Signs and symptoms of neutropenia include fever, painful swallowing, gingival pain, skin abscesses, and otitis. These symptoms may exist because individuals with neutropenia often have infection

Children may show signs of irritability, and poor feeding. Additionally, hypotension has also been observed in individuals who suffer from this condition

Neutropenia or neutropaenia 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. Patients with neutropenia are more susceptible to bacterial infections and, without prompt medical attention, the condition may become life-threatening (neutropenic sepsis).

Neutropenia can be acute (temporary) or chronic (long lasting). The term is sometimes used interchangeably with "leukopenia" ("deficit in the number of white blood cells").

Febrile neutropenia can develop in any form of neutropenia, but is most generally recognized as a complication of chemotherapy when it is myelosuppressive (suppresses the bone marrow from producing blood cells).

Agranulocytosis may be asymptomatic, or may clinically present with sudden fever, rigors and sore throat. Infection of any organ may be rapidly progressive (e.g., pneumonia, urinary tract infection). Septicemia may also progress rapidly.

Cyclic neutropenia is a disorder that causes frequent infections and other health problems in affected individuals. People with this condition have recurrent episodes of neutropenia during which there is a shortage (deficiency) of neutrophils. Neutrophils are a type of white blood cell that plays a role in inflammation and in fighting infection. The episodes of neutropenia are apparent at birth or soon afterward. For most affected individuals, neutropenia recurs every 21 days and lasts about 3 to 5 days.

Neutropenia makes it more difficult for the body to fight off pathogens such as bacteria and viruses, so people with cyclic neutropenia typically develop recurrent infections of the sinuses, respiratory tract, and skin. Additionally, people with this condition often develop open sores (ulcers) in the mouth and colon, inflammation of the throat (pharyngitis) and gums (gingivitis), recurrent fever, or abdominal pain. People with cyclic neutropenia have these health problems only during episodes of neutropenia. At times when their neutrophil levels are normal, they are not at an increased risk of infection and inflammation.

The term "agranulocytosis" derives from the Greek: "a", meaning without; granulocyte, a particular kind of white blood cell (containing granules in its cytoplasm); and "osis", meaning condition [esp. disorder]. Consequently, agranulocytosis is sometimes described as "no granulocytes", but a total absence is not required for diagnosis.

However, "-osis" is commonly used in blood disorders to imply cell proliferation (such as in "leukocytosis"), while "-penia" to imply reduced cell numbers (as in "leukopenia"); for these reasons, granulopenia is a more etymologically consistent term, and as such, is sometimes preferred to "agranulocytosis" (which can be misinterpreted as "agranulocyt-osis", meaning proliferation of agranulocytes (i.e. lymphocytes and monocytes). Despite this, "agranulocytosis" remains the most widely used term for the condition.

The terms agranulocytosis, granulocytopenia and neutropenia are sometimes used interchangeably. Agranulocytosis implies a more severe deficiency than granulocytopenia. Neutropenia indicates a deficiency of neutrophils (the most common granulocyte cell) only.

To be precise, neutropenia is the term normally used to describe absolute neutrophil counts (ANCs) of less than 500 cells per microlitre, whereas agranulocytosis is reserved for cases with ANCs of less than 100 cells per microlitre.

The following terms can be used to specify the type of granulocyte referenced:

- Inadequate numbers of neutrophils: neutropenia (most common)

- Inadequate numbers of eosinophils: eosinopenia (uncommon)

- Inadequate numbers of basophils: basopenia (very rare)

In a general sense the pathogenesis of neutropenia can be divided into two categories;

- Inadequate or ineffective formation of granulocytes. This can be due to bone marrow failure such that occurs in aplastic anaemia, several leukaemias and chemotherapeutic agents. There can also be isolated neutropenias where only differentiated granulocyte precursors are affected as in the case of neoplastic proliferation of cytotoxic T cells or NK cells

- Accelerated destruction of neutrophils. Immune-mediated reactions to neutrophils which can be caused by drugs. An enlarged spleen can lead to splenic sequestration and accelerated removal of neutrophils. Utilization of neutrophils can occur in infections

Monocytopenia is a form of leukopenia associated with a deficiency of monocytes. The causes of monocytopenia include: acute infections, stress, treatment with glucocorticoids, aplastic anemia, hairy cell leukemia, acute myeloid leukemia, treatment with myelotoxic drugs and genetic syndromes, as for example MonoMAC syndrome.

It has been proposed as a measure to predict neutropenia, though some research indicates that it is less effective than lymphopenia.

Anemia may lead to malaise, pallor and associated symptoms such as palpitations.

Low platelet counts (thrombocytopenia) if present is associated with an increased risk of hemorrhage, bruising and petechiae. Low white blood cell counts (leukocytopenia) if present leads to an increased risk of infections which can be severe.

Bone marrow suppression also known as myelotoxicity or myelosuppression, is the decrease in production of cells responsible for providing immunity (leukocytes), carrying oxygen (erythrocytes), and/or those responsible for normal blood clotting (thrombocytes). Bone marrow suppression is a serious side effect of chemotherapy and certain drugs affecting the immune system such as azathioprine. The risk is especially high in cytotoxic chemotherapy for leukemia.

Nonsteroidal anti-inflammatory drugs (NSAIDs), in some rare instances, may also cause bone marrow suppression. The decrease in blood cell counts does not occur right at the start of chemotherapy because the drugs do not destroy the cells already in the bloodstream (these are not dividing rapidly). Instead, the drugs affect new blood cells that are being made by the bone marrow. When myelosuppression is severe, it is called myeloablation.

Because the bone marrow is the manufacturing center of blood cells, the suppression of bone marrow activity causes a deficiency of blood cells. This condition can rapidly lead to life-threatening infection, as the body cannot produce leukocytes in response to invading bacteria and viruses, as well as leading to anaemia due to a lack of red blood cells and spontaneous severe bleeding due to deficiency of platelets.

Parvovirus B19 inhibits erythropoiesis by lytically infecting RBC precursors in the bone marrow and is associated with a number of different diseases ranging from benign to severe. In immunocompromised patients, B19 infection may persist for months, leading to chronic anemia with B19 viremia due to chronic marrow suppression.

Leukopenia can be identified with a complete blood count.

Below are blood reference ranges for various types leucocytes/WBCs. The 2.5 percentile (right limits in intervals in image, showing 95% prediction intervals) is a common limit for defining leukocytosis.

Febrile neutropenia is the development of fever, often with other signs of infection, in a patient with neutropenia, an abnormally low number of neutrophil granulocytes (a type of white blood cell) in the blood. The term neutropenic sepsis is also applied, although it tends to be reserved for patients who are less well. In 50% of cases, an infection is detectable; bacteremia (bacteria in the bloodstream) is present in approximately 20% of all patients with this condition.

Low white cell count may be due to acute viral infections, such as a cold or influenza. It has been associated with chemotherapy, radiation therapy, myelofibrosis, aplastic anemia (failure of white cell, red cell and platelet production), stem cell transplant, bone marrow transplant, HIV, AIDS, and steroid use.

Other causes of low white blood cell count include systemic lupus erythematosus, Hodgkin's lymphoma, some types of cancer, typhoid, malaria, tuberculosis, dengue, rickettsial infections, enlargement of the spleen, folate deficiencies, psittacosis, sepsis, Sjögren's syndrome and Lyme disease. It has also been shown to be caused by deficiency in certain minerals, such as copper and zinc.

Pseudoleukopenia can develop upon the onset of infection. The leukocytes (predominately neutrophils, responding to injury first) start migrating toward the site of infection, where they can be scanned. Their migration causes bone marrow to produce more WBCs to combat infection as well as to restore the leukocytes in circulation, but as the blood sample is taken upon the onset of infection, it contains low amount of WBCs, which is why it is termed "pseudoleukopenia".

Aplastic anemia is a rare disease in which the bone marrow and the hematopoietic stem cells that reside there are damaged. This causes a deficiency of all three blood cell types (pancytopenia): red blood cells (anemia), white blood cells (leukopenia), and platelets (thrombocytopenia). "Aplastic" refers to inability of the stem cells to generate mature blood cells.

It is most prevalent in people in their teens and twenties, but is also common among the elderly. It can be caused by heredity, immune disease, or exposure to chemicals, drugs, or radiation. However, in about half the cases, the cause is unknown.

The definitive diagnosis is by bone marrow biopsy; normal bone marrow has 30–70% blood stem cells, but in aplastic anemia, these cells are mostly gone and replaced by fat.

First line treatment for aplastic anemia consists of immunosuppressive drugs, typically either anti-lymphocyte globulin or anti-thymocyte globulin, combined with corticosteroids and ciclosporin. Hematopoietic stem cell transplantation is also used, especially for patients under 30 years of age with a related matched marrow donor.

Bone marrow suppression due to azathioprine can be treated by changing to another medication such as mycophenolate mofetil (for organ transplants) or other disease-modifying drugs in rheumatoid arthritis or Crohn's disease.

Diamond–Blackfan anemia is characterized by normocytic or macrocytic anemia (low red blood cell counts) with decreased erythroid progenitor cells in the bone marrow. This usually develops during the neonatal period. About 47% of affected individuals also have a variety of congenital abnormalities, including craniofacial malformations, thumb or upper limb abnormalities, cardiac defects, urogenital malformations, and cleft palate. Low birth weight and generalized growth delay are sometimes observed. DBA patients have a modest risk of developing leukemia and other malignancies.

Autoimmune neutropenia is a form of neutropenia which is most common in infants and young children where the body identifies the neutrophils as enemies and makes antibody to destroy them.

Primary autoimmune neutropenia (AIN) is an autoimmune disease first reported in 1975 that primarily occurs in infancy. In autoimmune neutropenia, the immune system produces autoantibodies directed against the neutrophilic protein antigens in white blood cells known as granulocytic neutrophils (granulocytes, segmented neutrophils, segs, polysegmented neutrophils, polys). These antibodies destroy granulocytic neutrophils. Consequently, patients with autoimmune neutropenia have low levels of granulocytic neutrophilic white blood cells causing a condition of neutropenia. Neutropenia causes an increased risk of infection from organisms that the body could normally fight easily.

Who is Affected?

Primary autoimmune neutropenia has been reported as early as the second month of life although most cases are diagnosed in children between 5 and 15 months of age. Girls have a slightly higher risk of developing AIN than boys. In neutropenia discovered at birth or shortly after birth, a diagnosis of allo-immune neutropenia (from maternal white blood cell antibodies passively transferred to the infant) is more likely.

Neutropenia

In infants neutropenia is defined by absolute neutrophil counts less than 1000/uL. After the first year of life neutropenia is defined by absolute counts less than 1500/uL. Neutropenia may be primary in which it is the only blood abnormality seen. In secondary neutropenia, other primary conditions occur, including other autoimmune diseases, infections, and malignancies. Neutropenia is considered chronic when it persists for more than 6 months.

Symptoms and Disease Course

Neutropenia, which may be discovered on routine blood tests, typically causes benign infections even when the condition is severe. Ear infections (otitis media) are the most common infection seen in autoimmune neutropenia and typically infection responds to antibiotic treatment alone. Infections associated with primary AIN are usually mild and limited, including skin infections such as impetigo, gastroenteritis, upper respiratory tract infections, and ear infections. Rarely, cellulitis and abscesses may occur.

Studies of children studied for up to six years showed that most cases of autoimmune neutropenia resolved spontaneously after a median of 17 months. In 80 percent of patients, neutropenia persisted for 7 to 24 months.

Diagnosis

Patients with autoimmune neutropenia are diagnosed on the basis of blood tests showing neutropenia and the presence of granulocyte-specific antibodies. In some cases, tests for granulocyte-specific antibodies need to be repeated several times before a positive result is seen. Bone marrow aspiration, if performed, is typically normal or it can show increased cell production with a variably diminished number of segmented granulocytes.

s association with prior parvovirus B19 has been made, but this hasn’t been confirmed. Similar to the platelet deficiency idiopathic thrombocytopenic purpura, vaccines are suspected of triggering this disorder.

Treatment

Treatment consists of corticosteroids to reduce autoantibody production, antibiotics to prevent infection and granulocyte colony-stimulating factor (G-CSF) to temporarily increase neutrophil counts. In cases of severe infection or the need for surgery, intravenous immunoglobulin therapy may be used.

Cytopenia is a reduction in the number of mature blood cells. It takes a number of forms:

- Low red blood cell count: resulting in anemia.

- Low white blood cell count: leukopenia or neutropenia. Because neutrophils make up at least half of all white cells, they are almost always low in leukopenia .

- Low platelet count: thrombocytopenia.

- Low granulocyte count: granulocytopenia

- Low red blood cell, white blood cell, and platelet counts: pancytopenia.

Myelokathexis is a congenital disorder of the white blood cells that causes severe, chronic leukopenia (a reduction of circulating white blood cells) and neutropenia (a reduction of neutrophil granulocytes). The disorder is believed to be inherited in an autosomal dominant manner. Myelokathexis refers to retention (kathexis) of neutrophils in the bone marrow (myelo). The disorder shows prominent neutrophil morphologic abnormalities.

Myelokathexis is amongst the diseases treated with bone marrow transplantation and cord blood stem cells.

WHIM syndrome is a very rare variant of severe congenital neutropenia that presents with warts, hypogammaglobunemia, infections, and myelokathexis. A gain in function mutation resulting in a truncated form of CXCR4 is believe to be its cause.

Cyclic neutropenia (or cyclical neutropenia) is a form of neutropenia, a white blood cell deficiency, that tends to occur every three weeks and lasts three to six days at a time due to changing rates of cell production by the bone marrow.

Cyclic neutropenia is the result of autosomal dominantly inherited mutations in ELA2, the gene encoding neutrophil elastase,

and is estimated to occur in 1 in 1 million individuals worldwide. Treatment includes G-CSF and usually improves after puberty.

X-linked thrombocytopenia is typically diagnosed in infancy. The disease presents as a bleeding disorder with easy bruising, mucosal bleeding, such as nosebleeds, and mild to severe anemia. Anemia is a condition in which there is an insufficient number of red blood cells to carry adequate levels of oxygen to the body’s tissues. X-linked thrombocytopenia is considered to be the milder phenotype of the "WAS"-related disorders. As age increases, the severity of symptoms tends to decrease. However, individuals with X-linked thrombocytopenia have an increased risk for life-threatening brain hemorrhages and spontaneous bleeding.

Diamond–Blackfan anemia (DBA) is a congenital erythroid aplasia that usually presents in infancy. DBA causes low red blood cell counts (anemia), without substantially affecting the other blood components (the platelets and the white blood cells), which are usually normal. This is in contrast to Shwachman–Bodian–Diamond syndrome, in which the bone marrow defect results primarily in neutropenia, and Fanconi anemia, where all cell lines are affected resulting in pancytopenia.

A variety of other congenital abnormalities may also occur in DBA.

The onset of HLH occurs under the age of 1 year in ~70% of cases. Familial HLH should be suspected if siblings are diagnosed with HLH or if symptoms recur when therapy has been stopped. Each full sibling of a child with familial HLH has a 25% chance of developing the disease, a 50% chance of carrying the defective gene (which is very rarely associated with any risk of disease) and a 25% chance of not being affected and not carrying the gene defect.

Patients with HLH, especially when untreated, may need intensive therapy. Therefore, HLH should be included in the differential diagnosis of ICU (Intensive Care Unit) patients with cytopenia and hyperferritinemia.

HLH clinically manifests with fever, enlargement of the liver and spleen, enlarged lymph nodes, yellow discoloration of the skin and eyes, and a rash.

The differential diagnosis of HLH includes secondary HLH and macrophage-activation syndrome or other primary immunodeficiencies that present with hemophagocytic lymphohistiocytosis, such as X-linked lymphoproliferative disease.

Other conditions that may be confused with this condition include autoimmune lymphoproliferative syndrome. As a syndrome of intense inflammation it needs to be differentiated from sepsis, what may be extremely challenging.

The diagnosis of acquired, or secondary, HLH is usually made in association with infection by viruses, bacteria, fungi, or parasites or in association with lymphoma, autoimmune disease, or metabolic disease. Acquired HLH may have decreased, normal, or increased NK cell activity.

The disease occurs much more in males than females (due to the X-linked recessive pattern of inheritance) and is estimated to occur in between 1 and 10 males per million. The first signs of WAS are usually petechiae and bruising, resulting from a low platelet count. Spontaneous nose bleeds and bloody diarrhea are common. Eczema develops within the first month of life. Recurrent bacterial infections develop by three months. Enlargement of the spleen is not an uncommon finding. The majority of WAS children develop at least one autoimmune disorder, and cancers (mainly lymphoma and leukemia) develop in up to a third of patients. Immunoglobulin M (IgM) levels are reduced, IgA and IgE are elevated, and IgG levels can be normal, reduced, or elevated. In addition to low blood platelet counts (i.e. thrombocytopenia), ~30% of afflicted individuals exhibit eosinophilia, i.e. high blood eosinophil counts.

X-linked thrombocytopenia, also referred to as XLT or thrombocytopenia 1, is an inherited clotting disorder that primarily affects males. It is a "WAS"-related disorder, meaning it is caused by a mutation in the Wiskott-Aldrich Syndrome ("WAS") gene, which is located on the short arm of the X chromosome. "WAS"-related disorders include Wiskott-Aldrich syndrome, XLT, and X-linked congenital neutropenia (XLN). Of the "WAS"-related disorders, X-linked thrombocytopenia is considered to be the milder phenotype. Between 1 and 10 per million males worldwide are affected with this disorder. Females may be affected with this disorder but this is very rare since females have two X chromosomes and are therefore typically carriers of the mutation.