Congenital Neutropenia is present at birth. Severe congenital neutropenia is also called Kostmann syndrome. It causes very low neutrophil levels. In some cases, neutrophils are absent. This puts infants and young children at risk for serious infections.
Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria, bacterial fragments and immunoglobulin-bound viruses in the blood. People with neutropenia are more susceptible to bacterial infections and, without prompt medical attention, the condition may become life-threatening (neutropenic sepsis).[rx]
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]
Types of Neutropenia
- Mild neutropenia – (1000 <= ANC < 1500): minimal risk of infection
- Moderate neutropenia – (500 <= ANC < 1000): moderate risk of infection
- Severe neutropenia – (ANC < 500): severe risk of infection.
Each of these are either derived from laboratory tests or via the formula below:
Normal WBC – 4,500 – 11,000 cells/mm.3
Neutrophil count – 40-60% of total WBC (ANC > 1,500 cells/mm3).
There are several types of neutropenia exist
- Congenital – Congenital neutropenia is present at birth. Severe congenital neutropenia is also called Kostmann syndrome. It causes very low neutrophil levels. In some cases, neutrophils are absent. This puts infants and young children at risk for serious infections.
- Cyclic – Cyclic neutropenia is present at birth. Cyclic neutropenia causes neutrophil counts to vary in a 21-day cycle. Neutrophil counts fall from normal to low. A period of neutropenia may last a few days. Normal levels follow for the rest of the cycle. The cycle then resets and begins again.
- Autoimmune – In autoimmune neutropenia, your body makes antibodies that fight your neutrophils. These antibodies kill the neutrophils, and this causes neutropenia. Autoimmune neutropenia develops later in life.
- Idiopathic – Idiopathic neutropenia develops any time in life and can affect anyone. The cause is unknown.
- Kostmann’s syndrome – This is a genetic disorder where neutrophils are produced at lower levels. People with Kostmann’s syndrome are prone to infections from an early age.
- Chronic idiopathic neutropenia – This is a relatively common version of neutropenia, predominantly affecting women.
- Myelokathexis – This is a condition in which neutrophils fail to move from the bone marrow (where they are created) to the bloodstream.
- Shwachman-Diamond syndrome – This is a rare genetic disorder with multiple effects including dwarfism, problems with the pancreas, and a low neutrophil count.
- Isoimmune neonatal neutropenia – This is a condition where a mother’s antibodies cross the placenta and attack the developing fetus’ neutrophils. This condition generally resolves itself within 2 months of life. It can be asymptomatic or result in sepsis.
Neutrophils play a role in the immune defense against extracellular bacteria, including Staphylococci, Streptococci, and Escherichia coli, among others. They also protect against fungal infections, including those produced by Candida albicans. Once their count is below 1 x 10/L recurrent infections start. As compensation, the monocyte count may increase. In primary neutropenia disorders such as chronic granulomatous disease presents with recurrent infections affecting many organs since childhood. It is caused from a failure to produce toxic reactive oxygen species so that the neutrophils can ingest the microorganisms, but they are unable to kill them, as a significant consequence granuloma can obstruct organs such as the stomach, esophagus, or bladder. Patients with this disease are very susceptible to opportunistic infections by certain bacteria and fungi, especially with Serratia and Burkholderia.[rx]
Leukocyte adhesion deficiency has an autosomal recessive inheritance, and its functional defect is a failure of neutrophils to adhere to endothelial cells and so to traverse into tissues to ingest and kill bacteria. Chediak-Higashi syndrome is also an autosomal recessive problem, characterized by abnormal chemotaxis, so neutrophils fail to reach bacteria, and reduced microbicidal activity as lysosomes fail to fuse with phagosomes.[rx]
Causes of Neutropenia
Adhere to endothelial cells
Migrate into inflammation sites (abnormal chemotaxis)
Ingest and kill bacteria
Produce microbicidal compounds to kill fungi and other pathogens
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
Antineutrophil or autoimmune neutropenia has been observed in
Rheumatoid arthritis (Felty syndrome)
Inflammatory bowel disease
Chronic autoimmune hepatitis
Granulomatosis with polyangiitis
Almost any infection can cause neutropenia. The condition is also seen with folate, vitamin B12, and copper deficiency.
- Aplastic anemia
- Evans syndrome
- Felty syndrome
- Systemic lupus erythematosus
- HIV/AIDS infection
- Glycogen storage disease
- Cohen syndrome
- Congenital immunological disorder, e.g. ELA2 mutation, GATA2 deficiency
- Barth syndrome
- Copper deficiency
- Vitamin B12 deficiency
- Pearson syndrome
- Pudlak syndrome
Other causes of congenital neutropenia are Shwachman–Diamond syndrome, Cyclic neutropenia, bone marrow failure syndromes, cartilage–hair hypoplasia, reticular dysgenesis, and Barth syndrome. Viruses that infect neutrophil progenitors can also be the cause of neutropenia. Viruses identified that have an effect on neutrophils are rubella and cytomegalovirus.[rx] Though the body can manufacture a normal level of neutrophils, in some cases the destruction of excessive numbers of neutrophils can lead to neutropenia. These are:[rx]
- Bacterial or fungal sepsis
- Necrotizing enterocolitis, circulating neutrophil population depleted due to migration into the intestines and peritoneum
- Alloimmune neonatal neutropenia, the mother produces antibodies against fetal neutrophils
- Inherited autoimmune neutropenia, the mother has autoimmune neutropenia
- Autoimmune neutropenia of infancy, the sensitization to self-antigens
Symptoms of Neutropenia
Neutropenia itself may not cause any symptoms. People usually find out they have neutropenia from a blood test or when they get an infection. Some people will feel more tired when they have neutropenia. Your doctor will schedule regular blood tests to look for neutropenia and other blood-related side effects of chemotherapy.
For people with neutropenia, even a minor infection can quickly become serious. Talk with your health care team right away if you have any of these signs of infection:
- A fever, which is a temperature of 100.5°F (38°C) or higher
- Chills or sweating
- Sore throat, sores in the mouth, or a toothache
- Abdominal pain
- Pain near the anus
- Pain or burning when urinating, or urinating often
- Diarrhea or sores around the anus
- A cough or shortness of breath
- Any redness, swelling, or pain (especially around a cut, wound, or catheter)
- Unusual vaginal discharge or itching
- sinus infections
- otitis media, or an ear infection
- gingivitis, or gum inflammation
- omphalitis, or navel infection
- skin abscesses
Diagnosis of Neutropenia
In Chediak-Higashi syndrome, histologically present with giant lysosomal granules in secretory cells. The 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
Infections caused by rare bacteria and fungi
Frequent use of antibiotics and antifungals
Delayed separation of umbilical cord
Sinus and lung infections, e.g., pneumonia
Coarse facial features
Extensive cutaneous bacterial (Staphylococcal) infections
Granuloma with catalase-positive organisms
Skin abnormalities, e.g., pyodermitis
Poor wound healing
- A complete blood count (CBC) measures neutrophil counts.
- Intermittent CBC tests can help your doctor check for changes in neutrophil count three times per week for six weeks.
- An antibody blood test checks for autoimmune neutropenia.
- Your doctor can use bone marrow aspirate to test bone marrow cells.
- A bone marrow trephine biopsy tests a piece of the bony part of bone marrow.
- Cytogenetic and molecular testing study the structures of cells.
Quantitative Serum Immunoglobulins
Blood Lymphocyte Subpopulations
B lymphocytes (CD19 and CD20)
Nitroblue tetrazolium (NBT) test (before and after stimulation with endotoxin)
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
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)
Cerebrospinal fluid (culture, chemistry, and histopathology)
Other investigations of immunodeficiency disorders
Complete blood cell count
Bone marrow biopsy
Levels of cytokines (granulocyte-colony stimulating factor)
Fluorescent in situ hybridization (FISH)
DNA testing (for most congenital disorders)
Laboratory diagnosis of neutropenia should be confirmed by review of peripheral blood smear or by a manual differential of the CBC. Once neutropenia is confirmed, an extensive history and physical exam should be taken to elucidate the underlying cause.
A complete blood cell count with manual white blood cell differentiation should be performed. Other tests may be needed to determine the underlying cause of neutropenia; however, some patients will need no further laboratory testing.
Other tests that can be performed to identify the cause are:
- Bone marrow aspiration/biopsy. Cytogenetic studies for monitoring for progression to MDS/AML.
- Antineutrophil antibody screens.
- HIV, hepatitis B testing.
- Metabolic studies: cooper, vitamin B12, folate levels.
- Chromosomal fragility/breakage studies.
- Pancreatic exocrine function study.
Treatment of Neutropenia
The following therapies can also treat infections that occur due to the disorder:
- anti-inflammatory drugs
- immunosuppressive drugs
- white blood cell transfusions
Application of granulocyte-colony stimulating factor (G-CSF) can improve neutrophil functions and numbers.[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]
Recombinant granulocyte-colony stimulating factor preparations, such as filgrastim[rx] can be effective in people with congenital forms of neutropenia including severe congenital neutropenia and cyclic neutropenia;[rx] the amount needed (dosage) to stabilize the neutrophil count varies considerably (depending on the individual’s condition).[rx]
Guidelines for neutropenia regarding diet are currently being studied.[rx]
Most cases of neonatal neutropenia are temporary. Antibiotic prophylaxis is not recommended because of the possibility of encouraging the development of multidrug-resistant bacterial strains.[rx]
Neutropenia can be treated with hematopoietic growth factors, granulocyte-colony stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF). These are cytokines (inflammation-inducing chemicals) that are present naturally in the body. These factors are used regularly in cancer treatment with adults and children. The factors promote neutrophil recovery following anticancer therapy.[rx]
The administration of intravenous immunoglobulins (IVIGs) has had some success in treating neutropenias of alloimmune and autoimmune origins with a response rate of about 50%. Blood transfusions have not been effective.[rx]
If neutropenia is caused by medication, your doctor might tell you to stop the medication. If the cause is an underlying disease, that condition must be treated (as in the case of a vitamin deficiency). Your doctor might prescribe corticosteroids if you have an autoimmune disorder.
Patients with neutropenia caused by cancer treatment can be given antifungal drugs. A Cochrane review [rx] found that lipid formulations of amphotericin B had fewer side effects than conventional amphotericin B, though it is not clear whether there are particular advantages over conventional amphotericin B if given under optimal circumstances. Another Cochrane review [rx] was not able to detect a difference in effect between amphotericin B and fluconazole because available trial data analyzed results in a way that disfavoured amphotericin B.
Recurrent and fatal bacterial and fungal infections[rx]
Failure to thrive
How can you prevent infections if you have neutropenia?
Preventing infections if you have or are liable to develop neutropenia is key. These suggestions should help:
- Wash your hands frequently with soap and water. Wash your hands before and after you eat, after you use the toilet, after touching pets or things outside of your house, and after you cough or sneeze.
- Keep and use an alcohol-based hand sanitizer with you when you leave the house.
- Make sure you get the flu shot as early as you can, if your doctor says you can do this.
- Stay away from crowds of people and people who are sick.
- Do not share eating utensils, cups, food or beverages with other people.
- Do not share towels, razors or toothbrushes with other people.
- Wash raw fruits and vegetables.
- Keep raw meats, fish and poultry away from other foods.
- Use hot water and soap to clean the kitchen surfaces before you start cooking.
- Cook foods completely to the proper temperature.
- Use gloves if you are gardening in the dirt or working in the yard.
- It is best to not pick up pet waste. If you have to do so, use gloves. Wash your hands when you are done.
- Use a soft toothbrush to brush your teeth at least two times per day.
- Take a shower each day. Use lotion so your skin does not dry out and crack.
- Eat a healthy diet.
- Tell your doctor if you might need dental work so he or she can prescribe antibiotics before the work is done, if necessary.
- Do not get body piercings or tattoos.
- Do not swim in lakes or ponds.
- Avoid becoming constipated if you can.
Lifestyle precautions for people with neutropenia include:
- cleaning hands regularly, especially after using the toilet
- avoiding crowds and people who are ill
- not sharing personal items including toothbrushes, drinking cups, cutlery, or food
- bathing or showering daily
- cooking meat and eggs thoroughly
- not buying food in damaged packages
- cleaning the fridge thoroughly and not overfilling – doing so can raise the temperature
- carefully washing any raw fruit or vegetables or avoiding completely
- avoiding direct contact with pet waste and washing hands after handling any animals
- wearing gloves when gardening
- using a soft toothbrush
- using an electric shaver rather than a razor
- cleaning any wounds with warm water and soap and using antiseptic to clean the site
- wearing shoes outdoors
- not squeezing spots or picking scabs
- keeping surfaces clean
- getting the flu shot as soon as it becomes available