approaching neutropenia in children...neutropenia: diagnostic approach anc < 1000, acute onset o...

SW Florida Osteopathic Medical Society: 39th Annual Seminars in Family Practice

Approaching Neutropenia in Children

Approaching Neutropenia in Children

Emad Salman M.D Golisano Children’s Hospital of SW

Florida

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

Approaching Neutropenia in Children

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

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)

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,

•  Example: Wbc 10,000 cells/microliter; Differential: 25% Neutrophils, 5% bands.

•  ANC = 10,000 x (25+5)/100. •  ANC = 3000.

Absolute Neutrophil Count (ANC)

•  ANC normal 1500-8000. •  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.

Absolute Neutrophil Count (ANC)

Absolute Neutrophil Count (ANC)

Age WBC range (x103/µL)

Neutrophil (%)

ANC range

Birth 9-30 60-85 6000-26,000

1 week

5-21 45 1500-10,000

1 year 6-17.5 20-30 1500-8500

6 years 5-14.5 50 1500-8000

10 years 4.5-13.5 50-70 1800-8500

21 years 4.5-11 50-70 1800-7700

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

Neutropenia

¡  Mild: ANC 1000-1500 ¡  Moderate: ANC 500-1000 ¡  Severe: ANC < 500

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.

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

Neutropenia: Infections

¡  Signs and symptoms of local infection may be absent ( abscess, exudate, lymphadenopathy).

¡  Fever, Redness, pain, tenderness and warmth present. Cytokine mediated.

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.

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.

Neutropenia: Evaluation

Exam: ¡  growth and development ¡  Physical abnormalities ¡  Presence of bacterial infection on skin,

membranes etc ¡  Lymphadenopathy ¡  Hepatosplenomegaly ¡  Petechiae/purpura ¡  Temperature (avoid rectal temp)

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.

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.

Neutropenia: Diagnostic Approach

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).

o  Spleen enlarged consider Hypersplenism, Infection, Malignancy, Connective tissue disease.

Neutropenia: Diagnostic Approach ANC < 1000, acute onset

o  Repeat in 3-4 weeks ( transient myelosuppression viral).

o  Serology and cultures for infections (EBV,CMV, Rickettsia).

o  Stop medications associated with neutropenia (drug induced).

o  Neutrophil antibodies or red cell (auto-immune neutropenia, Evan’s syndrome)

o  Measure Immunoglobulins (immune dysfunction)

Neutropenia: Diagnostic Approach ANC < 500 on 3 separate tests

o  Marrow evaluation for Severe Congenital neutropenia, cyclic neutropenia.

o  Serial CBC 2 x/week for 6 weeks (Cyclic neutropenia).

o  Exocrine pancreatic function (Shwachman-Diamond).

o  Skeletal films (Shwachman-Diamond, Fanconi anemia)

Leukopenia: ALC < 1000

o  Repeat CBC in 3-4 weeks ( transient leukopenia) o  ALC <1000 on 3 separate tests consider - HIV Serology (HIV Infection) - Immunoglobulins, Lymphocyte subsets (congenital/acquired immunodeficiency)

Pancytopenia

o  Marrow assessment (leukemia, storage disorders, myelodysplasia).

o  B12 and Folate ( vitamin deficiencies)

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.

Acquired Neutropenias: Infection

¡  Bacterial infection, neutropenia due to a) redistribution from circulation to marginating pool. b) consumption c) decreased production

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

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

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

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

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

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

Acquired Neutropenias: Marrow replacement, Cancer therapy

¡  Leukemia. ¡  Aplastic anemia ¡  Chemotherapy. ¡  Radiation therapy ¡  High risk of infectious complications.

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

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.

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.

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)

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.

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.

•  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.

Neutropenia in Healthy Children

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

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

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.