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Outcomes of Isolated Neutropenia Referred to Pediatric Hematology

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Outcomes of Isolated Neutropenia Referred to Pediatric Hematology Outcomes of Isolated Neutropenia Referred to Pediatric Hematology-Oncology Clinic Vishnu Nagalapuram, MBBS,a David McCall, MD,b Prasannalaxmi Palabindela, MBBS,a Thomas H. Howard, MD,a Christina Bemrich-Stolz, MD, MSPH,a Jeffrey Lebensburger, DO, MSPH,a Lee Hilliard, MD,a Hope P. Wilson, MDa BACKGROUND: Children with isolated neutropenia (absolute neutrophil count [ANC] ,1500/mL) abstract are frequently referred to pediatric hematology and oncology clinics for further diagnostic evaluation. Scant literature exists on interventions and outcomes for isolated neutropenia. We hypothesized that children will have resolution of their neutropenia without the need for intervention(s) by a pediatric hematologist and oncologist. METHODS: We performed a 5.5-year institutional review board–approved retrospective chart review of children referred to our pediatric hematology and oncology clinics for isolated neutropenia. Neutropenia was categorized as mild (ANC of 1001–1500/mL), moderate (ANC of 500–1000 mL), severe (ANC of 201–500/mL), or very severe (ANC of #200/mL). RESULTS: Among 155 children referred with isolated neutropenia, 45 (29%) had mild neutropenia, 65 (42%) had moderate neutropenia, 30 (19%) had severe neutropenia, and 15 (10%) had very severe neutropenia. Only 29 (19%) children changed to an ANC category lower than their initial referral category. At a median follow-up of 12 months, 101 children had resolution of neutropenia, 40 children had mild neutropenia, 10 children had moderate neutropenia, 3 children had severe neutropenia, and 1 patient had very severe neutropenia. A specific diagnosis was not identified in most (54%) children. The most common etiologies were viral suppression (16%), autoimmune neutropenia (14%), and drug-induced neutropenia (8%). Black children had a 3.5 higher odds of having persistent mild neutropenia. Six (4%) children received granulocyte colony-stimulating factor therapy. CONCLUSIONS: Most children referred for isolated neutropenia do not progress in severity and do not require subspecialty interventions or hospitalizations. aDivision of Pediatric Hematology-Oncology, Department of Pediatrics, School of Medicine, The University of WHAT’S KNOWN ON THIS SUBJECT: Isolated Alabama at Birmingham, Birmingham, Alabama; and bMD Anderson Cancer Center, The University of Texas, neutropenia is a common referral to pediatric Houston, Texas hematology and oncology clinics. Dr Nagalapuram drafted the initial manuscript, collected data, and performed analyses; Drs McCall WHAT THIS STUDY ADDS: Isolated neutropenia most and Palabindela collected data and performed the initial analysis. Drs Wilson, Hilliard, Howard, and often resolves without intervention from a pediatric Bemrich-Stolz reviewed and revised the manuscript; Dr Lebensburger designed the study, data hematologist and oncologist. Children referred with collection instruments, and reviewed and revised the manuscript; and all authors have approved isolated neutropenia are not at high risk for the final manuscript as submitted and accept accountability for all aspects of the work. hospitalization, bacteremia, or progression to DOI: https://doi.org/10.1542/peds.2019-3637 leukemia. Accepted for publication Jul 13, 2020 Address correspondence to Hope P. Wilson, MD, Division of Pediatric Hematology-Oncology, To cite: Nagalapuram V, McCall D, Palabindela P, et al. Department of Pediatrics, Children’s Hospital of Alabama and The University of Alabama at Outcomes of Isolated Neutropenia Referred to Pediatric Birmingham, 1600 7th Ave South, Lowder 512, Birmingham, AL 35223. E-mail: [email protected] Hematology-Oncology Clinic. Pediatrics. 2020;146(4):e20193637 Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 146, number 4, October 2020:e20193637 ARTICLE Pediatric patients who have institution for isolated neutropenia Diagnoses and Outcomes a complete blood cell count (CBC) over a 5.5-year period. To identify cases of drug-induced drawn by their primary care provider neutropenia, we reviewed the (PCP) may be diagnosed with an medications for each patient that isolated neutropenia. The differential METHODS are known to be associated with diagnosis for isolated neutropenia neutropenia, in addition to includes both acquired and congenital Subjects determining if the resolution of causes, varying from transient neutropenia occurred after neutropenia associated with an We performed an institutional review discontinuation of the medication. acute illness to severe chronic board–approved retrospective cohort neutropenia.1 Neutropenia in children study of children who were referred $1 year of age is categorized by We recorded the results of to the University of Alabama at severity as mild absolute neutrophil antinuclear antibody testing (Quest Birmingham pediatric hematology- count (ANC) (1001–1500/mL), Diagnostics, Inc, San Juan Capistrano, oncology clinic for isolated moderate (501–1000/mL), severe CA) to identify patients with possible neutropenia from January 2013 (201–500/mL) and very severe rheumatologic etiology, through August 2018. We identified (#200/mL).1 Additionally, normative antineutrophil antibody testing 155 children ages 0 to 18 years who neutrophil counts can vary by race. (Versiti Blood Center of Wisconsin, were referred by their PCP for Benign ethnic neutropenia (BEN) is Milwaukee, WI) to identify patients isolated neutropenia (at least 1 ANC described in cohorts of individuals of with autoimmune neutropenia, and ,1500/mL). We excluded any African descent that have a baseline elastase, neutrophil-expressed children referred with neutropenia ANC ,1500/mL.2,3 On the basis of the (ELANE) gene testing (Versiti Blood who were found to have either severity of neutropenia, clinical Center of Wisconsin) to identify anemia and/or thrombocytopenia. history, physical examination, and/or patients with either congenital or We also excluded all children referred parental preference, PCPs may refer cyclic neutropenia. We examined the for neutropenia who did not adhere children with isolated neutropenia to bone marrow aspiration and biopsy to their referral evaluation. a pediatric hematologist and reports to identify patients with oncologist for additional evaluation. cancer or bone marrow failure Definition of Variables disorders. We reviewed microbiology and virology records to identify cases There are a few established cohort Neutropenia of documented infection-related studies in which researchers monitor neutropenia and clinic notes to the natural history and outcomes for Using the referral records, we identify cases of presumed viral children with established genetic and recorded the date of referral and the induced neutropenia. We identified bone marrow failure associated referral ANC. We also extracted the the need for interventions by neutropenia.4–8 In smaller studies, date of the first identified episode of reviewing all pediatric hematology- researchers have also explored the neutropenia and number of CBCs oncology clinic notes as well as outcomes of children with febrile performed before the referral visit. additional subspecialty referral notes. neutropenia,9–11 autoimmune We then reviewed the referral Finally, all admission diagnoses and neutropenia,12–15 neutropenia records and our electronic medical results from cultures (blood, wound, associated with viral and bacterial records to identify the lowest ANC urine, and cerebrospinal fluid) were infections,16,17 and BEN.18 However, and the current ANC. Additionally, we detailed. In the statistical analysis, there is a critical gap in the literature called the referring physicians to characteristics and outcomes of as it pertains to the outcomes of confirm the current ANC. We children referred for neutropenia children referred to a subspecialist categorized the referral, the lowest, were summarized by using for isolated neutropenia. and the current ANC as mild descriptive statistics. Comparison of Understanding the natural history for neutropenia (ANC: 1001–1500/mL), characteristics was performed by this specific referral population is moderate neutropenia (501–1000/mL), using a t test for normally distributed vital to improve the referral process. severe neutropenia (201–500/mL), or data and Wilcoxon rank test for non- We hypothesize that children referred very severe neutropenia (#200/mL). normally distributed data. Nominal with mild isolated neutropenia do not For the current ANC, we also logistic regression was used to model have severe or life-threatening categorized children as resolved if the odds of resolution of neutropenia illnesses that require intervention. To ANC .1500/mL. We documented the on the basis of race. All analyses were test this hypothesis, we evaluated the age, sex, race, and medications at conducted by using JMP Pro 14 (SAS course for all children referred to our the time of referral for all children. Institute, Inc, Cary, NC). Downloaded from www.aappublications.org/news by guest on September 24, 2021 2 NAGALAPURAM et al RESULTS Diagnostic Testing none changed to the very severe category. Among 30 children referred Study Population at Referral Eighty-four children underwent testing for antineutrophil antibodies, with severe neutropenia, 5 (17%) children changed to very severe Among 3216 outpatient referrals to and 23 (27%) children had positive neutropenia. our pediatric hematology-oncology testing results. Sixty-three children clinic over 5.5 years, we identified had an antinuclear antibody panel 195 children referred for a diagnosis
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