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.[rx][rx]

Causes of Neutropenia

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

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.[rx] 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[rx][rx][rx]:

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

The physical findings include[rx][rx][rx][rx][rx]:

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.[rx][rx]

Quantitative Serum Immunoglobulins

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.[rx][rx] Prophylactic use of antibiotics and antifungals is reserved for some forms of alteration in neutrophil function such as chronic granulomatous disease CGD).[rx][rx] 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 [rx], 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.[rx]