20201028 Outcomes of isolated neutropenia referred to pediatric hematology-oncology clinic

Outcomes of Isolated Neutropenia
Referred to Pediatric Hematology-Oncology Clinic
Presenter/ R2 曾子
政
R1 陳沛妘
PGY 黃郁婷
Supervisor/ VS 王建
得
CR 施銘洋

Children with isolated neutropenia (absolute neutrophil
count [ANC] <1500/mL)
 referred to pediatric hematology and oncology
clinics for further diagnostic evaluation
Citation/ PEDIATRICS Volume 146, number 4, October 2020

Benign ethnic neutropenia (BEN)
● Normative neutrophil counts can vary by race.
● Individuals of African descent that have a baseline
ANC<1500/mL

We hypothesized that children will have
resolution of their neutropenia without the need
for intervention(s) by a pediatric hematologist and
oncologist.

Subjects
● From January 2013 through August 2018
● Children who were referred to the University of
Alabama at Birmingham pediatric
hematologyoncology clinic for isolated
neutropenia
● 155 children ages 0 to 18 years

Excluded
● Children referred with neutropenia who were
found to have either anemia and/or
thrombocytopenia
● Children referred for neutropenia who did not
adhere to their referral evaluation

Mild Moderate Severe Very severe
Neutrophil
count (ANC)
1001–
1500/mL
501–
1000/mL
501–
1000/mL
< 200/mL
For the current ANC, we categorized children as resolved if ANC
>1500/mL.

Definition of Variables
● Extracted the date of the first identified episode of
neutropenia and number of CBCs performed
before the referral visit.
● Recorded the date of referral and the referral ANC.
● Identify the lowest ANC and the current ANC.
Neutropenia

 We documented the age, sex, race, and
medications at the time of referral for all children.

Diagnoses and Outcomes
• Drug-induced neutropenia: medications
• Rheumatologic etiology:
-antinuclear antibody testing
-antineutrophil antibody testing
• Congenital or cyclic neutropenia:
-elastase, neutrophil-expressed (ELANE) gene
testing

Diagnoses and Outcomes
• Cancer or bone marrow failure disorders:
-bone marrow aspiration and biopsy reports
• Infection-related neutropenia:
-microbiology and virology records
Descriptive statistics

Study Population at Referral
The mean age of children at the time of referral for isolated neutropenia
was 8.1 +- 5.9 years.
Mild
neutropenia
Moderate
neutropenia
Severe
neutropenia
Very
severe neutropenia
45 (29%) 65 (42%) 30 (19%) 15 (10%)
Boys Girls
92 (60%) 63 (40%)
Black white Asian American
87 (56%) 67 (43%) 1 (1%)

Referral Characteristics
• The median time from the first abnormal CBC to the
referral visit was 2 months.
- Severe neutropenia: 1 month
- Moderate neutropenia: 3 months
- Mild neutropenia: 2 months

Diagnostic Testing
• Antineutrophil antibodies: 23 / 84 (27%)
• Antinuclear antibody: 9 / 63 (14%)
• ELANE gene mutation: 4 / 25 (16%)
- heterozygous variation exon 5, sequence
variation exon 5 at codon 260 to threonine
- R144H variant

Diagnostic Testing
• Bone marrow aspiration and biopsy:
- normal 16 / 32
- hypocellular marrow
• No children were found to have a malignancy

Change From Referral ANC Category
to the Lowest ANC Category

Change From Lowest ANC Category
to Their Current ANC Category

Outcomes Based on Referral ANC

Current Diagnosis
• Common medications
responsible for
neutropenia
• AEDs
• Zonisamide
• Oxcarbazepine
• Diazepam
• Lacosamide
• Carbamazepine
• Lamotrigine
• Valproate
• Immunosuppressants
• Azathioprine
• Methotrexate
• Inﬂiximab
• Etanercept
• Mycophenolic acid
• Radioactive iodine

● 24 children with persistent mild neutropenia of unknown etiology, 20
(83%) of whom were Black.
● Black children had a 3.5 higher odds of having a persistent mild
neutropenia.
Racial Differences in Outcomes
Black Children White Children P
referral ANC 1038 per mm3 907 per mm3 0.11
current ANC 1892 per mm3 2528 per mm3 0.01
resolved
neutropenia
49 (56%) 50 (76%) 0.01

● 6 children (4%) received G-CSF
○ including 4 of 15 children referred with very severe
neutropenia
● 4 children discontinued offending medication
● 5 children required rheumatology or immunology
management
Interventions

● 10 children were admitted for a total of 16 admissions
among 155 children referred with isolated neutropenia
Hospitalizations
febrile neutropenia, n = 13, 81%
*others, n = 3, 19%
*cellulitis = 1, rash with neutropenia = 1, alloimmune neutropenia = 1

Discussion
 Majority of children referred with isolated neutropenia eventually
resolved without any intervention.
 Normal ANC at their initial referral visit: 30%
 No diagnosis of malignancy
 Low hospital admission rates
 No bacteremia was identified

Children with mild neutropenia
children with
mild neutropenia
complete resolution
continued to have
mild neutropenia
(-) Need of intervention
(-) Required hospitalization for febrile neutropenia
75%
25%

No standard of care guidelines exist to determine the
frequency of CBC monitoring in children with neutropenia.
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.

4% (6 patients)
hospitalization for febrile neutropenia or documented infection

Benign ethnic neutropenia (BEN)
 High proportion of Black children
- 27% of the black population in Alabama
- 56% of referral population self-identified as Black
 Black children with isolated neutropenia
less likely to have resolution of neutropenia
higher odds of having persistent mild isolated neutropenia
 Black children have differences in baseline neutrophil counts.
Although BEN is a diagnosis of exclusion, 83% of children with persistent
isolated mild neutropenia in this cohort were Black, suggesting this diagnosis.

Cause of isolated neutropenia
 Etiology is unknown in most cases.
Potential contributors to inability to identify a cause of isolated neutropenia
1. Diagnosed during an evaluation for an acute illness.
possible impression: transient neutropenia associated with an infection
(not confirmed, lack of positive viral testing result)
2. Autoimmune neutropenia may occur without a positive ANA testing.
3. BEN is a diagnosis of exclusion.

Drug-induced neutropenia
Antiepileptic and immunosuppressant medications were the most
commonly implicated drugs associated with drug-induced neutropenia.
 Mechanisms of drug-induced neutropenia
immune mediated destruction
dose-dependent granulopoietic inhibition
dose-independent idiosyncratic reaction

Limitations
(1) Only included children with isolated neutropenia that were adherent
to the initial pediatric hematology-oncology clinic visit
isolated mild neutropenia children is not associated with hematologic pathology
(2) Unstandardized follow-up duration between CBCs
affected the time of documented resolution
(3) Recurrence of neutropenia is unknown

Limitations
(4) We did not perform studies of patient reported outcomes
should evaluate the impact of referrals for isolated neutropenia on quality outcome
(5) No pediatric guidelines to ensure a systematic approach to ordering
definitive testing for diagnosis
increasing the prevalence of undiagnosed cases

Conclusions
[ Mild isolated neutropenia ]
did not progress in severity
did not require therapeutic interventions
[ The need of G-CSF ]
Rare for children with moderate or severe neutropenia to receive G-CSF

Conclusions
[ Hospital admission ]
Required hospital admission: <10%
[ Malignancy ]
No leukemia or any other malignancy

Conclusions
[ Diagnostic ability ]
Majority: not receive a definitive diagnosis
[ Overall ]
This study provides reassuring data for pediatricians.
May ultimately impact referral rates to a pediatric hematologist-oncolog
genetics of BEN
laboratory techniques

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Presenter/ R2 曾子政 R1 陳沛妘 PGY 黃郁婷
Supervisor/ VS 王建得 CR 施銘洋

20201028 Outcomes of isolated neutropenia referred to pediatric hematology-oncology clinic

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