Neutropenia – Causes, Symptoms, Diagnosis, Treatment

Neutropenia with decreased production with marrow hypoplasia can be primary and due to chronic benign neutropenia, cyclical neutropenia, and other congenital and familial neutropenias. It can be secondary to cytotoxic drugs, aplastic anemia, leukemia, drug reactions, and infections. Neutropenia, with increased destruction with marrow hyperplasia, is due to hypersplenism and immune neutropenia. Secondary causes are the commonest. For example, neutropenia caused as a side effect of chemotherapy for malignancies. Congenital forms are rare and vary in severity; some of them are life-threatening conditions including leukocyte adhesion deficiency, Chediak-Higashi syndrome, hyper-IgE, recurrent infection syndrome, and chronic granulomatous disease.

Causes of Neutropenia

The causes of primary defects of neutrophil function include failure of the following:

  • Adhere to endothelial cells
  • Migrate into inflammation sites (abnormal chemotaxis)
  • Ingest and kill bacteria
  • Produce microbicidal compounds to kill fungi and other pathogens
  • Form phagolysosomes
  • Make high concentrations of toxic reactive oxygen species

Low levels of neutrophils may be due to hypoplastic bone marrow, an infection, radiation exposure, tumor infiltration of the bone marrow, myelofibrosis, prolonged exposure to a drug, or a hereditary disorder. Congenital neutropenia or Kostmann syndrome is acquired in an autosomal recessive fashion.

Drugs known to cause neutropenia include:

  • Quinidine
  • Aminopyrine
  • Cephalosporin
  • Sulfonamides
  • Hydralazine
  • Penicillins
  • Heavy metals
  • Phenothiazine

Antineutrophil or autoimmune neutropenia has been observed in:

  • Rheumatoid arthritis (Felty syndrome)
  • Inflammatory bowel disease
  • Chronic autoimmune hepatitis
  • Granulomatosis with polyangiitis
  • Hodgkin lymphoma
  • Sjogren syndrome

Almost any infection can cause neutropenia. The condition is also seen with folate, vitamin B12, and copper deficiency.

Diagnosis of Neutropenia

In Chediak-Higashi syndrome, histologically present with giant lysosomal granules in secretory cells. Chronic granulomatous disease is characterized by the presence of granulomas, which are composed of histiocytes that can fuse to form multinucleated giant cells and might be surrounded by other immune cells such as lymphocytes and cover with collagen.

History and Physical

In neutropenia, there is a history of:

  • Recurrent infections
  • Infections caused by rare bacteria and fungi
  • Opportunistic infections
  • Frequent use of antibiotics and antifungals

The physical findings include:

  • Delayed separation of umbilical cord
  • Skin infections
  • Gingivitis
  • Deep abscesses
  • Peritonitis
  • Osteomyelitis
  • Lung abscesses
  • Pneumatoceles
  • Sinus and lung infections, e.g., pneumonia
  • Otitis media
  • Meningitis
  • Septicemia
  • Arthritis
  • Bacteremia
  • Fever
  • Coarse facial features
  • Mucocutaneous candidiasis
  • Cough
  • Malaise
  • Intestinal malabsorption
  • Bronchiectasis
  • Recurrent tonsillitis
  • Extensive cutaneous bacterial (Staphylococcal) infections
  • Sore throat
  • Purulent conjunctivitis
  • Granuloma with catalase-positive organisms
  • Skin abnormalities, e.g., pyodermitis
  • Splenomegaly
  • Diarrhea
  • Recurrent abscess
  • Aphthous stomatitis
  • Urinary sepsis
  • Vasculitis
  • Poor wound healing

Lab Test

The immunological investigation of a patient with neutropenia includes the assessment of immunoglobulins, complement system, and phagocytes.

Quantitative Serum Immunoglobulins

  • IgG
  • IgM
  • IgA
  • IgE

Blood Lymphocyte Subpopulations

  • B lymphocytes (CD19 and CD20)

Phagocytic Function

Nitroblue tetrazolium (NBT) test (before and after stimulation with endotoxin)

  • Unstimulated
  • Stimulated

Neutrophil mobility

  • In medium alone
  • In presence of chemoattractant

Complement System Evaluation

Measurement of individuals components by immunoprecipitation tests, ELISA, or Western blotting

  • C3 serum levels
  • C4 serum levels

Hemolytic assays

  • CH50

Complement system functional studies

  • Classical pathway assay (using IgM on a microtiter plate)
  • Alternative pathway assay (using LPS on a microtiter plate)
  • Mannose pathway assay (using mannose on a microtiter plate)

Microbiological studies

  • Blood culture
  • Urine culture
  • Stool culture
  • Sputum culture
  • Cerebrospinal fluid (culture, chemistry, and histopathology)

Other investigations of immunodeficiency disorders

  • Complete blood cell count
  • Bone marrow biopsy
  • Histopathological studies
  • Blood chemistry
  • Tumoral markers
  • Levels of cytokines (granulocyte-colony stimulating factor)
  • Chest x-ray
  • Diagnostic ultrasound
  • CT scan
  • Fluorescent in situ hybridization (FISH)
  • DNA testing (for most congenital disorders)

Treatment of Neutropenia

Application of granulocyte-colony stimulating factor (G-CSF) can improve neutrophil functions and number. Prophylactic use of antibiotics and antifungals is reserved for some forms of alteration in neutrophil function such as chronic granulomatous disease CGD). The utilization of antimicrobials is compulsory if recurrent infections exist. Interferon-gamma has been successfully used to improve the quality of life of the patient suffering from neutropenia. Allogenic bone marrow transplantation from an HLA-matched related donor can cure CGD but has a high mortality rate , and gene therapy is also a therapeutic option for treating disorders with neutropenia. Furthermore, intravenous immunoglobulins can be another option in the management of these disorders.

Complications

  • Recurrent and fatal bacterial and fungal infections
  • Bacteremia
  • Septic shock
  • Premature death
  • Failure to thrive
  • Protein-energy malnutrition
  • Multiorgan failure

References

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