BACKGROUND:

Children with isolated neutropenia (absolute neutrophil count [ANC] <1500/μL) 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/μL), moderate (ANC of 500–1000 μL), severe (ANC of 201–500/μL), or very severe (ANC of ≤200/μL).

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.

What’s Known on This Subject:

Isolated neutropenia is a common referral to pediatric hematology and oncology clinics.

What This Study Adds:

Isolated neutropenia most often resolves without intervention from a pediatric hematologist and oncologist. Children referred with isolated neutropenia are not at high risk for hospitalization, bacteremia, or progression to leukemia.

Pediatric patients who have a complete blood cell count (CBC) drawn by their primary care provider (PCP) may be diagnosed with an isolated neutropenia. The differential diagnosis for isolated neutropenia includes both acquired and congenital causes, varying from transient neutropenia associated with an acute illness to severe chronic neutropenia.1  Neutropenia in children ≥1 year of age is categorized by severity as mild absolute neutrophil count (ANC) (1001–1500/μL), moderate (501–1000/μL), severe (201–500/μL) and very severe (≤200/μL).1  Additionally, normative neutrophil counts can vary by race. Benign ethnic neutropenia (BEN) is described in cohorts of individuals of African descent that have a baseline ANC <1500/μL.2,3  On the basis of the severity of neutropenia, clinical history, physical examination, and/or parental preference, PCPs may refer children with isolated neutropenia to a pediatric hematologist and oncologist for additional evaluation.

There are a few established cohort studies in which researchers monitor the natural history and outcomes for children with established genetic and bone marrow failure associated neutropenia.48  In smaller studies, researchers have also explored the outcomes of children with febrile neutropenia,911  autoimmune neutropenia,1215  neutropenia associated with viral and bacterial infections,16,17  and BEN.18  However, there is a critical gap in the literature as it pertains to the outcomes of children referred to a subspecialist for isolated neutropenia. Understanding the natural history for this specific referral population is vital to improve the referral process. We hypothesize that children referred with mild isolated neutropenia do not have severe or life-threatening illnesses that require intervention. To test this hypothesis, we evaluated the course for all children referred to our institution for isolated neutropenia over a 5.5-year period.

We performed an institutional review board–approved retrospective cohort study of children who were referred to the University of Alabama at Birmingham pediatric hematology-oncology clinic for isolated neutropenia from January 2013 through August 2018. We identified 155 children ages 0 to 18 years who were referred by their PCP for isolated neutropenia (at least 1 ANC <1500/μL). We excluded any children referred with neutropenia who were found to have either anemia and/or thrombocytopenia. We also excluded all children referred for neutropenia who did not adhere to their referral evaluation.

Neutropenia

Using the referral records, we recorded the date of referral and the referral ANC. We also extracted the date of the first identified episode of neutropenia and number of CBCs performed before the referral visit. We then reviewed the referral records and our electronic medical records to identify the lowest ANC and the current ANC. Additionally, we called the referring physicians to confirm the current ANC. We categorized the referral, the lowest, and the current ANC as mild neutropenia (ANC: 1001–1500/μL), moderate neutropenia (501–1000/μL), severe neutropenia (201–500/μL), or very severe neutropenia (≤200/μL). For the current ANC, we also categorized children as resolved if ANC >1500/μL. We documented the age, sex, race, and medications at the time of referral for all children.

Diagnoses and Outcomes

To identify cases of drug-induced neutropenia, we reviewed the medications for each patient that are known to be associated with neutropenia, in addition to determining if the resolution of neutropenia occurred after discontinuation of the medication.

We recorded the results of antinuclear antibody testing (Quest Diagnostics, Inc, San Juan Capistrano, CA) to identify patients with possible rheumatologic etiology, antineutrophil antibody testing (Versiti Blood Center of Wisconsin, Milwaukee, WI) to identify patients with autoimmune neutropenia, and elastase, neutrophil-expressed (ELANE) gene testing (Versiti Blood Center of Wisconsin) to identify patients with either congenital or cyclic neutropenia. We examined the bone marrow aspiration and biopsy reports to identify patients with cancer or bone marrow failure disorders. We reviewed microbiology and virology records to identify cases of documented infection-related neutropenia and clinic notes to identify cases of presumed viral induced neutropenia. We identified the need for interventions by reviewing all pediatric hematology-oncology clinic notes as well as additional subspecialty referral notes. Finally, all admission diagnoses and results from cultures (blood, wound, urine, and cerebrospinal fluid) were detailed. In the statistical analysis, characteristics and outcomes of children referred for neutropenia were summarized by using descriptive statistics. Comparison of characteristics was performed by using a t test for normally distributed data and Wilcoxon rank test for non-normally distributed data. Nominal logistic regression was used to model the odds of resolution of neutropenia on the basis of race. All analyses were conducted by using JMP Pro 14 (SAS Institute, Inc, Cary, NC).

Among 3216 outpatient referrals to our pediatric hematology-oncology clinic over 5.5 years, we identified 195 children referred for a diagnosis of neutropenia. We identified 155 children with isolated neutropenia over the 5.5-year study period, excluding 40 children who had additional cytopenias. The mean age of children at the time of referral for isolated neutropenia was 8.1 ± 5.9 years. Ninety-two children (60%) were boys, and 63 (40%) were girls. Eighty-seven (56%) of the children referred were Black, 67 (43%) were white, and 1 (1%) was Asian American. On the basis of initial referral CBC, 45 (29%) were categorized as having mild neutropenia, 65 (42%) had moderate neutropenia, 30 (19%) had severe neutropenia, and 15 (10%) had very severe neutropenia.

The median time from the first abnormal CBC to the referral visit was 2 months (range of 1–74 months). The time line for referral was significantly impacted by the severity of neutropenia. Children with severe neutropenia attended their first clinic visit at a median of 1 month from their initial CBC, children with moderate neutropenia were evaluated at a median of 3 months, and those with mild neutropenia were seen at a median of 2 months (P = .013). The median number of CBCs performed before the referral visit was 3 (range of 1–31). We did not identify a significant association between the number of CBCs before referral and resolution of neutropenia. Children with persistent neutropenia had a median of 4 CBCs before referral in comparison with children with resolved neutropenia who had a mean of 3 CBCs before referral (P = .88).

Eighty-four children underwent testing for antineutrophil antibodies, and 23 (27%) children had positive testing results. Sixty-three children had an antinuclear antibody panel performed, of which 9 (14%) had positive results. Four (16%) of the 25 children tested for an ELANE gene mutation were found to have the mutation. These abnormalities were heterozygous variation exon 5, sequence variation exon 5 at codon 260 to threonine (both of unknown pathologic significance; current ANC of 1940 and 3970, respectively), c.655G>A, p.V219I (benign variant; current ANC of 740), and R144H variant (variant of uncertain significance; current ANC of 1190). Bone marrow aspiration and biopsy was performed in 32 children. The most common reported findings were normal (16) and hypocellular marrow (12). No children were found to have a malignancy.

Thirty (19%) children changed to a lower ANC category than their initial referral ANC category (Table 1). In contrast, neutropenia had resolved in 46 (30%) children by their initial visit. Of the 45 children referred with mild neutropenia, 14 (31%) changed to moderate neutropenia. No children referred for mild isolated neutropenia changed to severe or very severe neutropenia. Of the 65 children referred with moderate neutropenia, 11 (17%) changed to severe neutropenia, but none changed to the very severe category. Among 30 children referred with severe neutropenia, 5 (17%) children changed to very severe neutropenia.

TABLE 1

Change From Referral ANC to Their Lowest ANC Category

Referral ANC CategoryLowest ANC category
Mild NeutropeniaModerate NeutropeniaSevere NeutropeniaVery Severe NeutropeniaTotal, n
Mild neutropenia 31 (69%) 14 (31%) 0 (0%) 0 (0%) 45 
Moderate neutropenia 0 (0%) 54 (83%) 11 (17%) 0 (0%) 65 
Severe neutropenia 0 (0%) 0 (0%) 25 (83%) 5 (17%) 30 
Very severe neutropenia 0 (0%) 0 (0%) 0 (0%) 15 (100%) 15 
Total, n 31 68 36 20 155 
Referral ANC CategoryLowest ANC category
Mild NeutropeniaModerate NeutropeniaSevere NeutropeniaVery Severe NeutropeniaTotal, n
Mild neutropenia 31 (69%) 14 (31%) 0 (0%) 0 (0%) 45 
Moderate neutropenia 0 (0%) 54 (83%) 11 (17%) 0 (0%) 65 
Severe neutropenia 0 (0%) 0 (0%) 25 (83%) 5 (17%) 30 
Very severe neutropenia 0 (0%) 0 (0%) 0 (0%) 15 (100%) 15 
Total, n 31 68 36 20 155 

Thirty-one children were categorized as mild neutropenia by using their lowest ANC (Table 2). Twenty-four (77%) of these children had resolved neutropenia, and 7 (23%) children continued to have persistent mild neutropenia on their most recent CBC. Sixty-nine children were categorized as moderate neutropenia by using their lowest ANC. Thirty-eight (55%) of these children had currently resolved neutropenia, 25 (36%) children improved to mild neutropenia, and 5 (7%) children had persistent moderate neutropenia. Thirty-five children were categorized as severe neutropenia by using their lowest ANC. Twenty-three (66%) children had currently resolved neutropenia, 7 (20%) children improved to mild neutropenia, 3 (8%) children improved moderate neutropenia, and 2 (6%) children had persistent severe neutropenia on their most recent CBC. Among 20 children with very severe neutropenia as the lowest category, 16 (80%) children resolved, 1 (5%) patient improved to mild neutropenia, 2 (10%) children improved to moderate neutropenia, and 1 (5%) patient had persistence of very severe neutropenia on the most recent CBC.

TABLE 2

Change From Lowest ANC Category to Their Current ANC Category

Lowest ANC CategoryCurrent ANC Category
ResolvedMild NeutropeniaModerate NeutropeniaSevere NeutropeniaVery Severe NeutropeniaTotal, n
Mild neutropenia 24 (77%) 7 (23%) 0 (0%) 0 (0%) 0 (0%) 31 
Moderate neutropenia 38 (55%) 25 (36%) 5 (7%) 1 (1%) 0 (0%) 69 
Severe neutropenia 23 (66%) 7 (20%) 3 (9%) 2 (6%) 0 (0%) 35 
Very severe neutropenia 16 (80%) 1 (5%) 2 (10%) 0 (0%) 1 (5%) 20 
Total, n 101 40 10 155 
Lowest ANC CategoryCurrent ANC Category
ResolvedMild NeutropeniaModerate NeutropeniaSevere NeutropeniaVery Severe NeutropeniaTotal, n
Mild neutropenia 24 (77%) 7 (23%) 0 (0%) 0 (0%) 0 (0%) 31 
Moderate neutropenia 38 (55%) 25 (36%) 5 (7%) 1 (1%) 0 (0%) 69 
Severe neutropenia 23 (66%) 7 (20%) 3 (9%) 2 (6%) 0 (0%) 35 
Very severe neutropenia 16 (80%) 1 (5%) 2 (10%) 0 (0%) 1 (5%) 20 
Total, n 101 40 10 155 

The median time to resolution of neutropenia from the earliest documented CBC was 5.5 months (Table 3). Children with persistent neutropenia continued to be managed for a median of 12 months. Forty-five children were referred with mild neutropenia. Thirty-four children (76%) resolved, whereas 11 (24%) children continued with mild neutropenia. Sixty-five children were referred with moderate neutropenia. Thirty-five (54%) children resolved, 22 (34%) children had mild neutropenia, 7 (11%) children had persistent moderate neutropenia, and 1 (1%) patient changed to severe neutropenia, but none changed to the very severe neutropenia category. The patient with severe neutropenia was diagnosed with drug-induced neutropenia because the neutropenia improved after stopping the offending medication. Twenty-nine children were referred with severe neutropenia, 18 (62%) resolved, 7 (24%) children had mild neutropenia, 1 (3%) patient had moderate neutropenia, 2 (7%) children persisted with severe neutropenia (ultimately diagnosed with autoimmune neutropenia and juvenile rheumatoid arthritis), and 1 (3%) patient changed to very severe neutropenia (diagnosed with autoimmune neutropenia). Fifteen children were referred with very severe neutropenia, 13 (87%) children resolved, and 2 (13%) children continued to have moderate neutropenia. Characteristics of those children currently with moderate, severe, and very severe neutropenia are presented in Table 4.

TABLE 3

Outcomes Based on Referral ANC

Referral ANC CategoryCurrent ANC Category
ResolvedMild NeutropeniaModerate NeutropeniaSevere NeutropeniaVery Severe NeutropeniaTotal, n
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 
Severe neutropenia 19 (62%) 7 (24%) 1 (3%) 2 (7%) 1 (3%) 30 
Very severe neutropenia 13 (87%) 0 (0%) 2 (13%) 0 (0%) 0 (0%) 15 
Total, n 101 40 10 155 
Referral ANC CategoryCurrent ANC Category
ResolvedMild NeutropeniaModerate NeutropeniaSevere NeutropeniaVery Severe NeutropeniaTotal, n
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 
Severe neutropenia 19 (62%) 7 (24%) 1 (3%) 2 (7%) 1 (3%) 30 
Very severe neutropenia 13 (87%) 0 (0%) 2 (13%) 0 (0%) 0 (0%) 15 
Total, n 101 40 10 155 
TABLE 4

Characteristics of Children Currently With ANC Categorized as Moderate, Severe, and Very Severe

Patient IdentifierReferral ANC CategoryLowest ANC CategoryCurrent ANC CategoryCurrent DiagnosisInterventions
001 Severe Very severe Very severe Autoimmune neutropenia None 
002 Severe Severe Severe Juvenile rheumatoid arthritis None 
003 Moderate Severe Severe Drug induced (mycophenolic acid) G-CSF 
004 Severe Severe Severe Autoimmune neutropenia None 
005 Moderate Moderate Moderate Undiagnosed None 
006 Moderate Severe Moderate Undiagnosed Immunology, rheumatology referral 
007 Severe Severe Moderate Undiagnosed None 
008 Moderate Moderate Moderate Viral suppression None 
009 Moderate Severe Moderate Moderate aplastic anemia None 
010 Moderate Moderate Moderate Autoimmune neutropenia None 
011 Very Severe Very severe Moderate Autoimmune neutropenia None 
012 Moderate Moderate Moderate Viral suppression None 
013 Moderate Moderate Moderate Autoimmune neutropenia None 
014 Very Severe Very severe Moderate Autoimmune neutropenia G-CSF 
Patient IdentifierReferral ANC CategoryLowest ANC CategoryCurrent ANC CategoryCurrent DiagnosisInterventions
001 Severe Very severe Very severe Autoimmune neutropenia None 
002 Severe Severe Severe Juvenile rheumatoid arthritis None 
003 Moderate Severe Severe Drug induced (mycophenolic acid) G-CSF 
004 Severe Severe Severe Autoimmune neutropenia None 
005 Moderate Moderate Moderate Undiagnosed None 
006 Moderate Severe Moderate Undiagnosed Immunology, rheumatology referral 
007 Severe Severe Moderate Undiagnosed None 
008 Moderate Moderate Moderate Viral suppression None 
009 Moderate Severe Moderate Moderate aplastic anemia None 
010 Moderate Moderate Moderate Autoimmune neutropenia None 
011 Very Severe Very severe Moderate Autoimmune neutropenia None 
012 Moderate Moderate Moderate Viral suppression None 
013 Moderate Moderate Moderate Autoimmune neutropenia None 
014 Very Severe Very severe Moderate Autoimmune neutropenia G-CSF 

We present the current diagnosis distribution in Table 5. We did not identify specific etiologies for neutropenia in 54% of children. The most commonly identified causes were viral suppression (16%), autoimmune neutropenia (14%), and drug-induced neutropenia (8%). The most common medications responsible for neutropenia were either antiepileptic medications (zonisamide, oxcarbazepine, diazepam, lacosamide, carbamazepine, lamotrigine, and valproate) or immunosuppressant medication (azathioprine, methotrexate, infliximab, etanercept, mycophenolic acid, and radioactive iodine). These medications are well-known causes of neutropenia, highlighting the importance of obtaining a thorough medication history in patients presenting with neutropenia. We identified autoimmune neutropenia in 22 children.

TABLE 5

Current Diagnosis for Referred Children

Current DiagnosisNPercentage Resolved, %
Undiagnosed: resolved 60 100 
Undiagnosed: not resolved 24 
Viral suppression 24 66.67 
Autoimmune neutropenia 22 50 
Drug-induced neutropenia 13 61.5 
Alloimmune neutropenia 50 
Cyclic neutropenia 
ELANE 
Hyper IgE syndrome 100 
JRA 
MBL deficiency 100 
Aplastic anemia 
Nephrotic syndrome 100 
SLE 100 
CVID 100 
Total 155 65 
Current DiagnosisNPercentage Resolved, %
Undiagnosed: resolved 60 100 
Undiagnosed: not resolved 24 
Viral suppression 24 66.67 
Autoimmune neutropenia 22 50 
Drug-induced neutropenia 13 61.5 
Alloimmune neutropenia 50 
Cyclic neutropenia 
ELANE 
Hyper IgE syndrome 100 
JRA 
MBL deficiency 100 
Aplastic anemia 
Nephrotic syndrome 100 
SLE 100 
CVID 100 
Total 155 65 

CVID, common variable immunodeficiency; IgE, immunoglobulin E; JRA, juvenile rheumatoid arthritis; MBL, mannose-binding lectin; SLE, systemic lupus erythematosus.

We identified no significant difference in the referral ANC for Black children in comparison with white children (1038 vs 907 per mm3; P = .11). However, the current ANC was significantly lower in Black children, in comparison with white children (1892 vs 2528 per mm3; P = .01). Forty-nine (56%) Black children and 50 (76%) white children had resolved neutropenia (P = .01). We identified 24 children with persistent mild neutropenia of unknown etiology, 20 (83%) of whom were Black. Black children had a 3.5 higher odds (95% confidence interval: 1.1–11.7) of having a persistent mild neutropenia.

Six children (4%) received granulocyte colony-stimulating factor (G-CSF) prophylaxis at some point for their neutropenia, including 4 of the 15 children referred with very severe neutropenia. Four children were found to have drug-induced neutropenia requiring discontinuation of the offending medication. Five children required further evaluation and management by either the rheumatology or immunology departments. Characteristics of children who required G-CSF injections are presented in Table 6.

TABLE 6

Characteristics of Children Who Received G-CSF

Patient IdentifierReferral ANC CategoryLowest ANC CategoryCurrent ANC CategoryCurrent DiagnosisReason
Very Severe Very severe Resolved Alloimmune neutropenia Concern for acute abdomen in the setting of very severe neutropenia 
Moderate Severe Severe Drug induced (mycophenolic acid) Severe neutropenia in the setting of cardiac transplant 
Very Severe Very severe Resolved Autoimmune neutropenia Concern for pneumonia in the setting of very severe neutropenia 
Very Severe Very severe Moderate Autoimmune neutropenia Concern for sepsis in the setting of very severe neutropenia 
Very Severe Very severe Resolved Autoimmune neutropenia Concern for varicella infection in the setting of very severe neutropenia 
Very Severe Very severe Resolved Autoimmune neutropenia History of recurrent infections in the setting of very severe neutropenia 
Patient IdentifierReferral ANC CategoryLowest ANC CategoryCurrent ANC CategoryCurrent DiagnosisReason
Very Severe Very severe Resolved Alloimmune neutropenia Concern for acute abdomen in the setting of very severe neutropenia 
Moderate Severe Severe Drug induced (mycophenolic acid) Severe neutropenia in the setting of cardiac transplant 
Very Severe Very severe Resolved Autoimmune neutropenia Concern for pneumonia in the setting of very severe neutropenia 
Very Severe Very severe Moderate Autoimmune neutropenia Concern for sepsis in the setting of very severe neutropenia 
Very Severe Very severe Resolved Autoimmune neutropenia Concern for varicella infection in the setting of very severe neutropenia 
Very Severe Very severe Resolved Autoimmune neutropenia History of recurrent infections in the setting of very severe neutropenia 

Among 155 children referred with isolated neutropenia, 10 children were admitted for a total of 16 admissions to Children’s of Alabama. We followed children with persistent neutropenia for a mean of 2.2 years from diagnosis to either resolution or the end of the study period. The most common reason for admission was for febrile neutropenia (n = 13) without a subsequent bacteremia; the other admission diagnoses included cellulitis (n = 1), rash with neutropenia (n = 1), and alloimmune neutropenia (n = 1).

This study revealed that the majority of children referred with isolated neutropenia eventually resolved without any intervention from a pediatric hematologist-oncologist. Thirty percent of children had a normal ANC at their initial referral visit. No children referred for isolated neutropenia were diagnosed with a malignancy. Despite concerns that prolonged neutropenia can be associated with an increased risk of acute illness or bacteremia, hospital admission rates were low, and no bacteremia was identified.

We hypothesized that the majority of children with isolated mild neutropenia would not progress in current severity category or need an intervention from a pediatric hematologist-oncologist. Three-fourths of children referred with mild neutropenia had complete resolution of neutropenia, and the remaining 25% continued to have mild neutropenia. No children in this referral category needed an intervention or required hospitalization for febrile neutropenia. Because no standard of care guidelines exist to determine the frequency of CBC monitoring in children with neutropenia, in this study, we could not determine how long PCPs should monitor CBCs before referring a child with persistent mild isolated neutropenia. However, we identified a median time of 5 months from initial CBC to the first identified resolved CBC.

Although only 4% (n = 6) of all children referred received G-CSF, two-thirds of these children had very severe neutropenia at the time of referral. The remaining 2 were referred with moderate and severe neutropenia. Four of the children treated with G-CSF were diagnosed with autoimmune neutropenia and received G-CSF in the setting of hospitalization for febrile neutropenia or documented infection (See Table 6).

A high proportion of referrals for isolated neutropenia were Black children. Although only 27% of the population in Alabama is Black, 56% of our referral population self-identified as Black.19 

Black children were less likely to have resolution of neutropenia in comparison with their white counterparts. Furthermore, the odds of having persistent mild isolated neutropenia were higher in Black children, consistent with previously published evidence that Black children have differences in baseline neutrophil counts.2,3  Although BEN is a diagnosis of exclusion, 83% of children with persistent isolated mild neutropenia in this cohort were Black, suggesting this diagnosis.

A specific etiology was not found in most of the children referred for isolated neutropenia. There are several potential contributors to our inability to identify a cause of isolated neutropenia. First, several children were diagnosed with neutropenia by a PCP during an evaluation for an acute illness. The most likely diagnosis for these cases would be a transient neutropenia associated with an infection. However, this was not confirmed because either no virus was identified at the time of the referral visit or the pediatric hematologist-oncologist did not obtain extensive viral testing. Secondly, autoimmune neutropenia may occur without a positive antineutrophil antibody test result. We acknowledge that there are limitations with use of antineutrophil antibody testing due to lack of standardization among laboratories. In an effort to alleviate this, we were consistent at our center by sending our neutrophil antibody testing to Versiti Blood Center of Wisconsin. This laboratory uses a flow cytometry-based method for detection of neutrophil antibodies to the following, most common antigens: human neutrophil antigen-1a, -1b, -1c, -2a, -3a, and -4a (https://www.versiti.org/home). Finally, BEN is a potential diagnosis in several of our Black patient referrals, but this is a diagnosis of exclusion. With technological advances, future research could better define an etiology for the majority of children referred for neutropenia. Among the cases of drug-induced neutropenia, antiepileptic and immunosuppressant medications were the most commonly implicated drugs. Immunosuppressant medications are known to inhibit myelopoiesis, and the mechanisms of drug-induced neutropenia include immune mediated destruction, dose-dependent granulopoietic inhibition, and dose-independent idiosyncratic reaction.2022 

Although our study adds valuable information to the medical literature on outcomes for isolated neutropenia at our institution, these findings must be interpreted in the setting of some limitations. First, we only included children with isolated neutropenia that were adherent to the initial pediatric hematology-oncology clinic visit. We expect that several children with isolated mild neutropenia that were nonadherent to their referral clinic visits either remained stable or resolved, thus not warranting a second referral. This limitation would likely strengthen our findings that isolated mild neutropenia children is not associated with hematologic pathology. Second, the follow-up duration between CBCs was at the treating physicians’ discretion and, therefore, not standardized. The time of documented resolution reflects the timing of laboratory evaluations rather than the exact day neutropenia resolved. However, it is not standard of care to obtain very frequent CBCs in patients with isolated neutropenia, and there are no clinical implications of identifying the exact time of resolution. Third, after resolution of neutropenia, we did not recommend serial monitoring for recurrence of neutropenia. Therefore, children with documented resolved isolated neutropenia may have developed recurrent neutropenia, and, if asymptomatic, the PCP may not have repeated a CBC. Additionally, we cannot confirm whether children with initial resolved neutropenia had recurrence and perhaps were referred to a different institution. Fourth, we did not perform studies of patient reported outcomes, which could enhance this research; future research should evaluate the impact of referrals for isolated neutropenia on quality outcomes. Finally, pediatric guidelines do not exist to ensure a systematic approach to ordering definitive testing for viral, autoimmune, or other disorders in children with mild isolated neutropenia, increasing our prevalence of undiagnosed cases. We will use the findings of our study going forward to develop an algorithm to standardize the way we workup and manage pediatric patients referred to us with isolated neutropenia. Future studies are needed to analyze the cost and patient reported outcomes associated with workup for isolated mild neutropenia.

In this study, we categorize the outcomes for children on the basis of neutropenia severity categories at the time of referral. Children with mild isolated neutropenia at the time of referral did not tend to progress in severity nor did they require therapeutic interventions from a pediatric hematologist-oncologist. It was also rare for children with moderate or severe neutropenia to receive G-CSF. Less than 10% of children referred required hospital admission. No children with isolated neutropenia, regardless of severity category, developed leukemia or any other malignancy. Although the majority of children with isolated neutropenia may not receive a definitive diagnosis, additional research into the genetics of BEN and improved sensitivity of laboratory techniques for viral and autoimmune neutropenia could enhance our diagnostic ability. Overall, this study provides reassuring data for pediatricians to use when counseling patients about isolated neutropenia outcomes, which could ultimately impact referral rates to a pediatric hematologist-oncologist.

We acknowledge Lisa Allred, RN, for keeping records of the referral information in our division.

Dr Nagalapuram drafted the initial manuscript, collected data, and performed analyses; Drs McCall and Palabindela collected data and performed the initial analysis. Drs Wilson, Hilliard, Howard, and Bemrich-Stolz reviewed and revised the manuscript; Dr Lebensburger designed the study, data collection instruments, and reviewed and revised the manuscript; and all authors have approved the final manuscript as submitted and accept accountability for all aspects of the work.

FUNDING: No external funding.

ANC

absolute neutrophil count

BEN

benign ethnic neutropenia

CBC

complete blood cell count

ELANE

elastase, neutrophil-expressed

G-CSF

granulocyte colony-stimulating factor

PCP

primary care provider

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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.