Basics
Description
A decrease in the number of circulating neutrophils (both segmented and band forms), strictly defined as an absolute total neutrophil count (ANC) of <1,500/ ¼L in children older than 1 year of age, <1,000/ ¼L in children younger than 1 year of age, and <5,000/ ¼L in the 1st week of life
- To calculate ANC, multiply the total WBC count by the percentage of segmented neutrophils and band forms.
- For example: WBC count 5,200/ ¼L with 15% segs/polys, 4% bands, 76% lymphocytes, 5% monocytes: ANC = 5,200 (0.15 + 0.04) = 988
- Severe neutropenia is defined as an ANC <500/ ¼L.
Epidemiology
- Normal values for total WBC counts and ANC vary with age and race.
- Children of some ethnic groups, including African and Middle-Eastern groups, have lower total WBC counts and lower ANCs than do white children.
- Lower end of normal range for ANC may be 800/ ¼L in 30% of African Americans and does not represent an increased risk for infection.
- Infants have a higher total WBC count and a higher percentage of lymphocytes in their differential counts.
- Prevalence of congenital and idiopathic neutropenia: 2.1 cases per million in the United States
- Incidence of neonatal alloimmune neutropenia: 2 per 1,000 live births
Risk Factors
Genetics
- A number of mutations causing severe congenital neutropenia have been identified.
- Autosomal recessive: Kostmann syndrome (HAX1)
- Autosomal dominant: ELA2, GFL1, GATA2, others
- X-linked: WASP
- Cyclic neutropenia: autosomal dominant or sporadic (ELA2)
Etiology
- Decreased production of neutrophils
- Viral suppression
- Marrow suppression by drugs, chemotherapy, or radiation
- Nutritional deficiencies
- Primary disorders of myelopoiesis
- Increased destruction of neutrophils
- Immune-mediated destruction
- Increased use (usually with overwhelming infection)
- Sequestration in the spleen
Diagnosis
History
- Recent or current viral infection
- Current or recurrent fever, skin abscesses, infections, or oral ulceration
- Temporal pattern of symptoms
- Symptoms of malabsorption, such as diarrhea or failure to thrive
- Delayed cord separation
- Medication use or toxin exposure
- Diet: evidence of nutritional deficiency
- Developmental history
- Ethnicity
- Family history of neutropenia, recurrent infection, or early death; consanguinity
- Results of prior CBC with differential: Prior normal WBC count and ANC essentially rule out severe congenital neutropenia.
Physical Exam
- Growth curve
- Oral ulceration or gingival irritation
- Phenotypic abnormalities (thumb anomalies, dwarfism, partial albinism)
- Hepatosplenomegaly or lymphadenopathy
- Bruises, petechiae, pallor
- Birthmarks (cafe au lait spots)
- Neurologic exam
- Signs of infection
- Fever (temperature should not be taken rectally)
- Tachycardia or hypotension
- Pharyngitis or thrush
- Cellulitis, perirectal or labial abscesses
- Signs of local infection (such as inflammation, pus) may be diminished due to lack of neutrophils.
Diagnostic Tests & Interpretation
Lab
- Repeat CBC with differential
- Neutropenia due to viral suppression is extremely common and counts may normalize on repeat exam.
- Hemoglobin and platelets are important as well; can help determine if this is an isolated neutropenia or pancytopenia
- Serial CBCs, twice weekly for 6 weeks, to rule out cyclic neutropenia
- Evaluation of exocrine pancreatic function if Shwachman-Diamond syndrome is a consideration
- Immunologic evaluation (immunoglobulins, lymphocyte subsets) to rule out immunodeficiency
- Antineutrophil antibodies: can often be detected in autoimmune neutropenia if multiple methods of testing are used; use unclear, however, given imperfect sensitivity and specificity
- Cross-typing maternal serum and paternal neutrophils in evaluation of neonatal alloimmune neutropenia
- Genetic testing for certain disorders
Diagnostic Procedures/Other
- Bone marrow aspirate and biopsy indicated in severe chronic neutropenia, pancytopenia, or when there is other concern for a marrow disorder
- Biopsy may be normal, or may reveal a decrease in the number of myeloid precursors or a maturational arrest of the myeloid line (usually in the later stages), depending on the cause of neutropenia.
Differential Diagnosis
- Neutropenia associated with infection
- Viral suppression is a very common cause of transient neutropenia.
- Viral: hepatitis A and B, parvovirus B19, respiratory syncytial virus (RSV), influenza A and B, rubeola, rubella, varicella, cytomegalovirus (CMV), Epstein-Barr virus (EBV), HIV
- Bacterial: group B streptococcal disease, tuberculosis, brucellosis, tularemia, typhoid, paratyphoid
- Other: malaria, visceral leishmaniasis, scrub typhus, sandfly fever
- Drug induced
- Antibiotics: sulfonamides (trimethoprim/sulfamethoxazole is a common offender), penicillin, chloramphenicol (may be irreversible)
- Chemotherapy agents: alkylating agents, antimetabolites, anthracyclines
- Antipyretics: aspirin, acetaminophen (uncommon)
- Sedatives: barbiturates, benzodiazepines
- Phenothiazines: chlorpromazine, promethazine
- Antirheumatic agents: gold, penicillamine, phenylbutazone
- Immunologic
- Benign neutropenia of childhood: very common cause of chronic neutropenia; immune-mediated; onset usually <2 years of age; typically a benign course with resolution within several years
- Isoimmune neonatal neutropenia: due to transplacental transfer of maternal antibodies against paternal antigens
- Manifestation of an autoimmune disease: systemic lupus erythematosus, autoimmune lymphoproliferative syndrome (ALPS), Felty syndrome (neutropenia, splenomegaly, and rheumatoid arthritis), others
- Congenital
- Severe congenital neutropenia
- Cyclic neutropenia: regular oscillations in the number of circulating neutrophils (periodicity every 7 " 36 days; duration of neutropenia, 3 " 10 days)
- Marrow failure syndromes
- Shwachman-Diamond Syndrome: neutropenia and exocrine pancreatic insufficiency
- Part of evolving aplastic anemia: acquired (idiopathic), Fanconi anemia, dyskeratosis congenital, Diamond-Blackfan anemia
- Primary immunodeficiencies
- Cartilage/hair hypoplasia: neutropenia, dwarfism, abnormal cellular immunity
- Reticular dysgenesis
- Chediak-Higashi syndrome: oculocutaneous albinism, platelet dysfunction, leukocyte inclusions
- Other abnormalities in T and B lymphocytes
- Bone marrow infiltration
- Malignancy: leukemia or solid tumors metastatic to bone marrow
- Osteopetrosis
- Gaucher disease (lysosomal storage disorder)
- Metabolic
- Nutritional: malnutrition, copper deficiency, zinc deficiency, megaloblastic anemia secondary to folate or vitamin B12 deficiency
- Inborn errors of metabolism: Barth syndrome (skeletal myopathy, dilated cardiomyopathy, neutropenia), glycogen storage disease I, others
- Miscellaneous
- Hypersplenism
- Radiation injury
Treatment
Medication
- Granulocyte colony-stimulating factor (G-CSF)
- Indicated for severe congenital neutropenia and cyclic neutropenia (decreases infections and mortality)
- May be used in some patients with neutropenia due to other causes
Additional Therapies
General Measures
- Isolation of hospitalized patient: prudent until the cause of the neutropenia is identified
- "Neutropenic precautions " Standard hand hygiene is sufficient (no need for masks/gowns/gloves).
- Correction of underlying cause of neutropenia (discontinue drug, treat infection, correct nutritional deficiency)
- Treatment of fever and suspected infection when neutropenic: Initially, broad-spectrum antibiotics are indicated; after the diagnosis has been established, this may not always be necessary (i.e., individuals with chronic benign neutropenia).
- Prophylactic antibiotics are not usually beneficial and may predispose to systemic fungal infection.
- Stool softeners may be helpful in the profoundly neutropenic patient at risk for constipation to prevent development of a perirectal abscess.
- No therapy may be required if neutropenia is not severe and there are no serious or recurrent infections (often the case in chronic benign neutropenia).
Additional Therapies
- Withdrawal of offending drug in drug-induced neutropenia
- Treatment of underlying disorder in many cases of acquired neutropenia
- Stem cell transplant may be indicated in some patients with severe congenital neutropenia or neutropenia due to other causes (such as bone marrow failure syndromes).
Issues for Referral
- Chronic or profound neutropenia
- History of recurrent unusual or severe infections
- When bone marrow examination is indicated
Ongoing Care
Follow-up Recommendations
Management of febrile episodes (depends on etiology of neutropenia)
- Prompt evaluation by a physician
- Obtain CBC with differential and blood culture.
- Treat with IV antibiotics.
- Hospitalize if ill-appearing or high-risk for infection.
- Monitor daily CBC with differential.
Patient Monitoring
- CBCs and physical exams at regular intervals while the patient is neutropenic
- Depending on the etiology of the neutropenia, annual bone marrow biopsy surveillance for leukemia or MDS
Prognosis
- Duration of neutropenia depends on diagnosis.
- Neutropenia resulting from infection or drug-related marrow suppression is usually short lived.
- Autoimmune neutropenia (benign neutropenia of childhood) typically resolves within 2 years.
- Congenital neutropenia syndromes may result in chronic lifelong neutropenia.
- Likelihood of infection depends on severity of neutropenia (higher risk if <500/ ¼L) and cause of neutropenia (higher risk in disorders of neutrophil production).
Complications
- Systemic infections, including pneumonia and sepsis
- Localized infections such as cellulitis, labial abscesses, perirectal abscesses, oral mucosal ulceration, thrush, otitis media, stomatitis, or gingivitis
- Typical pathogens:
- Bacterial: staphylococci, streptococci, enterococci, Pseudomonas, gram-negative bacilli
- Fungal: Candida or Aspergillus
- Transformation to leukemia or MDS
Additional Reading
- Fioredda F, Calvillo M, Bonanomi S, et al. Congenital and acquired neutropenia consensus guidelines on diagnosis from the Neutropenia Committee of the Marrow Failure Syndrome Group of the AIEOP (Associazione Italiana Emato-Oncologia Pediatrica). Pediatr Blood Cancer. 2011;57(1):10 " 17. [View Abstract]
- Lehrnbecher T, Phillips R, Alexander S, et al. Guideline for the management of fever and neutropenia in children with cancer and/or undergoing hematopoietic stem-cell transplantation. J Clin Oncol. 2012;30(35):4427 " 4438. [View Abstract]
- Walkovich K, Boxer LA. How to approach neutropenia in childhood. Pediatr Rev. 2013;34(4):173 " 184. [View Abstract]
Codes
ICD09
- 288.00 Neutropenia, unspecified
- 288.01 Congenital neutropenia
- 288.02 Cyclic neutropenia
- 288.04 Neutropenia due to infection
- 288.03 Drug induced neutropenia
ICD10
- D70.9 Neutropenia, unspecified
- D70.0 Congenital agranulocytosis
- D70.4 Cyclic neutropenia
- D70.3 Neutropenia due to infection
- D70.2 Other drug-induced agranulocytosis
SNOMED
- 165517008 neutropenia (finding)
- 89655007 Congenital neutropenia (disorder)
- 191347008 Cyclical neutropenia (disorder)
- 46359005 Neutropenia associated with infectious disease (disorder)
- 47318007 Drug-induced neutropenia (disorder)
FAQ
- Q: Do all patients with neutropenia require G-CSF?
- A: No. Patients with severe congenital neutropenia have fewer infections when treated with G-CSF. Patients with benign neutropenia generally do not need G-CSF.
- Q: Can a neutropenic patient receive vaccinations?
- A: Yes, if neutropenia is the only immunologic abnormality
- Q: Should a child with neutropenia be kept in isolation?
- A: No. Neutropenic patients may go to school and do not need to wear masks.