Neutrophil Disorders

Dysfunction of neutrophils or paucity of neutrophils compromises host defenses. Organisms present on the skin surface or in the gut cause infections. The most common are skin (cellulitis), pulmonary infections (pneumonia, sinusitis), and G.I. tract (stomatitis, gingivitis, perirectal abcess). Infections in unusual areas such as liver or brain abcesses, or involving uncommon organisms such as Aspergillus pneumonia, Serratia marescens, Nocardia, Pseudomonas cepacia should also raise the suspicion of phagocyte inadequacy.

Qualitative Disorders

Hyperimmunoglobin E (Job Syndrome)

Inheritance: AD
Etiology: Impaired chemotaxis.
Symptoms: Severe dermatitis: maculopapular rash presents in first weeks of life and becomes lichenified, preference for extensor surfaces (Versus atopic dermatitis, which begins months later and is more common on flexor surfaces). Associated with "cold" nonerythematous abcesses, pneumatoceles and osteoporosis. Most common organism: Staph aureus. Common: H. influenzae, E. coli, C. albicans.
Lab Findings: Elevated IgE, eosinophila.
Tx: Antibiotics. Place patient on TMP/SMX prophylaxis. Consider s.c. gamma-interferon.

Leukocyte Adhesion Defiency

Inheritance: AR
Etiology: Decreased expression of CD11/CD18 glycoproteins. Decreased binding of neutrophils to C3bi and endothelial ICAM1 and ICAM2.
Symptoms: Soft tissue infections, slow healing, impaired pus formation despite neutrophilia in peripheral blood. Delayed umbilical cord scission.
Lab Findings: Decrease or absent CD11/CD18 on neutrophils by flow cytometry.
Tx: Antibiotics. Place patient on TMP/SMX prophylaxis. If severe, consider BMT if HLA-compatible sibling available.

Chediak-Higashi Syndrome

Inheritance: AR
Etiology: Lysosomal granule fusion. Decreased neutrophil chemotaxis, degranulation.
Symptoms: Recurrent pyogenic infections. Associated with oculocutaneous albinism (due to fusion of melanosomes in the retina). Other cells affected. May have mild bleeding disorder related to platelet granule fusion. NK cell abnormalities, ineffective myelopoesis, peripheral neuropathy. May progress to T-cell proliferation in liver/spleen/marrow and organomegaly.
Lab Findings: Giant cytoplasmic granules by light microscopy.
Tx: Antibiotics. Place patient on TMP/SMX prophylaxis. Ascorbic acid (10-20 mg/day) may improve microbicidal activity. T-cell proliferative disease requires BMT.

Chronic Granulomatous Disease (CGD)

Inheritance: X linked (gp91-phox), or AR (p22, p47, p67-phox)
Etiology: Inability to kill catalase positive organisms because of mutations in the NADPH oxidase pathway. Superoxide cannot be generated by the neutrophils. The most common defect is lack of a 91 kDa component of cytochrome b558 which is coded on the X chromosome. The other two common mutations are in a 47kDa or 67kDa cytosolic protein. Most common organism: S. aureus. Others: S. marcensens, Pseudomonas spp., Aspergillus spp., and C. albicans.
Symptoms: Recurrent lymphadenitis, hepatic abcesses, osteomyelitis (particularly hands/feet).
Lab Findings: Nitroblue Tetrazolium test (NBT).
Tx: Antibiotics; surgery for abcesses. Place patients on TMP/SMX prophylaxis. Consider gamma-interferon. BMT.

Myeloperoxidase Deficiency

Inheritance: AR, common 1:2000.
Etiology: Lack of myeloperoxidase in neutrophils.
Symptoms: Occassionally, increased candidal infections in patients with diabetes mellitus
Lab Findings: Negative peroxidase stain of peripheral smear.
Tx: Antibiotics if symptomatic.

Quantitative Disorders

Neutropenia is categorized as severe if the absolute neutrophil count ([%segs + %bands] * WBC) is less than 500/mm³. If the ANC is between 500/mm³ and 1000/mm³, the neutropenia is moderate. An ANC between 1000/mm³ and 1500/mm³ is considered mild neutropenia, although some people's normal neutrophil counts may fall into this range, particular people of African ancestry. The ANC trend on serial CBCs may be more important than the absolute value; for example, a patient who has received chemotherapy and whose ANC is 1200/mm³ but falling rapidly needs antibiotics more than someone whose baseline ANC is 1100/mm³.

Inherited

Severe Congenital Neutropenia (Kostman Syndome)

Inheritance: Sporadic
Etiology: Arrest at promyelocyte stage due to cytokine signal pathway error.
Symptoms: Infections. Omphalitis common.
Lab Findings: Monocytosis, eosinophilia.
Tx: G-CSF. Watch for possible transformation to MDS, often assoc. with monosomy 7.

Cyclic Neutropenia

Inheritance: AD in some
Etiology: Unknown
Symptoms: Oscillations in neutrophil count over about 21 day period. When neutropenic: oral ulcers, pharyngitis, lymphadenopathy. 10% of patients die with infectious complications, especially C. perfringens sepsis.
Lab Findings: BM aspirate during neutropenia: hypoplasia or arrest in myelocyte stage.
Dx: Evaluate twice weekly for 6 weeks to establish periodicity if any. Confirm with BM, send cytogenetics.

Severe Chronic Idiopathic Neutropenia

Inheritance: ?
Etiology: Unknown.
Symptoms: Skin and oral lesions; onset at 2 years of age or more.
Lab Findings: Chronic neutrophil counts < 500/mm³, BM shows arrest anywhere up to band form. Sometimes associated with quantitative Ig abnormality.

Chronic Benign Neutropenia of Childhood

Inheritance:
Etiology: Unknown.
Symptoms: Infections rare (if common, it's not benign).

Schwachman Syndrome

Inheritance: AR
Etiology: Unknown.
Symptoms: Bacterial infections + malabsorbtion, steattorhea, FTT (secondary to pancreatic exocrine insufficiency). A quarter of cases progress to aplastic anemia.
Lab Findings: Neutrophil counts < 500/mm³ . Xray: metaphyseal dysostosis. Atrophy and fatty replacement of pancreas. Distinguished from CF by normal sweat test and no primary pulmonary disease.
Dx: Stool trypsin, Xray

Cartilage Hair-Hypoplasia

Inheritance: AR, more common in Amish population
Etiology: Unknown.
Symptoms: Infections. Varicella may be life-threatening.
Lab Findings: Neutropenia 100-2000 cells/mm³.
Tx: For severe infection, HLA identical sib transplant

Dyskeratosis Congenita

Inheritance: X-linked
Etiology: Unknown.
Symptoms: Nail dystrophy, leukoplakia, reticulated hyperpigmentation of the skin. Serious infections not common.
Lab Findings: BM hypoplasia.

Acquired

Infection

Etiology: Almost any infectious agent can activate cytokines, causing marginalization of neutrophils out of peripheral circulation, myeloid depression, and increased neutrophil destruction. RSV, Influenza A & B, measles, rubella are well known for this. EBV, hepatitis viruses, and HIV can cause severe/prolonged neutropenia. Sepsis in neonates depletes the neutrophil pool rapidly.
Tx: Treat underlying infection.

Drug (see table)

Mechanisms

Idiosyncratic marrow toxicity: about 2 to 6 weeks after drug dose. E.g., phenothiazines. May last for a long time.
Hypersensitivity: delayed onset. E.g., phenobarbitol, phenytoin. Lasts a few days.
Immune neutropenia: Drug functions as hapten. 1 to 2 weeks after re-exposure to drug. May be associated with fever, chills, prostration. Lasts about a week.
Treatment: Stop drug. If severe, consider G-CSF.

Immune Neutropenia

Presence of antineutrophil antibodies causes complement mediated lysis or clearance by spleen.

Isoimmune Neonatal Neutropenia

Analagous to Rh disease of the newborn: materal trans-placental IgG against fetal neutrophils. Counts normal by 7 weeks.

Autoimmune Neutropenia

Analogous to immune thrombocytopenic purpura. A variant is autoimmune neutropenia of infancy (ANI). In this condition, ANC is usually less than 500/mm³. Median age of Dx: 8 months. Patient may present with relatively minor infections. Median duration 30 months. 95% normal by 4 years of age. If serious infection, consider G-CSF to boost counts.

Sequestration by reticuloendothelial system

E.g., as result of hypersplenism. Usually, other cell lines proportionally affected.

Marrow infiltration

Leukemia; metastatic lymphoma, rhabdomyosarcoma, Ewing sarcoma; myelofibrosis, osteopetrosis

Ineffective myelopoesis

B₁₂, folate deficiency (e.g., from long term TMP/SMX)
Starvation (anorexia, marasmus)
TPN

Marrow toxicity

Chemotherapy

Heme-Onc

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