord blood transplantation.

While umbilical cord blood is increasingly utilized as a stem cell source, immune complications associated with the procedure have been recognized. These complications result from significant immune system dysregulation and defective reconstitution following transplant causing an imbalance between T-cell subsets, aberrant B cells, and abnormal antibody production. This may occur up to 12 months after transplant coinciding with thymic regeneration in adults. The aim of our review is to describe the incidence, pathophysiology, clinical features, and prognosis of autoimmune cytopenias following umbilical cord blood transplant. Furthermore, we review the treatment strategies reported in the existing literature, describe the authors' experience with the complication, and highlight novel treatment options being studied. The knowledge of the occurrence and timing of autoimmune complications of umbilical cord blood transplantation is essential for detection and treatment of the disease. Emerging therapeutic options include interleukin-2 (IL-2), which is also being studied for the treatment of acute and chronic graft-versus-host disease. IL-2 has favorable effects on growth, differentiation, and function of regulatory T cells. Monoclonal antibody treatments, such as daratumumab, are also on the forefront and more experience with them will guide further treatment strategies.

Dealing with pre-existing chronic neutropenia in cancer patients-considerations and consequences in the clinical praxis.

Chronic neutropenia is a rare but important challenge with substantial clinical implications for patients receiving antineoplastic treatment. Treatment-induced neutropenia is a well-known adverse event during chemotherapy and some targeted treatments. Guidelines for administering chemotherapy are rather strict to protect the patient from severe and life-threatening complications. Consequently, patients with chronic neutropenia may receive suboptimal antineoplastic treatment. Autoimmune neutropenia or chronic idiopathic neutropenia (CIN) may affect the antineoplastic treatment by causing delayed drug delivery, dose reductions and early discontinuation of treatment. CIN is characterised by the onset in late childhood or adulthood, affects mostly women, is clinically benign and has rare spontaneous remission. Here, we elucidate the challenges related to chronic neutropenia when administering chemotherapy through two clinical cases. Guidelines may need to be revised in order to optimise the treatment of patients with asymptomatic chronic neutropenia, thus personalising the medical decisions for each patient.

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.