Neutropenia is a deficiency in the number of neutrophils, also known as polymorphonuclear leukocytes, or PMNs. Neutropenia is generally defined as an absolute neutrophil count <1,500/mL. Counts of <500/mL represent severe, life-threatening deficiency. Neutropenia often accompanies other disorders, but here we describe neutropenia when it occurs in isolation or as the predominant characteristic of disease. Most cases are acquired due to increased destruction of neutrophils (eg, from infections, drugs, immune defects) or decreased production of neutrophils (eg, from nutritional defects, malignancies). Chemotherapeutic treatment is a common cause of neutropenia. Some congenital disorders are also associated with neutropenia and vary in severity, from mild conditions such as benign familial or constitutional neutropenia, which may not lead to infections, to severe congenital disorders that result in serious chronic infections (Gibson, 2014). Infection-related neutropenia in children may be caused by a virus (Gibson, 2014). Laboratory testing for neutropenia includes CBC, immunoglobulin evaluation, flow cytometry, and genetic testing.
Diagnosis
Indications for Testing
- In neonates – recurrent bacterial infections
- In older children, adolescents, adults
- Low neutrophil count as incidental finding on CBC
- Recurrent infections, oral ulcerations, or delayed healing
- Acute febrile illness or sepsis
- Existing neutropenia, which must be monitored for severity
Laboratory Testing
- Initial testing
- CBC
- At least three CBCs recommended to demonstrate persistent neutropenia
- Blood smear
- Lymphocyte flow cytometry panel testing – to rule out cellular defects
- CBC
- Other testing based on clinical presentation
- Neutrophil antibody testing
- Rheumatic disorder testing (eg, antinuclear antibodies [ANAs])
- Nutritional assessment (eg, B12)
- Bone marrow biopsy and aspirate
- Genetic testing – may be necessary to confirm specific disorder
Differential Diagnosis
- Benign ethnic or constitutional neutropenia
- Causes mild neutropenia with no increased incidence of infection
- Increased prevalence in individuals of African or Mediterranean descent
- Often associated with the Duffy red blood cell antigen-negative phenotype (caused by a variant in the DARC gene encoding the Duffy antigen) in African Americans
- Nutritional defects
- Vitamin B12
- Folate
- Copper
- Protein-calorie malnutrition
- Infection induced
- Viral – cytomegalovirus, Epstein-Barr virus, HIV, parvovirus
- Bacterial – Brucella spp, ;Mycobacterium tuberculosis, Francisella tularensis, Rickettsia typhi, Rickettsia rickettsii
- Protozoan – Plasmodium spp
- Sepsis
- Drug induced
- Chemotherapeutic agents
- Antipsychotics
- Antiplatelets
- Antirheumatics
- Antimicrobials
- Thionamides
- Nonsteroidal anti-inflammatory drugs
- Anticonvulsants
- Immune mediated
- Autoimmune disorders
- Neonatal isoimmune disorders (caused by maternally derived antibodies against paternal antigens)
- Malignancy
- Myelodysplasia
- Leukemia
- Malignant infiltration of bone marrow (eg, neuroblastoma)
- Paroxysmal nocturnal hemoglobinuria
- Intravascular hemolytic anemia
Background
Epidemiology
- Neutropenia
- Increased prevalence in African Americans; less common in Whites and Mexican Americans (Hsieh, 2007)
- Congenital neutrophil disorders
- Incidence – rare (3-8/million) (Donadieu, 2013)
- Age – more severe disorders usually discovered before 1 year; less severe disorders may be discovered later
- Sex – M:F, equal (except for X-linked disorders)
Clinical Presentation
- Clinical presentation and severity vary based on etiology (Gibson, 2014)
- Benign familial or constitutional neutropenia
- Typically not associated with clinical sequelae; no follow-up is needed after diagnosis is established
- Congenital neutropenia
- Recurrent infections – omphalitis, septicemia, abscess formation early in life
- Those who survive infancy frequently show progressive periodontitis
- May occur as part of a syndrome (eg, Chediak-Higashi syndrome, Shawchman-Diamond, or cartilage hair hypoplasia; see Specific Diseases below)
- Cyclic neutropenia
- Congenital disease – neutropenic episodes occur every 2-5 weeks
- Typically mild, but infections or mouth ulcers can develop during neutropenic period
- Drug-induced agranulocytosis (absence of granulocytes)
- Acute febrile illness or sepsis
- Primary autoimmune neutropenia
- Typically occurs during infancy (first year)
- May be severe, with serious infections, but usually resolves within 2 years
- Secondary autoimmune neutropenia
- Typically in adults in connection with systemic autoimmune disease
- Recurrent infections and neutrophil count <500/mL
- Felty’s syndrome
- Triad involving neutropenia, rheumatoid arthritis, and splenomegaly
- Serious bacterial infections
- Large granular lymphocyte leukemia-associated neutropenia
- Associated with rheumatoid arthritis, splenomegaly, and human leukocyte antigen DR4
- Chronic idiopathic neutropenia
- Unknown pathogenesis
- Diagnosis of exclusion
- Often benign but occasionally results in recurrent infections
- Benign familial or constitutional neutropenia
Pathophysiology
- Immunologic and hematologic parameters are diverse (see Specific Diseases below)
- Congenital neutropenias
- Exact molecular pathogenesis varies by genetic defect, but all lead to maturation arrest of precursor myeloid cells due to increased apoptosis
- Increased apoptosis might be caused by the unfolded protein response due to accumulation of misfolded proteins (eg, ELANE, G6PC3), mitochondrial membrane potential (HAX1), or defective mitosis and cytokinesis (WAS)
Genetics
Autosomal recessive (AR), autosomal dominant (AD), or X-linked (XL) inheritance (see Specific Diseases below)
Specific Diseases
The following tables are based on the International Union of Immunological Societies 2017 Primary Immunodeficiencies report (Picard, 2018)
Disorder | Gene(s) | Inheritance | Associated Features |
---|---|---|---|
SCN1 (elastase deficiency) |
ELANE |
AD |
Severe congenital or cyclic neutropenia; susceptibility to MDS/leukemia |
SCN2 (GFI1 deficiency) |
GFI1 |
AD |
|
SCN3 (Kostmann disease; HAX1 deficiency) |
HAX1 |
AR |
Cognitive/neurologic defects, susceptibility to MDS/leukemia |
SCN4 (G6PC3 deficiency) |
G6PC3 |
AR |
Heart defects, urogenital abnormalities, inner ear deafness, venous angiectasias of trunk and limbs |
SCN5 (VPS45 deficiency) |
VPS45 |
AR |
Bone marrow fibrosis, nephromegaly, extramedullary hematopoiesis |
Glycogen storage disease type 1b |
G6PT1 |
AR |
Fasting hypoglycemia, lactic acidosis, hyperlipidemia, hepatomegaly |
X-linked neutropenia/myelodysplasia WAS GOF |
WAS |
XL |
Neutropenia, monocytopenia, myeloid maturation arrest, variable lymphoid anomalies |
P14/LAMTOR2 deficiency |
LAMTOR2 |
AR |
Neutropenia, hypogammaglobulinemia, partial albinism, growth failure |
Barth syndrome |
TAZ |
XL |
Cardiomyopathy, myopathy, growth retardation, neutropenia |
Cohen syndrome |
VPS13B |
AR |
Dysmorphism, deafness, mental retardation, obesity, neutropenia |
Clericuzio syndrome |
USB1 |
AR |
Retinopathy, poikiloderma, developmental delay, facial dysmorphisms |
JAGN1 deficiency |
JAGN1 |
AR |
Myeloid maturation arrest, osteopenia |
3-methylglutaconic aciduria |
CLPB |
AR |
Neurocognitive developmental abnormalities, microcephaly, hypoglycemia, seizures, hypotonia, ataxia, intrauterine growth retardation, cataracts |
G-CSF receptor deficiency |
CSF3R |
AR |
|
SMARCD2 deficiency |
SMARCD2 |
AR |
Neutropenia, developmental and skeletal abnormalities, hematopoietic stem cells, myelodysplasia |
HYOU1 deficiency |
HYOU1 |
AR |
Hypoglycemia, inflammatory complications |
WDR1 deficiency |
WDR1 |
AR |
Mild neutropenia, poor wound healing, neutrophil nuclei herniate, severe stomatitis |
Neutropenia with combined immunodeficiency as result of MKL1 deficiency |
MKL1 |
AR |
Mild thrombocytopenia |
GOF, gain of function; MDS, myelodysplastic syndrome; WAS, Wiskott-Aldrich syndrome |
Disorder | Gene(s) | Inheritance | Associated Features |
---|---|---|---|
Wiskott-Aldrich syndrome |
WAS |
XL |
Thrombocytopenia, recurrent bacterial/viral infections, bloody diarrhea, eczema, lymphoma, autoimmune disease, IgA nephropathy, vasculitis; XL neutropenia is caused by missense mutations in GTPase binding domain of WASp |
GINS1 deficiency |
GINS1 |
AR |
Neutropenia, IUGR, low NK cells |
MTHFD1 deficiency |
MTHFD1 |
AR |
Neutropenia, recurrent bacterial infections, Pneumocystis jirovecii, megaloblastic anemia, seizures, intellectual disability, folate responsive |
Disorder | Gene(s) | Associated Features |
---|---|---|
Large granular lymphocytosis | STAT3 (GOF) somatic mutations | Neutropenia, anemia, splenomegaly |
GOF, gain of function |
Disorder | Gene(s) | Inheritance | Associated Features |
---|---|---|---|
Chediak-Higashi syndrome |
LYST |
AR |
Neutropenia, cytopenias, partial albinism, recurrent infections, fever, HSMG, HLH, bleeding tendency |
Hermansky-Pudlak syndrome, type 2 |
AP3B1 |
AR |
Neutropenia, partial albinism, pulmonary fibrosis, recurrent infections, increased bleeding, HLH |
Hermansky-Pudlak syndrome, type 10 |
AP3D1 |
AR |
Severe neutropenia, oculocutaneous albinism, seizures, recurrent infections, hearing loss, neurodevelopmental delay |
HLH, hemophagocytic lymphohistiocytoses; HSMG, hepatosplenomegaly |
Disorder | Gene(s) | Inheritance | Associated Features |
---|---|---|---|
CD40 deficiency |
CD40a |
AR |
Neutropenia, gastrointestinal and liver/biliary tract disease, opportunistic infections, Cryptosporidium infections |
CD40 ligand deficiency |
CD40LGa |
XL |
Neutropenia, thrombocytopenia, hemolytic anemia, opportunistic infections, liver/biliary tract disease, Cryptosporidium infections |
MST1 deficiency |
STK4 |
AR |
Intermittent neutropenia, autoimmune cytopenias, recurrent bacterial/viral/candidal infections (including human papillomavirus infection), Epstein-Barr virus-driven lymphoproliferation, lymphoma, congenital heart disease |
Moesin deficiency |
MSN |
XL |
Recurrent infections with bacteria, varicella, neutropenia |
TFRC |
TFRC |
AR |
Recurrent infections, neutropenia, thrombocytopenia |
aGene included on Primary Antibody Deficiency Panel, Sequencing and Deletion/Duplication – ARUP test code 2011156 |
Disorder | Gene(s) | Inheritance | Associated Features |
---|---|---|---|
WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome | CXCR4a | AD GOF | Warts, neutropenia, low B-cell number, hypogammaglobulinemia |
aGene included on Primary Antibody Deficiency Panel, Sequencing and Deletion/Duplication – ARUP test code 2011156 |
Disorder | Gene(s) | Inheritance | Associated Features |
---|---|---|---|
TWEAK | TNFSF12 | AD | Neutropenia, pneumonia, bacterial infections, warts, thrombocytopenia |
ARUP Laboratory Tests
Use to assist in evaluation of neutropenia
Cytochemical Stain
Use to rule out cellular defects
Quantitative Flow Cytometry
Support the diagnosis of immune neutropenia in various autoimmune disorders
A positive result is not definitive for specific antineutrophil antibodies; anti-HLA antibodies and immune complexes may also cause a positive result; the results of this test should be correlated to clinical history and other data
Qualitative Flow Cytometry
Preferred genetic test for individual with clinical phenotype of primary antibody deficiency (eg, hyper-IgM syndrome, agammaglobulinemia, or common variable immunodeficiency)
For hyper-IgM syndrome genetic testing, refer to the hyper-IgM sequencing and deletion/duplication panel
For agammaglobulinemia genetic testing, refer to the agammaglobulinemia sequencing and deletion/duplication panel
Refer to Test Fact Sheet for a complete list of the genes tested and test limitations
Massively Parallel Sequencing/Sequencing
Preferred test for evaluating vitamin B12 deficiency in individuals with macrocytic or unexplained anemia, or unexplained neurologic disease
Quantitative Chemiluminescent Immunoassay/Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
Aid in detection of vitamin B12 and folate deficiency in individuals with macrocytic or unexplained anemia, or unexplained neurologic disease
Quantitative Chemiluminescent Immunoassay
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