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 October 2, 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 October 2, 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 performed, of which 9 (14%) had Change From Lowest ANC Category to of neutropenia. We identified 155 positive results. Four (16%) of the 25 Their Current ANC Category children with isolated neutropenia children tested for an ELANE gene over the 5.5-year study period, mutation were found to have the Thirty-one children were categorized excluding 40 children who had mutation. These abnormalities were as mild neutropenia by using their additional cytopenias. The mean age heterozygous variation exon 5, lowest ANC (Table 2). Twenty-four of children at the time of referral for sequence variation exon 5 at codon (77%) of these children had resolved isolated neutropenia was 8.1 6 5.9 260 to threonine (both of unknown neutropenia, and 7 (23%) children years. Ninety-two children (60%) pathologic significance; current ANC continued to have persistent mild were boys, and 63 (40%) were girls. of 1940 and 3970, respectively), neutropenia on their most recent Eighty-seven (56%) of the children c.655G.A, p.V219I (benign variant; CBC. Sixty-nine children were referred were Black, 67 (43%) were current ANC of 740), and R144H categorized as moderate neutropenia white, and 1 (1%) was Asian variant (variant of uncertain by using their lowest ANC. Thirty- American. On the basis of initial significance; current ANC of 1190). eight (55%) of these children had referral CBC, 45 (29%) were Bone marrow aspiration and biopsy currently resolved neutropenia, 25 categorized as having mild was performed in 32 children. The (36%) children improved to mild neutropenia, 65 (42%) had moderate most common reported findings were neutropenia, and 5 (7%) children had neutropenia, 30 (19%) had severe normal (16) and hypocellular marrow persistent moderate neutropenia. neutropenia, and 15 (10%) had very (12). No children were found to have Thirty-five children were categorized severe neutropenia. a malignancy. as severe neutropenia by using their lowest ANC. Twenty-three (66%) Referral Characteristics Change From Referral ANC Category children had currently resolved to the Lowest ANC Category neutropenia, 7 (20%) children The median time from the first Thirty (19%) children changed to improved to mild neutropenia, 3 abnormal CBC to the referral visit was a lower ANC category than their (8%) children improved moderate 2 months (range of 1–74 months). initial referral ANC category neutropenia, and 2 (6%) children had The time line for referral was (Table 1). In contrast, neutropenia persistent severe neutropenia on significantly impacted by the severity had resolved in 46 (30%) children by their most recent CBC. Among 20 of neutropenia. Children with severe their initial visit. Of the 45 children children with very severe neutropenia attended their first clinic referred with mild neutropenia, 14 neutropenia as the lowest category, visit at a median of 1 month from (31%) changed to moderate 16 (80%) children resolved, 1 (5%) their initial CBC, children with neutropenia. No children referred for patient improved to mild moderate neutropenia were mild isolated neutropenia changed to neutropenia, 2 (10%) children evaluated at a median of 3 months, severe or very severe neutropenia. Of improved to moderate neutropenia, and those with mild neutropenia the 65 children referred with and 1 (5%) patient had persistence of were seen at a median of 2 months moderate neutropenia, 11 (17%) very severe neutropenia on the most (P = .013). The median number of changed to severe neutropenia, but recent CBC. CBCs performed before the referral visit was 3 (range of 1–31). We did not identify a significant association TABLE 1 Change From Referral ANC to Their Lowest ANC Category between the number of CBCs Referral ANC Category Lowest ANC category before referral and resolution of Mild Neutropenia Moderate Severe Very Severe Total, n neutropenia. Children with persistent Neutropenia Neutropenia Neutropenia neutropenia had a median of 4 CBCs Mild neutropenia 31 (69%) 14 (31%) 0 (0%) 0 (0%) 45 before referral in comparison with Moderate neutropenia 0 (0%) 54 (83%) 11 (17%) 0 (0%) 65 children with resolved neutropenia Severe neutropenia 0 (0%) 0 (0%) 25 (83%) 5 (17%) 30 who had a mean of 3 CBCs before Very severe neutropenia 0 (0%) 0 (0%) 0 (0%) 15 (100%) 15 referral (P = .88). Total, n 31 68 36 20 155

Downloaded from www.aappublications.org/news by guest on October 2, 2021 PEDIATRICS Volume 146, number 4, October 2020 3 TABLE 2 Change From Lowest ANC Category to Their Current ANC Category iodine). These medications are Lowest ANC Category Current ANC Category well-known causes of neutropenia, Resolved Mild Moderate Severe Very Severe Total, n highlighting the importance of Neutropenia Neutropenia Neutropenia Neutropenia obtaining a thorough medication Mild neutropenia 24 (77%) 7 (23%) 0 (0%) 0 (0%) 0 (0%) 31 history in patients presenting with Moderate neutropenia 38 (55%) 25 (36%) 5 (7%) 1 (1%) 0 (0%) 69 neutropenia. We identified Severe neutropenia 23 (66%) 7 (20%) 3 (9%) 2 (6%) 0 (0%) 35 autoimmune neutropenia in 22 Very severe 16 (80%) 1 (5%) 2 (10%) 0 (0%) 1 (5%) 20 children. neutropenia Total, n 101 40 10 3 1 155 Racial Differences in Outcomes We identified no significant difference Outcomes Based on Referral ANC autoimmune neutropenia and in the referral ANC for Black children juvenile rheumatoid arthritis), and 1 in comparison with white children The median time to resolution of (3%) patient changed to very severe (1038 vs 907 per mm3; P = .11). neutropenia from the earliest neutropenia (diagnosed with However, the current ANC was documented CBC was 5.5 months autoimmune neutropenia). Fifteen significantly lower in Black children, (Table 3). Children with persistent children were referred with very in comparison with white children neutropenia continued to be managed severe neutropenia, 13 (87%) (1892 vs 2528 per mm3; P = .01). for a median of 12 months. Forty-five children resolved, and 2 (13%) Forty-nine (56%) Black children and children were referred with mild children continued to have moderate 50 (76%) white children had resolved neutropenia. Thirty-four children neutropenia. Characteristics of those neutropenia (P = .01). We identified (76%) resolved, whereas 11 (24%) children currently with moderate, 24 children with persistent mild children continued with mild severe, and very severe neutropenia neutropenia of unknown etiology, 20 neutropenia. Sixty-five children were are presented in Table 4. (83%) of whom were Black. Black referred with moderate neutropenia. children had a 3.5 higher odds (95% Thirty-five (54%) children resolved, Current Diagnosis confidence interval: 1.1–11.7) of 22 (34%) children had mild We present the current diagnosis having a persistent mild neutropenia. neutropenia, 7 (11%) children had distribution in Table 5. We did not persistent moderate neutropenia, and identify specific etiologies for Interventions 1 (1%) patient changed to severe neutropenia in 54% of children. The Six children (4%) received neutropenia, but none changed to the most commonly identified causes granulocyte colony-stimulating factor very severe neutropenia category. The were viral suppression (16%), (G-CSF) prophylaxis at some point for patient with severe neutropenia was autoimmune neutropenia (14%), and their neutropenia, including 4 of the diagnosed with drug-induced drug-induced neutropenia (8%). The 15 children referred with very severe neutropenia because the neutropenia most common medications neutropenia. Four children were improved after stopping the offending responsible for neutropenia were found to have drug-induced medication. Twenty-nine children either antiepileptic medications neutropenia requiring were referred with severe (zonisamide, oxcarbazepine, discontinuation of the offending neutropenia, 18 (62%) resolved, 7 diazepam, lacosamide, medication. Five children required (24%) children had mild neutropenia, carbamazepine, lamotrigine, and further evaluation and management 1 (3%) patient had moderate valproate) or immunosuppressant by either the rheumatology or neutropenia, 2 (7%) children medication (azathioprine, immunology departments. persisted with severe neutropenia methotrexate, infliximab, etanercept, Characteristics of children who (ultimately diagnosed with mycophenolic acid, and radioactive required G-CSF injections are presented in Table 6. TABLE 3 Outcomes Based on Referral ANC Hospitalizations Referral ANC Category Current ANC Category Among 155 children referred with Resolved Mild Moderate Severe Very Severe Total, n Neutropenia Neutropenia Neutropenia Neutropenia isolated neutropenia, 10 children were admitted for a total of 16 Mild neutropenia 34 (76%) 11 (24%) 0 (0%) 0 (0%) 0 (0%) 45 ’ Moderate neutropenia 35 (54%) 22 (34%) 7 (11%) 1 (1%) 0 (0%) 65 admissions to Children s of Alabama. Severe neutropenia 19 (62%) 7 (24%) 1 (3%) 2 (7%) 1 (3%) 30 We followed children with persistent Very severe 13 (87%) 0 (0%) 2 (13%) 0 (0%) 0 (0%) 15 neutropenia for a mean of 2.2 years neutropenia from diagnosis to either resolution or Total, n 101 40 10 3 1 155 the end of the study period. The most

Downloaded from www.aappublications.org/news by guest on October 2, 2021 4 NAGALAPURAM et al TABLE 4 Characteristics of Children Currently With ANC Categorized as Moderate, Severe, and Very Thirty percent of children had Severe a normal ANC at their initial referral Patient Referral ANC Lowest ANC Current ANC Current Diagnosis Interventions visit. No children referred for isolated Identifier Category Category Category neutropenia were diagnosed with 001 Severe Very severe Very severe Autoimmune None a malignancy. Despite concerns that neutropenia prolonged neutropenia can be 002 Severe Severe Severe Juvenile rheumatoid None associated with an increased risk of arthritis acute illness or bacteremia, hospital 003 Moderate Severe Severe Drug induced G-CSF (mycophenolic admission rates were low, and no acid) bacteremia was identified. 004 Severe Severe Severe Autoimmune None neutropenia We hypothesized that the majority of 005 Moderate Moderate Moderate Undiagnosed None children with isolated mild 006 Moderate Severe Moderate Undiagnosed Immunology, neutropenia would not progress in rheumatology referral current severity category or need an 007 Severe Severe Moderate Undiagnosed None intervention from a pediatric 008 Moderate Moderate Moderate Viral suppression None hematologist-oncologist. Three- 009 Moderate Severe Moderate Moderate aplastic None fourths of children referred with mild anemia neutropenia had complete resolution 010 Moderate Moderate Moderate Autoimmune None neutropenia of neutropenia, and the remaining 011 Very Severe Very severe Moderate Autoimmune None 25% continued to have mild neutropenia neutropenia. No children in this 012 Moderate Moderate Moderate Viral suppression None referral category needed an 013 Moderate Moderate Moderate Autoimmune None intervention or required neutropenia 014 Very Severe Very severe Moderate Autoimmune G-CSF hospitalization for febrile neutropenia neutropenia. Because no standard of care guidelines exist to determine the frequency of CBC monitoring in common reason for admission was DISCUSSION children with neutropenia, in this for febrile neutropenia (n = 13) study, we could not determine how without a subsequent bacteremia; the This study revealed that the majority long PCPs should monitor CBCs other admission diagnoses included of children referred with isolated before referring a child with cellulitis (n = 1), rash with neutropenia eventually resolved persistent mild isolated neutropenia. neutropenia (n = 1), and alloimmune without any intervention from However, we identified a median time neutropenia (n = 1). a pediatric hematologist-oncologist. of 5 months from initial CBC to the first identified resolved CBC.

TABLE 5 Current Diagnosis for Referred Children Although only 4% (n = 6) of all Current Diagnosis N Percentage children referred received G-CSF, Resolved, % two-thirds of these children had very Undiagnosed: resolved 60 100 severe neutropenia at the time of Undiagnosed: not resolved 24 0 referral. The remaining 2 were Viral suppression 24 66.67 referred with moderate and severe Autoimmune neutropenia 22 50 Drug-induced neutropenia 13 61.5 neutropenia. Four of the children Alloimmune neutropenia 2 50 treated with G-CSF were diagnosed Cyclic neutropenia 2 0 with autoimmune neutropenia and ELANE 10received G-CSF in the setting of Hyper IgE syndrome 1 100 hospitalization for febrile JRA 1 0 MBL deficiency 1 100 neutropenia or documented infection Aplastic anemia 1 0 (See Table 6). Nephrotic syndrome 1 100 SLE 1 100 CVID 1 100 A high proportion of referrals for Total 155 65 isolated neutropenia were Black CVID, common variable immunodeficiency; IgE, immunoglobulin E; JRA, juvenile rheumatoid arthritis; MBL, mannose- children. Although only 27% of the binding lectin; SLE, systemic lupus erythematosus. population in Alabama is Black, 56%

Downloaded from www.aappublications.org/news by guest on October 2, 2021 PEDIATRICS Volume 146, number 4, October 2020 5 TABLE 6 Characteristics of Children Who Received G-CSF dependent granulopoietic inhibition, Patient Referral ANC Lowest ANC Current Current Diagnosis Reason and dose-independent idiosyncratic – Identifier Category Category ANC reaction.20 22 Category A Very Severe Very severe Resolved Alloimmune Concern for acute abdomen Although our study adds valuable neutropenia in the setting of very information to the medical literature severe neutropenia on outcomes for isolated neutropenia B Moderate Severe Severe Drug induced Severe neutropenia in the fi (mycophenolic setting of cardiac at our institution, these ndings must acid) transplant be interpreted in the setting of some C Very Severe Very severe Resolved Autoimmune Concern for pneumonia in limitations. First, we only included neutropenia the setting of very severe children with isolated neutropenia neutropenia that were adherent to the initial D Very Severe Very severe Moderate Autoimmune Concern for sepsis in the neutropenia setting of very severe pediatric hematology-oncology clinic neutropenia visit. We expect that several children E Very Severe Very severe Resolved Autoimmune Concern for varicella with isolated mild neutropenia that neutropenia infection in the setting of were nonadherent to their referral very severe neutropenia clinic visits either remained stable or F Very Severe Very severe Resolved Autoimmune History of recurrent neutropenia infections in the setting of resolved, thus not warranting very severe neutropenia a second referral. This limitation would likely strengthen our findings that isolated mild neutropenia of our referral population self- Secondly, autoimmune neutropenia children is not associated with identified as Black.19 may occur without a positive hematologic pathology. Second, the antineutrophil antibody test result. follow-up duration between CBCs Black children were less likely to have We acknowledge that there are was at the treating physicians’ resolution of neutropenia in limitations with use of antineutrophil discretion and, therefore, not comparison with their white antibody testing due to lack of standardized. The time of counterparts. Furthermore, the odds standardization among laboratories. documented resolution reflects the of having persistent mild isolated In an effort to alleviate this, we were timing of laboratory evaluations neutropenia were higher in Black consistent at our center by sending rather than the exact day neutropenia children, consistent with previously our neutrophil antibody testing to resolved. However, it is not standard published evidence that Black Versiti Blood Center of Wisconsin. of care to obtain very frequent CBCs children have differences in baseline This laboratory uses a flow in patients with isolated neutropenia, neutrophil counts.2,3 Although BEN is cytometry-based method for and there are no clinical implications a diagnosis of exclusion, 83% of detection of neutrophil antibodies to of identifying the exact time of children with persistent isolated mild the following, most common antigens: resolution. Third, after resolution of neutropenia in this cohort were human neutrophil antigen-1a, -1b, neutropenia, we did not recommend Black, suggesting this diagnosis. -1c, -2a, -3a, and -4a (https://www. serial monitoring for recurrence of A specific etiology was not found in versiti.org/home). Finally, BEN is neutropenia. Therefore, children with most of the children referred for a potential diagnosis in several of our documented resolved isolated isolated neutropenia. There are Black patient referrals, but this is neutropenia may have developed several potential contributors to our a diagnosis of exclusion. With recurrent neutropenia, and, if inability to identify a cause of isolated technological advances, future asymptomatic, the PCP may not have neutropenia. First, several children research could better define an repeated a CBC. Additionally, we were diagnosed with neutropenia by etiology for the majority of children cannot confirm whether children with a PCP during an evaluation for an referred for neutropenia. Among the initial resolved neutropenia had acute illness. The most likely cases of drug-induced neutropenia, recurrence and perhaps were diagnosis for these cases would be antiepileptic and immunosuppressant referred to a different institution. a transient neutropenia associated medications were the most commonly Fourth, we did not perform studies of with an infection. However, this was implicated drugs. patient reported outcomes, which not confirmed because either no virus Immunosuppressant medications are could enhance this research; future was identified at the time of the known to inhibit myelopoiesis, and research should evaluate the impact referral visit or the pediatric the mechanisms of drug-induced of referrals for isolated neutropenia hematologist-oncologist did not neutropenia include immune on quality outcomes. Finally, pediatric obtain extensive viral testing. mediated destruction, dose- guidelines do not exist to ensure

Downloaded from www.aappublications.org/news by guest on October 2, 2021 6 NAGALAPURAM et al a systematic approach to ordering isolated neutropenia at the time of patients about isolated neutropenia definitive testing for viral, referral did not tend to progress in outcomes, which could ultimately autoimmune, or other disorders in severity nor did they require impact referral rates to a pediatric children with mild isolated therapeutic interventions from hematologist-oncologist. neutropenia, increasing our a pediatric hematologist-oncologist. It prevalence of undiagnosed cases. We was also rare for children with ACKNOWLEDGMENT will use the findings of our study moderate or severe neutropenia to going forward to develop an receive G-CSF. Less than 10% of We acknowledge Lisa Allred, RN, for algorithm to standardize the way we children referred required hospital keeping records of the referral workup and manage pediatric admission. No children with isolated information in our division. patients referred to us with isolated neutropenia, regardless of severity neutropenia. Future studies are category, developed leukemia or any needed to analyze the cost and other malignancy. Although the patient reported outcomes associated majority of children with isolated ABBREVIATIONS with workup for isolated mild neutropenia may not receive ANC: absolute neutrophil count neutropenia. adefinitive diagnosis, additional BEN: benign ethnic neutropenia research into the genetics of BEN and CBC: complete blood cell count ELANE CONCLUSIONS improved sensitivity of laboratory : elastase, neutrophil- techniques for viral and autoimmune expressed In this study, we categorize the neutropenia could enhance our G-CSF: granulocyte colony- outcomes for children on the basis of diagnostic ability. Overall, this study stimulating factor neutropenia severity categories at the provides reassuring data for PCP: primary care provider time of referral. Children with mild pediatricians to use when counseling

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2020 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: Dr Lebensburger receives grant support from the National Lung, Blood, and Heart Institute (5K23HL127100) and is on the steering committee for Novartis. Both projects are related to sickle cell kidney disease; the other authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

REFERENCES 1. James RM, Kinsey SE. The investigation 5. Myers KC, Bolyard AA, Otto B, et al. syndrome. Haematologica. 2012;97(9): and management of chronic Variable clinical presentation of 1312–1319 neutropenia in children. Arch Dis Child. Shwachman-Diamond syndrome: 8. Dale DC, Cottle TE, Fier CJ, et al. Severe 2006;91(10):852–858 update from the North American chronic neutropenia: treatment and Shwachman-Diamond Syndrome 2. Broun GO Jr., Herbig FK, Hamilton JR. follow-up of patients in the Severe Registry. J Pediatr. 2014;164(4):866–870 Leukopenia in Negroes. N Engl J Med. Chronic Neutropenia International 1966;275(25):1410–1413 6. Makaryan V, Zeidler C, Bolyard AA, et al. Registry. Am J Hematol. 2003;72(2): 82–93 3. Caramihai E, Karayalcin G, Aballi AJ, The diversity of mutations and clinical Lanzkowsky P. Leukocyte count outcomes for ELANE-associated 9. Downes KJ, Zaoutis TE, Shah SS. differences in healthy white and black neutropenia. Curr Opin Hematol. 2015; Guidelines for management of children children 1 to 5 years of age. J Pediatr. 22(1):3–11 with fever and neutropenia. J Pediatric 1975;86(2):252–254 7. Donadieu J, Fenneteau O, Beaupain B, Infect Dis Soc. 2013;2(3):281–285 4. Roberts AE, Nixon C, Steward CG, et al. et al; Associated Investigators of the The Barth Syndrome Registry: French Severe Chronic Neutropenia 10. Wittmann O, Rimon A, Scolnik D, distinguishing disease characteristics Registry. Classification of and risk Glatstein M. Outcomes of and growth data from a longitudinal factors for hematologic complications immunocompetent children presenting study. Am J Med Genet A. 2012;158A(11): in a French national cohort of 102 with fever and neutropenia. J Emerg 2726–2732 patients with Shwachman-Diamond Med. 2018;54(3):315–319

Downloaded from www.aappublications.org/news by guest on October 2, 2021 PEDIATRICS Volume 146, number 4, October 2020 7 11. Serwint JR, Dias MM, Chang H, Sharkey 15. Audrain M, Martin J, Fromont P, Prié N, 19. US Census Bureau. QuickFacts: M, Walker AR. Outcomes of febrile Thomas C, Muller EJ-Y. Autoimmune Alabama. Available at: https://www. children presumed to be neutropenia in children: analysis of 116 census.gov/quickfacts/al. Accessed May immunocompetent who present with cases. Pediatr Allergy Immunol. 2011; 20, 2019 leukopenia or neutropenia to an 22(5):494–496 ambulatory setting. Clin Pediatr (Phila). 20. Schröder H, Evans DA. Acetylator 2005;44(7):593–600 16. Karavanaki K, Polychronopoulou S, phenotype and adverse effects of Giannaki M, et al. Transient and chronic 12. Teachey DT, Lambert MP. Diagnosis and sulphasalazine in healthy subjects. Gut. neutropenias detected in children with management of autoimmune 1972;13(4):278–284 different viral and bacterial infections. cytopenias in childhood. Pediatr Clin Acta Paediatr. 2006;95(5):565–572 North Am. 2013;60(6):1489–1511 21. Gibson C, Berliner N. How we evaluate and treat neutropenia in adults. Blood. 17. Alexandropoulou O, Kossiva L, Haliotis F, 13. Farruggia P, Dufour C. Diagnosis and 2014;124(8):1251–1258; quiz 1378 management of primary autoimmune et al. Transient neutropenia in children neutropenia in children: insights for with febrile illness and associated infectious agents: 2 years’ follow-up. 22. Hodinka L, Géher P, Merétey K, Gyódi EK, clinicians. Ther Adv Hematol. 2015;6(1): Petrányi GG, Bozsóky S. Levamisole- – Eur J Pediatr. 2013;172(6):811–819 15 24 induced neutropenia and 14. Bux J, Behrens G, Jaeger G, Welte K. 18. Hsieh M, Chin K, Link B, et al. Benign agranulocytosis: association with HLA Diagnosis and clinical course of ethnic neutropenia in individuals of B27 leukocyte agglutinating and autoimmune neutropenia in infancy: African descent: incidence, granulocyte lymphocytotoxic antibodies. Int Arch analysis of 240 cases. Blood. 1998;91(1): mobilization, and gene expression Allergy Appl Immunol. 1981;65(4): 181–186 profiling. Blood. 2005;106(11):3069 460–464

Downloaded from www.aappublications.org/news by guest on October 2, 2021 8 NAGALAPURAM et al Outcomes of Isolated Neutropenia Referred to Pediatric Hematology-Oncology Clinic Vishnu Nagalapuram, David McCall, Prasannalaxmi Palabindela, Thomas H. Howard, Christina Bemrich-Stolz, Jeffrey Lebensburger, Lee Hilliard and Hope P. Wilson Pediatrics originally published online September 3, 2020;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2020/09/01/peds.2 019-3637 References This article cites 21 articles, 5 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2020/09/01/peds.2 019-3637#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Hematology/Oncology http://www.aappublications.org/cgi/collection/hematology:oncology _sub Blood Disorders http://www.aappublications.org/cgi/collection/blood_disorders_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on October 2, 2021 Outcomes of Isolated Neutropenia Referred to Pediatric Hematology-Oncology Clinic Vishnu Nagalapuram, David McCall, Prasannalaxmi Palabindela, Thomas H. Howard, Christina Bemrich-Stolz, Jeffrey Lebensburger, Lee Hilliard and Hope P. Wilson Pediatrics originally published online September 3, 2020;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/early/2020/09/01/peds.2019-3637

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2020 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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