Approaching Neutropenia in Children. SW Florida Osteopathic Medical Society: 39 th Annual Seminars in Family Practice
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1 Approaching Neutropenia in Children SW Florida Osteopathic Medical Society: 39 th Annual Seminars in Family Practice
2 Approaching Neutropenia in Children Emad Salman M.D Golisano Children s Hospital of SW Florida
3 Approaching Neutropenia in Children Objectives: 1. Recognition of Neutropenia in Children that have a serious underlying condition requiring further investigation. 2. Define Mild, moderate and severe neutropenia. 3. Understand etiology of neutropenia. 4. Understand risk of neutropenia and bacterial infections. 5. Know when to refer to a Pediatric Hematologist/ Oncologist
4 Approaching Neutropenia in Children Neutropenia defined as abnormally low level of Neutrophils in the blood. Decrease in the absolute number of circulating neutrophils and bands. Absolute Neutrophil Count (ANC) <1500
5 Approaching Neutropenia in Children Majority of neutrophils are in bone marrow (90% of the total in body) 5-8% of neutrophils are attached to endothelial surfaces or in tissue 2-5% of neutrophils are free floating in (only ones counted on CBC)
6 Absolute Neutrophil Count (ANC) - Absolute Neutrophil count (ANC). - Total WBC count x percentage of neutrophils and bands. - Example: Wbc 10,000 cells/ microliter, 25% Neutrophils,
7 Absolute Neutrophil Count (ANC) Example: Wbc 10,000 cells/microliter; Differential: 25% Neutrophils, 5% bands. ANC = 10,000 x (25+5)/100. ANC = 3000.
8 Absolute Neutrophil Count (ANC) ANC normal In a healthy children 20-70% of white cells may be neutrophils About 30% of African Americans have ANC as low as 800 and are considered healthy.
9 Absolute Neutrophil Count (ANC) Age WBC range (x10 3 /µl) Neutrophil (%) ANC range Birth ,000 1 week ,000 1 year years years years
10 Neutropenia Acute vs Chronic: <3 months vs >4 months Chronic neutropenia may arise from reduced production, increased destruction or excessive splenic sequestration. Acquired vs Intrinsic disorders
11 Neutropenia Mild: ANC Moderate: ANC Severe: ANC < 500
12 Neutropenia: Infections Risk of bacterial infections increase with severity of neutropenia especially in disorders of bone marrow production. Many patients with chronic neutropenia and normal marrow cellularity do not suffer serious infections. Gingivitis may be common.
13 Neutropenia Infections are common. Endogenous Flora Gram-positive cocci (staph. Aureus; staph. Epidermidis, enterococcus spp) Gram-negative rods (pseudomonas) Cellulitis Pneumonia Stomatitis Bacteremia and sepsis. Omphalitis
14 Neutropenia: Infections Signs and symptoms of local infection may be absent ( abscess, exudate, lymphadenopathy). Fever, Redness, pain, tenderness and warmth present. Cytokine mediated.
15 Neutropenia: Evaluation History of recurrent infections. > 2 systemic infections (meningitis, sepsis) >2 serious respiratory infections Multiple bacterial infections (cellulitis, lymphadenitis) Chronic gingivitis, recurrent aphthous ulcers.
16 Neutropenia: Evaluation If ANC <1000, request manual diff to look for blasts. Thorough History. History of recent viral illness History of infections: Type, frequency, severity. Drug history for toxic exposures. Family History of recurrent infections or unexplained infant death.
17 Neutropenia: Evaluation Exam: growth and development Physical abnormalities Presence of bacterial infection on skin, membranes etc Lymphadenopathy Hepatosplenomegaly Petechiae/purpura Temperature (avoid rectal temp)
18 Neutropenia: Evaluation Labs: After recent viral infection, repeat CBC in 3-4 weeks. Infant remaining neutropenic and asymptomatic consider sending neutrophil antibodies. Bone marrow aspirate usually not needed for acute onset neutropenia.
19 Neutropenia: Evaluation Labs: Child with history of recurrent infections, gingivitis, persistent neutropenia should be referred to Hematologist. CBC twice weekly for 6 weeks to rule out Cyclic neutropenia may be considered. Presence of pancytopenia requires possible marrow evaluation. History of failure to thrive, malabsorption and neutropenia may be from Shwachman- Diamond Syndrome.
20 Neutropenia: Diagnostic Approach o o In a patient with history of acute/chronic neutropenia with stomatitis, dental defects, congenital anomalies consider Congenital syndromes (Shwachman-Diamond; Wiskott- Aldrich; Fanconi anemia, immunodeficiencies). Spleen enlarged consider Hypersplenism, Infection, Malignancy, Connective tissue disease.
21 Neutropenia: Diagnostic Approach ANC < 1000, acute onset o o o o o Repeat in 3-4 weeks ( transient myelosuppression viral). Serology and cultures for infections (EBV,CMV, Rickettsia). Stop medications associated with neutropenia (drug induced). Neutrophil antibodies or red cell (auto-immune neutropenia, Evan s syndrome) Measure Immunoglobulins (immune dysfunction)
22 Neutropenia: Diagnostic Approach ANC < 500 on 3 separate tests o o o o Marrow evaluation for Severe Congenital neutropenia, cyclic neutropenia. Serial CBC 2 x/week for 6 weeks (Cyclic neutropenia). Exocrine pancreatic function (Shwachman- Diamond). Skeletal films (Shwachman-Diamond, Fanconi anemia)
23 Leukopenia: ALC < 1000 o o Repeat CBC in 3-4 weeks ( transient leukopenia) ALC <1000 on 3 separate tests consider - HIV Serology (HIV Infection) - Immunoglobulins, Lymphocyte subsets (congenital/acquired immunodeficiency)
24 Pancytopenia o o Marrow assessment (leukemia, storage disorders, myelodysplasia). B12 and Folate ( vitamin deficiencies)
25 Acquired Neutropenias: Infection Neutropenia acute over a few days (1-2 days) Viral infections major cause ( Varicella, RSV, EBV, CMV, Influenza A,B, measles, Rubella). Persist for 3-8 days. Severe neutropenia seen with bacterial, severe fungal infections, Rickettsia.
26 Acquired Neutropenias: Infection Bacterial infection, neutropenia due to a) redistribution from circulation to marginating pool. b) consumption c) decreased production
27 Acquired Neutropenias: Drug- Induced Immunologic or hypersensitivity reactions Incidence 10% in children, greater in adults older than 60. Common drugs: Phenothiazines, Sulfonamides, anticonvulsants, penicillins) Reversible after stopping medication
28 Acquired Neutropenias: Immune Neutropenia Presence of circulating antineutrophil antibodies. Directed against specific neutrophils antigens independent of HLA. Titers may be low. May need to repeat antibody testing up to 3 times to diagnose. Presence of red cell antibodies and neutrophil antibodies frequently seen in Common Variable Immunodeficiency. May be associated with SLE and other connective tissue disorders
29 Acquired Neutropenias: Alloimmune Neonatal Neutropenia Transplacental transfer of maternal alloantibodies. 0.2% of pregnancies. IgG mediated. Symptomatic infants may present with delayed separation of umbilical cord, fever, pneumonia, omphalitis. Resolves in 2-4 months
30 Acquired Neutropenias: Autoimmune Neutropenia (AIN) AKA Chronic Benign Neutropenia Presents at 5-15 months of age Resolves spontaneously at 3-5 years of age In 90% of infants not associated with increased risk of pyogenic infections. Little correlation between severity of neutropenia and risk for infection Bone marrow evaluations show all stages of granulocyte development
31 Acquired Neutropenias: Autoimmune Neutropenia (AIN) Management Until evidence exists that patient has ample marrow reserve: Admit or see daily for empiric parenteral antibiotics pending cultures Once evidence exists that patient has ample marrow reserve: Evaluate, treat identified infections only
32 Acquired Neutropenias: Hypersplenism/Sequestration Seen in storage disorders or systemic disease Splenic hyperplasia leading to increased trapping or destruction of neutrophils. Other cytopenias usually present
33 Acquired Neutropenias: Marrow replacement, Cancer therapy Leukemia. Aplastic anemia Chemotherapy. Radiation therapy High risk of infectious complications.
34 Acquired Neutropenias: ineffective myelopoeisis B12 or folic acid deficiency. Uncommon in children Seen in infants of vegans exclusively breastfed. Extended use of Bactrim can lead to folic acid deficiency
35 Intrinsic Disorders of Neutropenia: Cyclic Neutropenia Rare congenital granulopoietic disorder Autosomal dominant Regular, periodic oscillations of neutrophil counts Cycle 21 days (±4 days) Incidence 0.6/million Mutation in the Neutrophil elastase gene. Oral ulcers, cutaneous infections, enlarge lymph nodes. Pneumonia, stomatitis.
36 Intrinsic Disorders of Neutropenia: Cyclic Neutropenia Nadir accompanied by elevation of monocytes. Diagnosed twice weekly CBC for 6 weeks. ELANE 2 gene analysis now available Treatment with GCSF increases ANC at peak and nadir, but cycling persists Goal is to provide enough GCSF to keep ANC > 500 at all times. GCSF does not cause increased AML in these patients.
37 Intrinsic Disorders of Neutropenia: Severe Congenital Neutropenia (SCN) Arrest of myeloid maturation at promyelocyte stage ANC <200 1 in 1 million Autosomal dominant Elastase gene mutation in 60% of cases and Autosomal recessive in consanguineous populations. Autosomal recessive disorder (Kostmann syndrome)
38
39 Intrinsic Disorders of Neutropenia: Severe Congenital Neutropenia (SCN) Life threatening condition with death in first year of life Omphalitis, bacteremia, cellulitis, gingivitis, pneumonia, stomatitis, skin abscesses, deep abscesses. Treatment of SCN with GCSF improves neutropenia in 95% of cases. Survivors at risk for AML/MDS. Stem cell transplant reserved for non-responders, MDS/AML, cytogenetic abnormalities.
40 Neutropenia in Healthy Children If febrile, what is the risk? Little data in non-cancer patients. 119 children without Heme-Onc diagnosis 9 severely neutropenic 36 were neutropenic > 30 days 4 infections (stomatitis x 2, cellulitis, pneumonia), none severe. 83 were neutropenic < 30 days No infections Alario et al, Am J Dis Child. 1989;143(8):973.
41 Neutropenia in Healthy Children 91 patients ANC < 1000 in ED All with blood cultures 5 positive blood cultures 13 with non-oncologic disease 2 with leukemia Both with pancytopenia. Serwint et al, Clin Pediatr (Phila). 2005;44(7):593.
42 Neutropenia in Healthy Children Prospective, 161 patients 25 found to have chronic neutropenia 68% with infections 5 cases requiring antibiotics 2 years later 143 available for follow-up 6 still neutropenic. Alexandropoulou et al, Eur J Pediatr. 2013;172(6):811
43 Summary: Neutropenia in Healthy Children Non-febrile neutropenic children can be followed. If neutropenia persists for > 1 month, may be referred for evaluation of chronic neutropenia by Pediatric Hematologist Febrile neutropenic patients should be evaluated for infection. Empiric therapy unless known neutrophil reserves
44 Summary: Neutropenia in Healthy Children Patients with two or more cell line abnormalities should be referred immediately Patients that are clinically unwell should be admitted or referred for evaluation and admission.
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