BASICS
DESCRIPTION
- A rare hematologic disorder characterized by recurrent fevers, mouth ulcers, and infections attributable to regularly recurring severe neutropenia
- Although inherited in an autosomal dominant pattern, mutations in the gene for neutrophil elastase (ELA-2), sporadic mutations can occur.
- Characterized by neutropenia that recurs every 14 to 35 days, with 90% of patients exhibiting a cycle of 21 days
- During the neutropenic period, blood neutrophil levels fall to <0.2 109/L for 3 to 5 days, before increasing to near the lower limit of normal, ~2 109/L.
EPIDEMIOLOGY
- Most patients present before the age of 5 years:
- 32% are <1 year of age
- 27% are between ages 1 and 5 years
- Occurs equally in both sexes
Incidence
1 in a million persons in the general population
ETIOLOGY AND PATHOPHYSIOLOGY
- Bone marrow during neutropenia demonstrates "maturation arrest " at the promyelocyte and myelocyte stage of development.
- At least 80% of cases of cyclic neutropenia are attributable to the mutations for neutrophil elastase (ELA-2/ELANE). The effect of these mutations shortens survival of neutrophil progenitors through accelerated apoptosis, making neutrophil production inefficient. It is not known if any other mutations can cause this disease.
- The cause of acquired cyclic neutropenia is unknown.
Genetics
- Inherited as an autosomal dominant disorder with full penetrance but varying severity of clinical manifestations (expression)
- Most commonly sporadic
- Due to mutations in the gene for neutrophil elastase (ELA-2 or ELANE) on chromosome 19p13.3 (1)[A]
RISK FACTORS
Family history is predictive, although patients proven to have the (ELA) mutation will lack positive family history due to subclinical presentation among family members, new mutation, or variability in expression.
GENERAL PREVENTION
Genetic counseling
DIAGNOSIS
HISTORY
- Usually an infant (age <1 year)
- Recurrent clinical syndrome and infections correlating with cyclic neutropenia
- May be asymptomatic during neutropenic periods
- Patients are usually asymptomatic, with normal exam between neutropenic periods.
- The cycling seems to decrease with age and can disappear by age 30 years in some patients.
- The clinical syndrome (2)[C]
- Phase 1
- 1 to 3 days
- Patient feels listless and irritable.
- Dullness to the eyes
- Swelling of lips
- Pallor
- Low-grade fever
- Phase 2
- 1 to 3 days
- Aphthous ulcers
- Tender cervical lymphadenopathy
- Temperature peaks
- Phase 3
- Fever resolves
- Return of well-being
- Healing of oral aphthae
- Additional manifestations:
- Most common
- Gingivitis
- Furunculosis
- Cellulitis
- Infection of cuts or abrasions
- Pharyngitis
- Sinusitis
- Otitis
- Less common
- Pneumonia
- Perianal abscesses
- Necrotic bowels and spontaneous perforation
- Bacteremia (Clostridium septicum)
PHYSICAL EXAM
Evaluate for bowel perforation (rare); with signs of peritonitis in presence of abdominal pain
DIFFERENTIAL DIAGNOSIS
- Kostmann agranulocytosis (severe congenital neutropenia)
- Neutropenia due to myelopoiesis and lymphopoiesis:
- Reticular dysgenesis (congenital aleukia)
- Neutropenia with associated B- or T-lymphocyte abnormalities
- X-linked agammaglobulinemia (Bruton disease)
- Dysgammaglobulinemia
- Neutropenia with associated inherited metabolic diseases
- Disorders of propionate and methylmalonate
- Branched chain organic aciduria
- Type 1B glycogen storage disease
- Neutropenia with associated phenotypic abnormalities
- Shwachman syndrome
- Cartilage-hair hypoplasia
- Dyskeratosis congenita
- Neutropenia with associated neutrophil morphologic abnormalities
- Drug-induced neutropenia
- Antibiotics: penicillins, chloramphenicol, sulfonamides
- Antithyroid medication
- NSAIDs
- Autoimmune neutropenia (chronic benign neutropenia)
- Neutropenia as part of aplastic anemia
- Neutropenia due to marrow infiltration by cancer cells
- Neutropenia due to sepsis
DIAGNOSTIC TESTS & INTERPRETATION
- Diagnostic:
- Serial blood counts are necessary to make the diagnosis (3)[A]:
- Obtained at least 3 days a week for ≥6 weeks
- Should show at least two neutrophil counts (nadirs) <0.2 109/L
- Cycle length should be about 21 days.
- Neutrophilic troughs are synchronous with mouth ulcers and other inflammatory features.
- Genetic testing (4)[A]
- Sequencing of ELA-2 gene is helpful in diagnosis.
- Not yet established as the primary method to establish the diagnosis
- Some patients with severe congenital neutropenia have mutations in the same region of the ELA-2 gene.
- DNA mutational analysis of ELANE gene is positive in 90% of patients and can be helpful in confirming the diagnosis.
- Bone marrow examination is only necessary to rule out other diagnoses.
- Nondiagnostic lab findings:
- Neutropenic episodes are usually associated with normal or near normal total leukocyte counts.
- Oscillations in monocyte, reticulocyte, and platelet counts are frequently observed (cyclic hematopoiesis).
- Cyclic oscillation of monocytes and reticulocytes is reciprocal to that of neutrophils, whereas platelet oscillation is similar.
- Typically, monocytosis occurs throughout most of the cycle.
- Despite cycling of blood elements, hemoglobin concentration and platelet counts remain in the normal range.
- Bone mineral density scan once diagnosis is made
Follow-Up Tests & Special Considerations
25 OH vitamin D level
TREATMENT
GENERAL MEASURES
- Genetic counseling
- Regular and aggressive dental care
- Antibacterial mouthwash Peridex is useful in decreasing gingivitis (5)[A].
- Use clinical judgment with respect to aggressive antibiotic therapy in febrile patients.
- Bone density screening is recommended; osteoporosis can develop during prolonged granulocyte-colony stimulating factor (G-CSF) treatment (6)[C].
- Maintaining adequate levels of vitamin D is recommended.
MEDICATION
First Line
- Patients respond well to treatment with G-CSF (7,8)[A].
- SC G-CSF on a daily or alternate-day basis is usually well tolerated by patients of all ages.
- Start with a low dose (1 Όg/kg/day) and increase if necessary. Most cases can be managed on <3 Όcg/kg/day (8)[A].
- The required response is
- To shorten the duration of neutropenia, usually reflected by resolution of mouth ulcers, fever, and other inflammatory symptoms
- To elevate the neutrophil counts at all other phases of the cycle
- To shorten the cycle length
- Avoidance of very high counts by constant low-dose treatment may prevent side effects:
- Bone pain and osteoporosis
- Myalgia and arthralgia
- Headaches
- Some patients with confirmed diagnosis and typical mutation are relatively asymptomatic and do not require G-CSF treatment.
Second Line
There is no other clearly beneficial therapy:
- Granulocyte-macrophage colony-stimulating factor has side effects and is less potent.
- Corticosteroids, lithium, and androgens are ineffective.
- Cyclic neutropenia can be cured by hematopoietic cell transplantation in an animal model and has been transferred from an affected human donor to a recipient following bone marrow transplantation. However, stem cell transplantation has not been used because of G-CSF effectiveness.
ADDITIONAL THERAPIES
No absolute guidelines regarding the use of antibiotics exist (5)[C]. Experienced clinicians suggest the following:
- Antibiotics are not required for every neutropenic period.
- Clinical judgment is more important than superficial microbial cultures.
- After infancy, mouth, cases of throat and skin ulcers, and inflammation during neutropenic periods can generally be managed without antibiotics.
- Antibiotics are recommended in the case of otitis, sinusitis, or lower respiratory tract infection.
- Neutropenic ileocolitis requires parenteral antibiotics if suspected (7)[A].
- Supplement vitamin D based on 25-OH vitamin D levels; unclear goal, but per IOM report, maximum tolerable upper limit is 4,000 IU/day
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
- Routine hospitalization for episodes of febrile neutropenia is usually not required, as the patients have active monocytosis during neutropenia and lymphocyte-mediated immunity is not impaired.
- Hospitalization is recommended in the case of severe abdominal symptoms (neutropenic ileocolitis) to prevent bowel necrosis and spontaneous perforation, with the following measurements (5)[C]:
- Bowel rest
- IV hydration
- Parenteral antibiotics to cover enteric organisms, especially clostridial species
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
Once the diagnosis is established and G-CSF treatment has started (2)[C]
- Blood counts should be obtained periodically to avoid overtreatment or undertreatment.
- On reaching a stable dose of G-CSF, blood counts can be monitored every few months.
DIET
No specific diet is generally recommended.
PATIENT EDUCATION
- Because of the great regularity of cycles, patients can learn to organize their lives around the disease.
- Patients can predict the neutropenic periods and avoid activities that might cause minor injuries.
- Dental work and surgery can be planned to avoid neutropenic periods.
- Patients can be reassured that incidental infections should respond uniformly and readily to antimicrobials.
- Patients should be counseled to seek medical attention if abdominal pain is persistent or associated with significant abdominal tenderness.
PROGNOSIS
- Cyclic neutropenia is a benign disease; patients grow and develop normally.
- Sepsis and death from bacteremias are uncommon but are a source of fear and concern for patients and their parents.
- Evolution to myeloid leukemia is not a recognized complication with or without treatment with G-CSF (8)[A].
- Evolution to myelodysplasia is not reported.
- Symptoms and the oscillations in the blood count abate as the patient gets older.
COMPLICATIONS
- Chronic gingivitis
- Increased dental caries
- Premature tooth mobility and loss
- Septic shock due to perforating colonic ulcers and infections of clostridial species and gram-negative organisms
- Increased rate of spontaneous abortions in women
REFERENCES
11 Germeshausen M, Deerberg S, Peter Y, et al. The spectrum of ELANE mutations and their implications in severe congenital and cyclic neutropenia. Hum Mutat. 2013;34(6):905 " 914.22 Wright DG, Dale DC, Fauci AS, et al. Human cyclic neutropenia: clinical review and long-term follow-up of patients. Medicine (Baltimore). 1981;60(1):1 " 13.33 Dale DC, Welte K. Cyclic and chronic neutropenia. Cancer Treat Res. 2011;157:97 " 108.44 Aprikyan AA, Dale DC. Mutations in the neutrophil elastase gene in cyclic and congenital neutropenia. Curr Opin Immunol. 2001;13(5):535 " 538.55 Dale DC, Hammond WPIV. Cyclic neutropenia: a clinical review. Blood Rev. 1988;2(3):178 " 185.66 Dale DC, Cottle TE, Fier CJ, et al. Severe chronic neutropenia: treatment and follow-up of patients in the Severe Chronic Neutropenia International Registry. Am J Hematol. 2003;72(2):82 " 93.77 Dale DC, Bonilla MA, Davis MW, et al. A randomized controlled phase III trial of recombinant human granulocyte colony-stimulating factor (filgrastim) for treatment of severe chronic neutropenia. Blood. 1993;81(10):2496 " 2502.88 Dale DC, Bolyard A, Aprikyan AA. Cyclic neutropenia. Semin Hematol. 2002: 39(2):89 " 94.
ADDITIONAL READING
- Dale DC. Cyclic and chronic neutropenia: an update on diagnosis and treatment. Clin Adv Hematol Oncol. 2011;9(11):868 " 869.
- Haurie C, Dale DC, Mackey MC. Cyclical neutropenia and other periodic hematological disorders: a review of mechanisms and mathematical models. Blood. 1998;92(8):2629 " 2640.
- Horwitz MS, Duan Z, Korkmaz B, et al. Neutrophil elastase in cyclic and severe congenital neutropenia. Blood. 2007;109(5):1817 " 1824.
CODES
ICD10
D70.4 Cyclic neutropenia
ICD9
288.02 Cyclic neutropenia
SNOMED
Cyclical neutropenia (disorder)
CLINICAL PEARLS
- Cyclic neutropenia is a benign disease; bowel necrosis and perforation are rare but may be associated with mortality.
- Although establishing the diagnosis requires obtaining three blood counts a week for 6 weeks to demonstrate the specific findings mentioned earlier, genetic testing can confirm the diagnosis.
- The mainstay of treatment is SC recombinant G-CSF, which is effective and well tolerated.