Approach to Pediatric Neutropenia

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1 Approach to Pediatric Neutropenia
June Stefani Doucette PGY-3

2 Objectives Recognize clinical presentations of neutropenia
ID patients needing work up for immunodeficiency Formulate differential diagnosis List risk factors for serious bacterial infection

3 Objectives Differentiate between benign and serious causes of neutropenia List treatment approaches for neutropenia Know when to refer to pediatric hematology/oncology

4 The Neutrophil

5 Terminology Neutropenia: decrease in the absolute number of circulating segmented neutrophils and band forms in the blood Absolute neutrophil count: multiply WBC by percentage of segmented and band forms of leukocytes Normal ANC x 109/L - Important to note that these normal values for ANC were developed using population studies of Caucasian children and therefore this normal range is not always applicable to kids of other ethnicities. For example, up to 30% kids of African American descent may have ANC as low as 0.8 and still be considered healthy

6 Definitions Acute neutropenia: less than 3 months duration
Chronic neutropenia: over four months duration Mild neutropenia: ANC x 109/L Moderate neutropenia: ANC x 109/L Severe neutropenia: ANC < 0.5 x 109/L

7 Clinical Presentations
Pyogenic infection: cellulitis, abscesses, furunculosis, pneumonia, septicemia Stomatitis, gingivitis Perirectal inflammation, AOM Diffuse intestinal lesions presenting with abdominal pain and diarrhea Neutropenic patients most likely to be colonized with endogenous flora and nosocomial organisms Intestinal lesions can be related to bacterial overgrowth

8 Caution! Don’t be reassured by “mild” infection
Signs and symptoms of localized infections diminished in neutropenic patients May not see as much exudate, abscess formation, regional lymphadenopathy Redness, pain, tenderness, warmth and fever are mediated by cytokines  should be present Infections in neutropenic patients may not seem as severe as in patients with normal numbers and function of their neutrophils Paucity of neutrophils means that patients may not be able to mount a normal inflammatory response to infection including production of exudate, formation of abscesses and regional lymphadenopathy Other signs and symptoms of infection including redness, tenderness, warmth, fever are mediated by cytokines and should still be present in neutropenic patients

9 Most Common Pathogens Staphylococcus aureus Gram negative organisms
Staphylococcus epidermidis Streptococci Enterococci

10 Risk of Severe Infection
Acute neutropenia d/t chemotherapy, BM failure, marrow exhaustion Neutropenic patients receiving cytotoxic or immunosuppressive drugs Patients with disorders of neutrophil production and release with higher risk of infection Patients receiving chemotherapy for malignancy at greater risk of infection Kids who develop acute neutropenia secondary to chemotherapy, bone marrow failure, marrow exhaustion more likely to develop severe infection than kids with severe chronic neutropenia which tends to arise from reduced production, increased destruction or excessive splenic sequestration of neutrophils Patients receiving cytotoxic or immunosuppressive drugs are more likely to develop serious bacterial infections because these drugs compromise both number and function of lymphocytes and monocytes which would have otherwise provided some protection against infection Patients with disorders of neutrophil production and release more at risk of serious bacterial infection than patients who have peripheral neutropenia with normal bone marrow function Patients receiving chemotherapy for malignancy also at greater risk of serious bacterial infection because the chemotherapy causes breakdown of the skin and mucosal membranes to allow more potential sites of entry for invasive bacterial and additionally nutritional status of patient is also affected in these cases

11 Evaluation of Neutropenia
With ANC < 1.0 x 109/L, ask for manual differential to rule out blasts or circulating immature neutrophils History and physical Severity and duration of neutropenia determines extent of lab evaluation and investigations ordered

12 History Onset of neutropenia Type, frequency, severity of infections
Drug or toxin exposures Family history of recurrent infection or unexplained infant deaths

13 Red Flags > 2 systemic bacterial infections /yr (sepsis, meningitis, osteomyelitis) > 2 episodes of pneumonia in a year Multiple bacterial infections in a year (cellulitis, draining AOM, lymphadenitis) Unusual infections involving liver, brain abscess Infections caused by unusual bugs (aspergillus, caididiasis, serratia, nocardia, burkholderia) Infections of unusual severity Chronic gingivitis, recurrent apthous ulcers

14 Physical Exam Growth and development Phyenotypic abnormalities
Mucous membranes, gingiva, skin, tympannic membranes, rectum Look for lymphadenopathy, hepatosplenomegaly, signs of possible underlying disease Look for petechiae and purpura Measure temp, but not rectally! Look for evidence of infections at various sites of mucous membranes including gingiva, skin, TMs, rectum Temperature should be recorded but avoid doing rectal temps in patients known to be neutropenic to prevent potential injury to the mucosa and entry of bacteria from the GI tract into the systemic circulation

15 Investigations Extent of work up depends on duration of symptoms
If neutropenic at present  rpt CBC in 3-4 weeks If neutropenia persists in an asymptomatic infant, order antineutrophil antibody If neutropenia persists in a symptomatic child consider referral to hematology for serial CBCs and consideration of BMA If neutropenia and malabsorption consider Scwachman- Diamond Syndrome First step is to repeat CBC and determine chronicity of neutropenia If CBC shows recovery of ANC< then most likely cause is transient bone marrow suppression If Neutropenia persists in an asymptomatic infant, consider ordering an antineutrophil antibody titre to rule out autoimmune neutropenia of infancy If neutropenia persists in a symptomatic child (recurrent bacterial infections, chronic gingivitis or mouth ulcers) then consider referral to hematology. They will order weekly CBCs to determing if there is a cyclic pattern to the neutropenia and may additionally consider ordering bone marrow studies to determine cellular morphology to determine extent of myeloid cell maturation If a child presents with neutropenia and symptoms of malabsorption consider SDS; these patients need assessment of their pancreatic enzymes as well as skeletal evaluation to rule out metaphyseal chondrodysplasia

16 Acquired Neutropenias
Infection Drug Induced Immune Neutropenia Sequestration/hypersplenism Marrow replacement, chemo, radiation effects Ineffective myelopoeisis

17 Infection Viral infection is the major cause!
RSV, varicella, flu A and B, measles, rubella, EBV Neutropenia seen into illness; lasts 3-8 days Mechanisms of neutropenia: Redistribution to marginating pool Increased use of neutrophils at sites of infection Decreased neutrophil production Infectious diseases are among the most common causes of acute neutropenia Viral infection is the major cause of acute neutropenia in childhood Commonly implicated viruses include: RSV, varicella, influenza A and B, measles, rubella, EBV Neutropenia happens in the first 24 – 48 hours and persists for 3 – 8 days (corresponds to the period of viremia) Mechanisms responsible for neutropenia in acute infections include: Redistribution of neutrophils from the peripheral circulating pool to the marginating pool Increased use of neutrophils at sites of infection Decreased neutrophil production Premature neonates especially prone to exhausting their bone marrow reserves of segmented neutrophils and rapidly succumbing to bacterial sepsis - Also see significant neutropenia with bacterial, protozoal, rickettsial and severe fungal infections

18 Drug Induced Immunologic, toxic, hypersensitivity mediated mechanisms of causing neutropenia Phenothiazines, sulfonamides, anticonvulsants, penicillins, aminopyrine Treat by discontinuing the offending agent If neutropenia does not improve and patient is symptomatic, consider 5ug/kg G-CSF Drugs cause severe neutropenia by immunologic, toxic, hypersensitivity mediated mechanisms; often the mechanism is incompletely understood More common in adults than children; only 10% drug mediated neutropenia happens in kids Most effective way to treat it is to stop the causative medication If neutropenia persists, consider giving a dose of G-CSF

19 Immune Neutropenias Circulating antineutrophil antibodies
Immunofluorescence and microcapillary agglutination assays are used to determine antibody presence If antibodies against RBCs and platelets are also present think about Evans syndrome Immune neutropenias are caused by the presence of circulating anti-neutrophil antibodies Antineutrophil andibody testing is achieved by using immunofluorescence and microcapillary agglutination assays Due to low avidity and potentially low titres, may take up to three attempts to detect antineutrophil antibodies If there are also antibodies present against red blood cells and platelets, important to think about Evans syndrome Frequently seen in common variable immunodeficiency and should be referred to a hematologist Responds well to prednisone to improve cell counts

20 Alloimmune Neonatal Neutroenia
Transplacental transfer of maternal alloantibodies against an antigen on infant’s neutrophils 0.2% pregnancies Delayed cord separation mild skin infections, fever, pneumonia in the first 2 weeks of life Recovers by 7 weeks after birth as maternal antibodies will no longer be present Supportive care, antibiotics, G-CSF if severe infection Caused by transplacental transfer of maternal alloantibodies against an antigen on infant’s neutrophils Affects 0.2% pregnancies Symptomatic infants present in the first two weeks of life with delayed cord separation, mild skin infections, fever and pneumonia Neutropenia is often severe and presents with infections, fever Causative organisms are those usually responsible for neonatal disease Resolves by 7 weeks of life as maternal antibodies are no longer present at that point Treatment is supportive care, antibiotics and occasionally G-CSF in severe cases

21 Autoimmune Neutropenia of Infancy
Caused by granulocyte specific autoantibodies Infants aged 5-15 months 90% do not have increased risk of pyogenic infections 95% undergo spontaneous remission in 7-30 months Repeat antibody screening until antibodies are detected Supportive treatment with antibiotics as needed These kids can receive live vaccines Seen most commonly in infants and is caused by granulocyte specific autoantibodies Typically diagnosed in infants aged 5 – 15 months In 90% of cases AIN is not associated with increased risk of recurrent pyogenic infections despite severe neutropenia 95% will undergo spontaneous remission within 7 – 30 months Repeat antibody screen until antibodies are found; they are often not detected in the serum Bone marrow usually normocellular or hypercellular and usually contains reduced number of segmented neutrophils Symptomatic treatment with antibiotics for infections is all that is needed for most infants These infants are able to be immunized with live vaccinesbecause cellular immune system is intact including normal B and T cell function

22 Sequestration/Hypersplenism
Splenic enlargement causing neutropenia Neutropenia most often mild to moderate Seen with thrombocytopenia and anemia Treat underlying disease and cytopenias improve Rarely splenectomy indicated to restore neutrophils Splenic enlargement due to storage diseases or systemic disorders causing hypersplenia (inflammation, neoplasia, hemolytic anemias) Most often neutropenia is mild to moderate and accompanied by varying degrees of thrombocytopenia and anemia When underlying disease is treated and hypersplenia starts resolving, cytopenias resolve too Rarely splenectomy may be needed to restore neutrophil count but this increases the risk of infection by encapsulated organisms Avoid splenectomy in patients with combined variable immunodeficiency because of high risk for predisposing the patient to sepsis

23 Marrow Replacement Malignancies suppress myelopoeisis by infiltrating BM Chemo and radiation damage BM stem cells Aplastic anemia also leads to neutropenia Manage with prompt treatment of infections with broad spectrum antibiotics to cover s.aureus and p.aeruginosa Only manifestation of infection might be fever Hematologic malignancies and metastatic solid tumors suppress myelopoeisis by infiltrating the bone marrow Myelodysplastic disorders characterized by neutropenia, peripheral cytopenias and macrocytic blood cells Chemotherapy and radiation damage stem cells present in bone marrow and prevent their maturaton into neutrophils, red blood cells, platelets Management of acute neutropenia related to malignancies, chemotherapy, radiation or immunosuppression is with prompt treatment of infections with broad spectrum anditbiotics to cover staph aureus and pseudomonas aeruginosa These infections might present with fever alone, which is why we take febrile neutropenia so seriously

24 Ineffective Myelopoeisis
Congenital or acquired vitamin B12/folate deficiency Rare in pediatrics! May be seen in infants with starvation/marasmus Adolescents with anorexia nervosa Extended use of antibiotics Ineffective myelopoesis due to nutritional deficiencies, specifically vitamin B12 or folate Rare to see in pediatrics Sometimes seen in infants with starvation or marasmus Teenagers with anorexia nervosa Children with extended use of antibiotics like septra which can lead to folate deficiency

25 Intrinsic Neutropenia
Congenital disorders Cyclic neutropenia Severe congenital neutropenia

26 Congenital Disorders Severe combined immunodeficiency syndromes
Hyper IgM syndrome Common variable immunodeficiencies Glycogen storage disease type 1b Schwachman Diamond syndrome Cyclic neutropenia Severe congenital neutropenia

27 Cyclic Neutropenia AD inheritance Incidence 0.6/million
Mutation in neutrophil elastase gene Regular periodic oscillations of neutrophils Reciprocity between neutrophil and monocyte counts Oral ulcers, stomatitis, cutaneous infections, pneumonia, mucosal ulcerations AD inheritance Incidence 0.6 per 1 million people Caused by mutation in neutrophil elastase gene Characterized by regular periodic oscillations of peripheral neutrophils with numbers ranging from normal to neutropenic values Nadir of neutropenia accompanied by elevated monocyte count which helps to differentiate this entity from other causes of neutropenia Average oscillatory period is 21 days plus or minus four days Clinical presentation is with oral ulcers, stomatitis, cutaneous infections, lymphadenopathy, pneumonia, abdominal pain from intestinal lesions, ulcerations of mucosa including oral, vaginal, rectal Prior to G-CSF 10% patients with cyclic neutropenia developed fatal clostridium or gram negative infections

28 Cyclic Neutropenia Repeat CBC 2-3 times per week for two months to establish oscillating pattern of cell counts Diagnosis confirmed with molecular genetic studies to demonstrate mutations in elastase gene Treat with daily G-CSF to decrease risk of fatal infections with clostridium or gram negatives and also to decrease amount of antibiotic use

29 Severe Congenital Neutropenia
Arrest in myeloid maturation at the promyelocyte stage ANC < 0.2 x 109/L three separate times in a month Incidence 1 per million AD and AR inheritance Mouth ulcers, gingivitis, stomatitis, AOM, resp infections, cellulitis, skin abscesses, pneumonia and deep tissue abscesses Arrest in myeloid maturation at the promyelocyte stage ANC < 0.2 x 10^9/L on three separate occasions over the time of a month Incidence 1 in 1 million AD inheritance and also AR inheritance is described in consanguineous populations AR form also known as Kostmann disease

30 Severe Congenital Neutropenia
Peripheral eosinophilia and monocytosis Thrombocytosis and anemia of chronic disease Bone marrow: arrest of myeloid cell maturation 10-20% develop MDS or AML Require yearly bone marrow studies to screen Following leukemic transformation, only treatment option is stem cell transplant Peripheral eosinophilia and monocytosis seen Also see on the CBC: thrombocytosis and anemia of chronic disease Maturational arrest of myeloid cell precursors in the bone marrow is what differentiates severe congenital neutropenia from idiopathic and immune mediates neutropenia Prior to the introduction of G-CSF, 2/3 patients died before adolescence due to infections 10-20% patients with severe congenital neutropenia will go on to develop myelodysplastic syndrome or AML Important to differentiate patients with SCN from patients with cyclic neutropenia as patients with cyclic neutropenia are not at an increased risk for leukemia and do not need to undergo annual bone marrow examinations For patients with SCN who go on to develop MDS or AML, traditional chemotherapy is ineffective and associated with high mortality. Stem cell transplant remains the only successful treatment for these patients once they have undergone leukemic transformation

31 Management Depends on cause! Viral induced, ANN, AIN: watchful waiting
Drug induced: stop offending drug if possible Chemo/radiation/immunosuppressed: antibiotics Cyclic neutropenia: G-CSF Severe congenital neutropenia: G-CSF or HSCT To quickly review the management of various forms of neutropenia, in summary it depends on the cause Neutropenia secondary to infection should be monitored with follow up CBC to ensure count recovery ANN: will spontaneously resolve within several weeks as maternal antibodies clear from the infants circulation. AIN: will spontaneously resolve within 7-30 months of presentation. Provide supportive care with antibiotics for severe infections until condition resolves Drug induced neutropenia: Stop offending drug if at all possible. If not, could consider G-CSF Chemo/radiation/immunosuppressed patients: Treat infections aggressively in these patients when they are neutropenic and wait for their counts to recover. Can also give G-CSF Cyclic neutropenia: requires daily subcutaneous injections of G-CSF Severe congenital neutropenia: Requires treatment with G-CSF, annual bone marrow screening for leukemic transformation and consideration of HSCT for patients who do not respond to G-CSF (5% patients will not respond) or patients who require high doses of G-CSF to maintain adequate neutrophil counts

32 Questions?

33 References Pomeranz, A. J. et al. (2016). Pediatric Decision Making Strategies 2nd edition. Philadelphia, PA: Elsevier Kliegman, R. M. et al. (2011). Nelson Textbook of Pediatrics 19th edition. Philadelphia, PA: Elsevier Walkovich, K., Boxer, L. A. “How to Approach Neutropenia in Childhood”. Pediatrics in Review. 34(4): insight.blogspot.ca/search/label/Get%20to%20immu- know%20the%20cells