Aetiology
Neutropenia may be acquired or congenital.
Acquired causes can be primary, arising within the bone marrow (leukaemia, lymphoma, and aplastic anaemia), or secondary (external causes such as infection, toxic effects, immune neutropenias, chronic inflammatory disease, and nutritional deficiency).
Congenital causes are usually inherited, but forms exist that are sporadic. Primary congenital causes are the bone marrow failure syndromes, which produce global failure of haematopoiesis, and isolated neutropenia syndromes, which produce selective failure of neutrophil production.
Secondary congenital causes are the immunodeficiency syndromes and inborn errors of metabolism.
Neutropenia usually renders the patient susceptible to bacterial and, less frequently, fungal infections, which can be life-threatening. The risk of viral and parasitic infection is not increased. There are a few conditions, such as immune neutropenias, in which neutropenia does not increase the risk of infection.
Infection
Infection is the most common cause of acquired neutropenia. The duration is usually brief. Bacteria, viruses, obligate intracellular pathogens, and parasites are all known causes.
Bacterial infection: bacterial sepsis or infection with Salmonella (typhoid) or brucella are most common.
Viral infection: HIV and hepatitis A, B, or C infection are important causes that must be excluded. Other viral causes include infectious mononucleosis, erythema infectiosum (parvovirus), influenza, respiratory syncytial virus, rubella, measles, varicella, and cytomegalovirus.
Obligate intracellular pathogens: causes include rickettsia and human granulocytic ehrlichiosis (a primary infection of granulocytes and macrophages).
Parasites: these are rare causes, and include malaria and leishmaniasis.
Drug or radiation toxicity
Drug-induced neutropenia is the second most common cause of acquired neutropenia.[10]
Cytotoxic chemotherapy produces neutropenia by destroying dividing myeloid progenitor cells; this is an expected effect directly related to the treatment's primary mechanism of action. Febrile neutropenia is commonly a dose-limiting toxicity of chemotherapy, resulting in treatment delays or decreased intensity.[15]
Late-onset neutropenia may occur following treatment with rituximab, but the mechanism of action is not clear.[16] A wide range of other medications produce neutropenia as an adverse drug reaction; those most likely to include antithyroid medications, macrolides, and procainamides. Severe agranulocytosis from a drug reaction is rare (1-10 patients per million population per year) and most frequently associated with clozapine, antithyroid drugs (thionamides), and sulfasalazine.[17][18][19][20]
Drug-induced neutropenia is more common in patients over 60 years of age, and women are more commonly affected than men.
Drug-induced neutropenia occurs by a number of mechanisms.
Antibody-mediated neutrophil destruction: the drug acts as an immunogenic hapten (a small molecule that can only elicit an immune response when bound to a larger carrier, such as a protein). The hapten stimulates the formation of antibodies, which then mediate the destruction of circulating neutrophils. Aminopyrine, propylthiouracil, penicillin, and gold compounds are the most common drugs associated with hapten formation.[21][22][23]
Acceleration of neutrophil apoptosis: antipsychotics (e.g., clozapine) produce metabolites that bind to the neutrophil, causing depletion of intracellular glutathione (an antioxidant), toxicity, and cell death.[23]
Complement-mediated lysis of neutrophils: the drug acts as an immunogenic hapten and stimulates the formation of antibodies. However, instead of directly attacking neutrophils, the antibodies activate complement, and neutrophils are destroyed by complement-mediated lysis.
Inhibition of haematopoiesis: drugs such as the beta-lactam antibiotics and some anticonvulsant drugs (carbamazepine and valproic acid) inhibit the production of granulocytes and macrophages in bone marrow. Ticlopidine, sulfasalazine, and chlorpromazine cause suppression of myeloid precursors in the bone marrow.[24]
Radiotherapy can cause neutropenia by producing direct radiation damage of dividing lymphoid stem and progenitor cells.
Acquired immune disease
Primary immune neutropenias are either autoimmune or alloimmune (immune response to non-self antigens from members of the same species). Neutropenia can also occur as part of a severe transfusion reaction.
Primary autoimmune neutropenia (AIN) in infancy: antibodies against neutrophil-specific antigen lead to splenic sequestration or complement lysis of neutrophils. The average age of onset is 6 to 12 months. Although the neutropenia is usually severe, life-threatening bacterial infection is rare. Most patients recover spontaneously in approximately 1 to 2 years.[25]
AIN in adults: the aetiology is the same as for primary AIN in infancy. In adults, AIN is often associated with chronic inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus, or Sjogren's syndrome.
Neonatal alloimmune neutropenia: neutrophil-specific antibodies from the serum of the mother react against antigens expressed on fetal neutrophils inherited from the father; these IgG antibodies enter the fetal circulation causing neutrophil destruction in utero and in the neonatal period. It can occur in a first pregnancy, and future pregnancies may be affected. Infection is rare, even if the neutropenia is severe. Spontaneous recovery usually occurs in approximately 11 weeks (range 3-28 weeks).
Acquired bone marrow disease
Acquired bone marrow disease compromises the production of normal neutrophils. There are 3 main types:
Aplastic anaemia: the autoimmune or toxic destruction of marrow haematopoietic stem cells, resulting in a pancytopenia.
Primary haematological malignancy: Hodgkin's and non-Hodgkin's lymphoma, myelodysplastic syndrome, acute or chronic myelogenous leukaemia, and acute or chronic lymphocytic leukaemia may all compromise production of neutrophils. The volume of dysfunctional malignant cells reduces the number of healthy, functional progenitor cells in the bone marrow.
Secondary malignancy: metastasis of solid tumours to the bone marrow can cause neutropenia by infiltration of the marrow space. Any tumour can metastasise to the bone marrow, but the most common are neuroblastoma in children, and breast, prostate, and lung cancer in adults. Metastasis to the bone marrow is a poor prognostic sign.
Nutritional deficiency
Nutritional deficiencies of B12, folate, and copper can cause neutropenia as well as anaemia. Neutropenia in people with alcohol-use disorder is attributed to nutritional deficiencies, most notably vitamin B12 and folate; direct alcohol-induced bone marrow toxicity is rare.
Vitamins B12 and folate are essential for DNA synthesis and their deficiency results in impaired haematopoiesis. The major effect is on erythroid cells, leading to anaemia, but myeloid cells are also affected, leading to neutropenia.
Copper deficiency produces anaemia and neutropenia by a mechanism that is not understood.
Inflammatory
Neutropenia can occur in the context of chronic inflammatory disease. The underlying mechanisms vary according to the condition.
Rheumatoid arthritis and systemic lupus erythematosus: the main mechanism of neutropenia is inflammatory. Large granular lymphocyte infiltration of the marrow compromises the production of mature neutrophils. However, patients can also develop an associated AIN.
Felty's syndrome: this is a syndrome of rheumatoid arthritis, splenomegaly, and neutropenia. Splenic sequestration and destruction of neutrophils is the major mechanism of neutropenia, but the trigger is unknown.
Sjogren's syndrome: the major mechanism is proposed to be autoimmune, similar to AIN.
Neutrophil maldistribution (pseudoneutropenia)
Neutrophils are distributed between the circulation (circulating pool) and the tissues (marginated pool). Redistribution or agglutination of neutrophils produces pseudoneutropenia.[2]
Increased neutrophil margination: redistribution of neutrophils into the marginated pool can lead to an apparent neutropenia in the circulating pool even though the total number of neutrophils is normal. This is a physiological variant of little pathological significance.
Increased neutrophil agglutination in the circulating pool leads to an underestimation of the neutrophil count when a blood sample is taken and processed. This is most commonly seen with anticoagulant treatment. The effect is also seen with paraproteinaemia, but this is a complex situation because the underlying causes of paraproteinaemia can also produce a true neutropenia.
Laboratory artifact: ethylenediaminetetraacetic acid (EDTA) is extensively used to prevent coagulation of blood samples for full blood count. However, if the sample is not processed soon enough, EDTA can cause agglutination of neutrophils in the sample tube, resulting in an underestimation of the neutrophil count. Repeating the measurement in a fresh sample reveals the error.
Congenital bone marrow failure syndromes
Severe congenital neutropenia and Kostmann's syndrome
Severe congenital neutropenias are a heterogeneous group of disorders. The first disorder described was Kostmann's disease, a syndrome of congenital agranulocytosis with autosomal-recessive inheritance. Many severe congenital neutropenias are now described, which can be autosomal dominant, autosomal recessive, X-linked, or sporadic neutropenia.
60% are related to mutations in the neutrophil elastase gene (ELA2). Kostmann's syndrome is specifically characterised by a mutation in the HAX1 gene and is autosomal recessive.[26]
Cytogenetic abnormalities may develop during the course of disease, indicating transformation into myelodysplastic syndrome or acute leukaemia. The most common abnormality is monosomy 7, accounting for 50% of cases. About 12% will develop acute leukaemia.[27][28][29]
Fanconi anaemia
Fanconi anaemia is usually autosomal recessive but can also be X-linked.
Mutations in 13 genes have been identified. The genes code for proteins that form a nuclear complex involved in the DNA damage response. However, the precise mechanism by which the mutations produce bone marrow failure is not known.
Shwachman-Diamond syndrome (SDS)
SDS is a rare autosomal-recessive disease that produces exocrine pancreatic dysfunction, neutropenia (which can be intermittent), and skeletal abnormalities.[30] In addition, the remaining neutrophils may be dysfunctional with impaired chemotaxis and motility.
Approximately 90% of patients harbour the SBDS gene, but the relationship of the mutation to bone marrow failure is not understood.[31]
Pearson's syndrome
Characterised by refractory sideroblastic anaemia with vacuolisation of bone marrow precursors, variable degrees of neutropenia and thrombocytopenia, and exocrine pancreatic failure.[32]
One of the mitochondriopathies, caused by mutations of mitochondrial DNA. Large deletions of mitochondrial DNA are a hallmark of this disease.[33]
Dyskeratosis congenita
Characterised by the triad of abnormal nails, reticulated skin rash, and leukoplakia. X-linked, autosomal-dominant, and autosomal-recessive inheritance patterns have been observed.
The genetic defects all decrease telomerase function. Telomeres maintain chromosomal stability, and the bone marrow is heavily dependent on telomere maintenance to maintain its high rate of proliferation. Loss of telomerase produces bone marrow failure. Mutations in the DKC1 gene are found in the X-linked form. Mutations in the TERC gene are associated with the autosomal-dominant form. Mutations in the NOP10 gene are associated with the autosomal-recessive form.
Griscelli's syndrome
Griscelli's syndrome is an autosomal-recessive syndrome comprised of albinism, neutropenia, thrombocytopenia, and haemophagocytic lymphohistiocytosis. Neurological changes, thought to be due to cerebral lymphohistiocytic infiltration, can occur.
Neutropenia is usually due to phagocytosis of neutrophils in the bone marrow by invading phagocytes (haemophagocytic syndrome).
There are 3 types of Griscelli's syndrome. Neutropenia is most frequently associated with type II Griscelli's syndrome, caused by a mutation in the RAB27a gene.
Barth's syndrome
This disorder produces neutropenia and cardiomyopathy.
Produced by mutations in the TAZ gene that result in cardiolipin deficiency and abnormal mitochondria.[34]
Congenital isolated neutropenia syndromes
Cyclic neutropenia
Produces a pattern of fluctuating neutropenia in which neutrophil counts cycle approximately every 21 days with a range from 14 to 36 days. Peak neutrophil levels in the cycle are normal, and nadirs reach 0 and last from 3 to 10 days. The condition is usually autosomal dominant with variable expression, but sporadic cases can also occur.
The genetic basis of the autosomal-dominant form is unknown. Sporadic cases are associated with mutations of the neutrophil elastase gene ELA2.[35]
Chronic idiopathic neutropenia
Describes patients with chronic neutropenia for which no cause can be found. It usually occurs in late childhood or adulthood. Neutrophil production is normal but the destruction of lymphocytes in the circulating pool is increased. Because of marrow reserve and adequate delivery of neutrophils to tissues, these patients do not develop recurrent infections.
The aetiology is unknown but is thought to be autoimmune, and approximately 35% of patients have a positive test for antineutrophil antibodies.[25] If this is confirmed, chronic idiopathic neutropenia would be classed as an immune neutropenia rather than a congenital neutropenia syndrome.
Myelokathexis
An autosomal-dominant disease that presents with moderate to severe neutropenia. The aetiology is incompletely understood, and may involve increased retention of neutrophils in the bone marrow. Neutrophils have a distinct morphology with cytoplasmic vacuoles and abnormal nuclei with hypersegmentation and only very thin filaments connecting the nuclear lobes. Most patients do not develop serious infections.[36]
Cohen's syndrome
Cohen's syndrome consists of multiple congenital anomalies with intellectual disability. The typical phenotype can include mild to severe psychomotor developmental delay, microcephaly, a cheerful disposition, characteristic facial features, childhood hypotonia and joint laxity, truncal obesity, intermittent neutropenia, progressive retinal dystrophy, and refractive myopia. It is an autosomal-recessive syndrome.
Neutropenia in these patients does not make them prone to infection. If neutropenia is diagnosed in the setting of Cohen's syndrome, no further work-up needs to be pursued.[37][38]
Mutations of the COH1 gene are present, but the normal function of the gene has not been definitively established. It is suggested that the COH1 gene product is involved in the sorting and trafficking of proteins within the cell, but it is unclear how the clinical features of the syndrome are produced.
Hermansky-Pudlak syndrome type II
Characterised by oculocutaneous albinism and platelet defects due to the absence of platelet dense bodies. It is an autosomal-recessive disorder. The neutropenia can be severe.
Caused by mutations that disrupt the adaptor protein-3 complex. This complex affects vesicular trafficking in melanocytes, platelets, cytotoxic T lymphocytes, and natural killer cells. The neutropenia is associated with decreased amounts of neutrophil elastase.[33]
P14 deficiency
Consists of partial albinism, short stature, and B-cell and cytotoxic T-cell deficiency. It is an autosomal-recessive condition and can produce severe neutropenia with an absolute neutrophil count <500/microlitre or <0.5 x 10^9/L.
Mutations in the MAPBIP gene are found.[33] The mutations decrease RNA stability, leading to decreased protein levels and aberrant lysosomal function.
Congenital immunodeficiency disease
Common variable immunodeficiency
A diverse autosomal-dominant syndrome of defective IgG, IgM, or IgA production and T-lymphocyte dysfunction.
Produced by gene mutations of TNFRSF13B, a mediator of isotype switching in B cells. The main effect is to prevent IgM production from being switched to IgG, IgA, and IgE. However, there are associated autosomal-recessive mutations that contribute to the diverse presentations of the disease.
The lack of IgG production and impairment of T-lymphocyte function produce neutropenia.[39]
X-linked agammaglobulinaemia
X-linked agammaglobulinaemia is an X-linked recessive disorder.
It is caused by a gene mutation in Bruton's tyrosine kinase (BTK). BTK is essential for B-cell maturation and mutations result in the production of immature B cells, which are incapable of synthesising antibodies.
The lack of IgG production produces neutropenia.[39]
Hyper IgM syndrome
Produced by an inability to switch antibody production from IgM to IgG, IgA, and IgE.
The lack of IgG production produces neutropenia.
Due to defects in CD40 signalling. CD40 is a surface receptor that enables T cells to signal a shift in IgG production by B-cells. Mutations of the receptor or its signalling cascade prevent T cells from signalling a shift in immunoglobulin (Ig) production.
The most common form is X-linked recessive, produced by a gene mutation of the receptor (CD40L). There are 4 additional autosomal-recessive forms. These are rare and affect proteins in the CD40 signalling pathway.[39]
Cartilage-hair hypoplasia
Produces short-limb dwarfism and immunodeficiency.
An autosomal-recessive disorder produced by a mutation of RMRP, a ribonucleoprotein essential for cell growth.
Neutropenia is predominantly due to defects in the T-cell system. It is unclear how the underlying mutation produces the immune deficits.[39]
Reticular dysgenesis
Produces a severe neutropenia due to the absence of lymphoid cells from the bone marrow.
The inheritance is autosomal recessive. The underlying genetic mutation is unknown.[39]
WHIM syndrome
A syndrome of warts, hypogammaglobulinaemia, infections, and myelokathexis (WHIM).
Produced by hypogammaglobulinaemia, which leads to neutropenia and extensive human papillomavirus (HPV) infection. The peripheral neutrophil counts are low from birth, but bone marrow is generally hypercellular with increased numbers of mature neutrophils. T-cell dysfunction can also be seen.
There is a selective lack of immunity to HPV; immunity to all other viruses is usually normal.
The majority of patients have a heterozygous mutation of the CXCR4 gene (which regulates release of neutrophils from the bone marrow) leading to retention of neutrophils in the bone marrow.[40]
Chediak-Higashi syndrome
A syndrome of partial albinism, mild bleeding diathesis, severe immunodeficiency, moderate neutropenia, and progressive neurological defects; 85% of patients will develop a monoclonal lymphohistiocytic infiltration of multiple organs leading to multiorgan system failure.[41]
Circulating granulocytes have a distinct appearance with very large azurophilic granules in all myelocytic lineages; this is pathognomonic.
Inheritance is autosomal recessive with mutations in the LYST gene. Loss of this protein modifies the normal regulation of secretory lysosomes, leading to dysregulated immune cell function and hypopigmentation.
Schimke's immuno-osseous dysplasia
A rare autosomal-recessive disorder that presents with variable multisystem clinical problems. These include spondyloepiphyseal dysplasia, growth retardation, proteinuria and renal failure, lymphopenia, neutropenia and other cytopenias, and defective cellular immunity.
Produced by mutations in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin gene, SMARCAL1.
Wiskott-Aldrich syndrome
An X-linked recessive syndrome characterised by thrombocytopenia with low platelet volume, immune deficiency, and eczema.
Results from activating mutations in the gene encoding the Wiskott-Aldrich syndrome protein, involved in the regulation of the actin cytoskeleton. Dysregulation of the cytoskeleton disrupts a wide range of white cell functions.
Inborn errors of metabolism
Neutropenia can be associated with several inborn errors of metabolism including glycogen storage disease 1B, methylmalonic aciduria, Neumann-Pick disease, and Gaucher's disease. The precise mechanism of the neutropenia in these patients is unknown, but may be due to apoptosis of neutrophils stimulated by the accumulation of metabolites in the cytoplasm and impaired energy production.
Use of this content is subject to our disclaimer