1. Neutropenia

2. Definition: 2 weeks to 1 year: Less than 1,000/L
Over 1 year: Less than 1,500/L
It is variable with race , age and other factors

3. Epidemiology of Neutropenia:
Ethnic groups (African and Arabs) 10%
Premature and SGA(6%) specially pre-eclampsia
Septic Newborns and Infants
Post infection
Congenital neutropenia ( 2/1,000,000)

4. Classification of Neutropenia: (Etiology)
Autoimmune(21%)
Chronic idiopathic(27%)
Drug induced(4%)
Post infection(28%)
Ethnic(13%)
Congenital(7%)

5. Classification of Neutropenia: (Etiology)
Congenital
1)Maturation arrest at promyelocyte/myelocyte level presenting in infancy
2)Identified mutation in genes known to cause neutropenia

6. Classification of Neutropenia: (Etiology)
Autoimmune
1)Prescence of anti-neutrophil antibodies
2)Granulocyte immunofloscence test
3)Granulocyte agglunitation test
4)Monoblonal antibody-specific immobilization of granulocyte antigens

7. Classification of Neutropenia: (Etiology)
Congenital
Pro-LL-37 level is predictive of congenital severe neutropenia

8. Classification of Neutropenia: (Etiology)
Post infection
1)Influenza like viruses
2)Common colds

9. Classification of Neutropenia: (Neutrophil Count)
Mild Neutropenia:
Neutrophils 1,000 to 1,500/L
Moderate Neutropenia:
Neutrophils 500 to 1,000/L
Severe Neutropenia:
Neutrophils Less than 500/L

10. Severe Neutropenia:
Risk of pyogenic infection;Particularly if neutropenia persist
Endogenous bacteria are the most frequent invaders
Monocyte provide only marginal protection against pyogenic infection
Cutaneous abscesses , furunculous, pneumonia ,septicemia

11. Severe Neutropenia(continue):
Cutaneous abscesses , furunculous, pneumonia ,septicemia
Stomatitis,gingivitis periodontitis,perirectal inflammation,Otitis media
S.aureus,gram-negative bacteria are the most common isolated organism

12. Classification of Neutropenia: (Etiology)
1)Neutropenia caused by intrinsic defects in Myeloid cells or their progenitor
2) Neutropenia caused by Extrinsic Factors

13. Intrinsic defects in Myeloid cells or their progenitor
Reticular Dysgenesis
Severe congenital neutropenia(Kostmann’s Dis.)
Cyclic Neutropenia
Myelokathexis
Schwachman’s Syndrome
Dyskeratosis Congenita
Familial benign neutropenia
Bone marrow failure syndromes

14. Neutropenia caused by Extrinsic Factors
Infection
Drug induced
Autoimmune neutropenia
Immune neonatal neutropenia
Neutropenia associated with immune dysfunction
Neutropenia associated with metabolic diseases
Nutritional deficiencies
Reticuloendothelial sequestration
Bone marrow infiltration
Chronic idiopathic neutropenia

15. Reticular Dysgenesis:
Selective failure of stem cells committed to myeloid & lymphoid
Severe neutropenia and moderate to severe lymphopenia
Agammaglobulinemia
Inherited disorder
BMT is the choice treatment

16. Severe Congenital Neutropenia (Kostmann’s Dis.):
Autosomal recessive
Typically appear from first month of life
Monocytosis and moderate eosinophilia
Fever,skin infection, abscess,stomatitis
BMA: normal till promyelocytes and myelocytes and depletion of mature cells
G-CSF treatment and BMT

17. Cyclic Neutropenia:
Regular periodic oscillations approximately every 21 days in peripheral blood neutrophils
In most cases,retculocytes ,platelets and other leukocytes also cycle.
Malaise,fever,oral ulcers,gingivitis and periodontitis,and pharyngitis associated with lymph node enlargement.

18. Cyclic Neutropenia(cont):
Pneumonias and peritonitis sepsis (Clostridium perfringens) are the most common cause of death.
Monocytosis and eosinophilia occur when neutrophil counts are at their lowest.
To establish the diagnosis of cyclic neutropenia , neutrophil counts must be monitored at least two times a week for 6 to 8 weeks.
Treatment: BMT & G-CSF

19. Myelokathexis Uncommon form of moderate to severe neutropenia.
Bizarre morphologic disturbances of PMN nucleus.
Neutrophil motility is abnormal.
One patient, has been successfully with G-CSF.

20. Schachman’s Syndrome:
Autosomal Recessive Trait
Metaphyseal Chondrodysplasia,dwarfism, Pancreatic exocrine insufficiency , Neutropenia
Almost all infants develop malabsorption by 4 months of age
There is no reciprocal Monocytosis.
Treatment: Pancreatic replacement + G-CSF

21. INFECTION:
The most common cause of transient neutropenia is Viral Infection .
Neutropenia develops during the first 24 to 48 hours of illness and may persist for 3-6 days.

22. INFECTION(Continue):
Hepatitis A &B
RSV
Influenza A & B
Measles
Rubella
Varicella
HIV(Leukopenia)
Sepsis(specially in newborns)

23. Drug Induced Neutropenia:
Disorder characterized by severe and selective reduction in the levels of circulating blood neutrophils and is due to an idiosyncratic reaction to offending drug
Mortality rate is reported as 32 percent in one series.

24. Drug Induced Neutropenia(Continue):
Antimicrobial Drugs:Penicillins,Sulfonamides
Anti-thyroid Drugs
Phenothiazines
Antipyretics:phenylbutazone,aspirin,acetaminophen
Anti-rheumatics:gold,levamisole,penicillamine
Sedatives:Benzodiazepines,Barbiturates

25. Drug Induced Neutropenia(Cont):
Duration of drug induced neutropenia is highly variable
Acute idiosyncratic:only few days
Chronic idiosyncratic:months to years
Immune-mediated: 6-8 Days

26. Evaluation of the Patient with Neutropenia:
History & Physical Examinations:
1)Related phenotypic abnormality
2)Determination of bacterial infection
3)Evaluation of organomegaly
4)History of recent infection or drug exposure

27. Evaluation of the Patient with Neutropenia(continue):
If the patient has isolated neutropenia and is asymptomatic and if other findings are absent; Clinical observation for several weeks is usually the best approach.

28. Evaluation of the Patient with Neutropenia(Lab Test):
Persistent Neutropenia:CBC twice weekly for 6-8 weeks
Coomb’s Test & Serum Immunoglobulins
T-cell Assay & HIV
BMA & BMB in selected patients (anemia,macrocytosis,thrombocytosis)

29. Evaluation of the Patient with Neutropenia(Lab test-continue):
Anti-neutrophilic anti-body
ANA,Complement(for Collagen Vascular Dis.
Metabolic and exocrine pancreatic disease
CXR and Long Bone survey
Vitamin B12,Folate and Copper levels

30. Neutropenia in premature infants
Natural course
Sepsis
Eclampsia
Recover till 7 days
Administration of G-CSF & IVIG controversial

31. Neutropenia in full-term infants
Immune-mediated disorders
Alloimmune,
Isoimmune
Autoimmune neutropenia (AIN).

32. Neonatal alloimmune neutropenia
The consequences may be quite severe, including severe omphalitis, cellulitis, acteraemia and meningitis.
Diagnosis:
Knowing possibility
testing maternal serum for anti-neutrophil antibodies to the antigens HNA1a, HNA-1b and HNA 1c and others that may be present on the infant and the infant’s father

33. Neonatal iso-immune neutropenia
Iso-immune neutropenia is caused by transplacental transfer of pre-existing IgG antibodies from mothers with AIN or who are FccRcRIIIb deficient
Diagnosis: mother neutropenia

34. Autoimmune neutropenia
AIN overlaps with alloimmune and iso-immune neutropenia because the neutrophil-specific antigens are often the same (i.e., HNA1a, HNA-1b and HNA 1c), but in AIN there are no neutrophil-specific antibodies in the maternal serum.

35. Autoimmune neutropenia
Primary AIN usually occurs in the first 2 years of life, with a very high spontaneous remission rate, perhaps greater than 90%. There are similar cases with and without neutrophil-specific autoantibodies.

36. Congenital causes for childhood neutropenia
Congenital or hereditary neutropenia usually presents in the first year of life as recurrent fever attributable to a common typ
more severe and recurrent infections.
the severe oral manifestations associated with the congenital disorders

37. ELANE mutation:
Mutations in ELANE, the gene for neutrophil elastase, are the most common cause for cyclic and severe congenital neutropenia (SCN), both primarily autosomal dominant diseases
ELANE is only expressed in myeloid tissues, and therefore mutations only affect neutrophils and monocytes.

38. Severe congenital neutropenia
SCN usually presents within the first year of life as fever and infections that do not resolve or resolve only very slowly
congenital anomalies and functional abnormalities in other systems are rare in patients with ELANE-associated neutropenia.

39. Severe congenital neutropenia
The diagnosis of SCN is usually based on a series of ANCs showing very severe neutropenia and a bone marrow aspirate showing maturation arrest
Genetic sequencing (selective, single gene, gene panels or exome sequencing) is helpful for diagnosis and prognosis.

40. Severe congenital neutropenia
In patients with mutations in ELANE, there is now sufficient genotype-phenotype information available to identify mutations which are more likely to be associated with poor response to G-CSF, risk of death from infections and a high risk of developing myelodysplasia (MDS) and acute myeloid leukaemia (AML)

41. Cyclic neutropenia
Cyclic neutropenia (CyN) is a rare disorder characterized by oscillating levels of blood neutrophils and monocytes, usually at 21-day intervals
ELANE-associated cyclic neutropenia (ELANE-CyN).
G-CSF, usually 1–3 lg/kg/day given daily or every other day, is warranted

42. HAX1-neutropenia
Kostmann syndrome, autosomal recessive SCN, is now attributable to mutations in HAX1, HCLS1 Associated Protein X-1, a protein associated with Lyn substrate 1 and with the F-actin-binding protein, cortactin.
‘maturation arrest’ at the promyelocyte stage of neutrophil development, very similar to those seen in patients with mutations in ELANE.

43. G6PC3-neutropenia
This is a rare autosomal recessive condition attributable to mutations in the glucose 6 phosphatase catalytic subunit 3 gene.
less severe marrow changes, less severe neutropenia and a variety of other haematological, cardiac and urogenital anomalies have now been described

44. Glycogen storage disease 1b SLC37A4 (G6PT1)-neutropenia
rare hereditary disorder
recurrent and severe hypoglycaemia,
hepatomegaly,
enterocolitis,
neutropenia and recurrent infections.

45. Barth syndrome TAZ-neutropenia
X-linked disease
Phospholipid metabolism ( mitochondrial membranes)
Childhood cardiomyopathy,
proximal myopathy,
delayed motor development,
growth delay and
neutropenia, chronic and recurrent infections.

46. Barth syndrome TAZ-neutropenia
The diagnosis is suggested by a five-fold or greater increase in urinary 3-methylglutaconic acid
increased monolysocardiolipin:cardiolipin ratio
DNA sequencing showing a disease-associated variant of TAZ

47. Shwachman-Diamond syndrome SBDS neutropenia
an autosomal recessive disorder attributable to mutations in the SBDS gene
Failure to thrive with steatorrhoea
Skeletal abnormalities
Bacterial infections very early in life
MDS and AML are well known complications.

48. Shwachman-Diamond syndrome SBDS neutropenia(Diagnosis)
evidence of exocrine pancreatic insufficiency,
skeletal abnormalities,
Neutropenia,
Findings of typical mutations in the SBDS gene are diagnostic, but there are patients with typical findings of SDS who lack mutations in SBDS

49. Wiskott-Aldrich syndrome WASneutropenia
Rare X-linked primary immunodeficiency disease
small platelets,
Eczema,
Recurrent infections,
Autoimmunity
Predilection to malignancies

51. Other causes of congenital neutropenia
TCIRG1-neutropenia is an autosomal dominant neutropenia
CXCR4-neutropenia: WHIM (warts, hypogammaglobulinemia, infections and myelokathexis) syndrome or myelokathexis is an immunodeficiency

52. Other causes of congenital neutropenia(continue)
JAGN1-neutropenia is a rare disorder characterized by neutrophils with few granules, aberrant glycosylated proteins and increased apoptosis of developing neutrophils. Patients are poorly responsive to G-CSF

53. Other causes of congenital neutropenia(continue)
Cohen syndrome and VPS13B-neutropenia is a rare autosomal recessive disorder with non-progressive psychomotor retardation, microcephaly retinal dystrophy and intermittent neutropenia due to mutations in VPS13B,

54. Other causes of congenital neutropenia(continue)
GFI1-neutropenia is attributable to mutations in the gene encoding the transcriptional repressor oncoprotein GFI1. Patients have immunodeficiency and circulating immature myeloid cells (Person et al, 2003).

55. Other causes of congenital neutropenia(continue)
VPS45-neutropenia
in infants from consanguineous families
myelofibrosis,
defective platelet aggregation
life-threatening neutropenia
refractory to G-CSF
(Stepensky et al, 2013; Vilboux et al, 2013).

56. Other causes of congenital neutropenia(continue)
WDR1-neutropenia syndrome
Recurrent infections,
severe stomatitis,
variable degrees of neutropenia
Impaired wound healing.
abnormalities in an actin-interacting protein as a result of a mutation in WDR1
(Kuhns et al, 2016).

57. Drug and chemotherapyassociated neutropenia in children
idiosyncratic reactions(4/10,000)

58. General principles for management of neutropenia in children
1 )Family history and the pattern of fever and infections in the patient are critical for accurate diagnosis and proper management.

59. General principles for management of neutropenia in children
2 )It is always good practice to obtain multiple white blood counts with differentials to determine if a patient has neutropenia and its severity. Infections tend to occur when neutrophil counts are the lowest, but patients come to the physician when they are ill and their counts are higher than baseline.

60. General principles for management of neutropenia in children
3) The value of genetic testing for the diagnosis of neutropenia is increasing rapidly as the genetically determined disorders of myeloid biology are described more and more precisely

61. General principles for management of neutropenia in children
4) G-CSF is the natural regulator of neutrophil production and deployment. It is widely used to treat neutropenia because of its potency and favourable adverse event pro- file. In the chronic neutropenias, both congenital and acquired, low dose G-CSF, e.g.,

62. General principles for management of neutropenia in children
5)For most patients with neutropenia, infections occur from surface organisms. For the long-term health of the child it is best to avoid chronic and repetitive antibiotics and excessive protectionism. Parental goals should be good school attendance, supportive social interactions and activities, and nutrition to support normal growth and development.

63. Thanks for your Attention