Neutropenia: Practice Essentials, Background, Pathophysiology (original) (raw)

The list for all the potential causes of neutropenia is extensive. The etiology of neutropenia can conceptually be viewed in two broad ways, by mechanism or etiologic category.

The mechanisms that cause neutropenia are varied and not completely understood. In many cases, neutropenia occurs after prolonged exposure to a drug or other substance, resulting in decreased neutrophil production by hypoplastic bone marrow. This suggests a direct stem cell toxic effect. In other cases, repeated but intermittent drug or other exposure is needed. This suggests an immune mechanism, although this idea has not been proven. In many clinical situations, the exact exposure and its duration in relation to the onset of neutropenia are not known.

In view of this incomplete understanding of the mechanisms for neutropenia, classification by broad etiologic category is simpler to retain. In this schema, the etiology of neutropenia can be classified as either congenital (hereditary) or acquired.

Hereditary neutropenias

The Table below lists some of the genetic conditions that can lead to neutropenia. Of note, these syndromes are all rare.

Table 1. Genetic (Hereditary) Conditions in Neutropenia (Open Table in a new window)

Syndrome Inheritance Gene Clinical Features
Cyclic neutropenia Autosomal dominant ELA2 Alternate 21-day cycling of neutrophils and monocytes
Kostmann syndrome Autosomal recessive Unknown Stable neutropenia, no MDS or AML
Severe congenital neutropenia Autosomal dominant ELA2 (35-84%) Stable neutropenia, MDS, or AML
Autosomal dominant GFI1 Stable neutropenia, circulating myeloid progenitors, lymphopenia
Sex-linked Wasp A neutropenic variant of Wiskott-Aldrich syndrome
Autosomal dominant G-CSFR G-CSF–refractory neutropenia, no AML or MDS
Hermansky-Pudlak syndrome type 2 Autosomal recessive AP3B1 Severe congenital neutropenia, platelet dense-body defect, oculocutaneous albinism
Chediak-Higashi syndrome Autosomal recessive LYST Neutropenia, oculocutaneous albinism, giant lysosomes, impaired platelet function
Barth syndrome Sex-linked TAZ Neutropenia, often cyclic; cardiomyopathy, methylglutaconic aciduria
Cohen syndrome Autosomal recessive COH1 Neutropenia, intellectual disability, dysmorphism
Thrombocytopenia with absent radii (TAR) Autosomal recessive RBM8A Thrombocytopenia, MDS, absent radii, abnormal ulna
Diamond-Blackfan anemia Autosomal dominant, X-linked recessive RPS19, RPL5, RPS26 Macrocytic anemia, other cytopenias, solid tumors, short stature, abnormal thumbs, cardiac septal defect
Fanconi syndrome Autosomal recessive (rarely, X-linked recessive or autosomal dominant) FANCA, FANCC, FANCG Pancytopenia, solid tumors, skin hyperpigmentation and café au lait spots, abnormal thumbs
Dyskeratosis congenita X-linked recessive, autosomal dominant, autosomal recessive DKC1, TINF2 Pancytopenia, MDS, nail dystrophy, leukoplakia, solid tumors
Source: Modified from Berliner et al, 2004. [23] AML = acute myeloid leukemia; G-CSF = granulocyte colony-stimulating factor; MDS = myelodysplastic syndrome.

Congenital neutropenia with associated immune defects

Neutropenia with abnormal immunoglobulins is observed in individuals with X-linked agammaglobulinemia, isolated immunoglobulin A (IgA) deficiency, X-linked hyperimmunoglobulin M (XHIGM) syndrome, and dysgammaglobulinemia type I. [24] In XHIGM, which is due to mutations in the CD40 ligand, patients can have normal or elevated levels of IgM but markedly decreased serum IgG levels. In all these disorders, the infection risk is high, and the treatment is intravenous immunoglobulin (IVIG).

Patients with reticular dysgenesis demonstrate severe neutropenia, no cell-mediated immunity, agammaglobulinemia, and lymphopenia. [24] Life-threatening infections occur that are refractory to granulocyte colony-stimulating factor (G-CSF). [25, 26, 27] Bone marrow transplantation is the treatment of choice.

Congenital or chronic neutropenias

Severe congenital neutropenia (SCN), or Kostmann syndrome, is most often caused by a recessive inheritance and is found in remote, isolated populations with a high degree of consanguinity. [28] Autosomal dominant and sporadic cases have also been reported, most often due to mutations in the G-CSF receptor. No uniform genetic defect exists in this syndrome. Mutations in ELA2, which are causative for cyclic neutropenia (see below) are not sufficient to explain the phenotype of Kostmann-like SCN.

Patients present by age 3 months with recurrent bacterial infections. The mouth and perirectum are the most common sites of infection. This type of neutropenia is severe, and the treatment is G-CSF. The risk of conversion to myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML) with monosomy 7 after G-CSF treatments is associated with additional acquired mutations. Most of these cases are caused by a mutation in the G-CSF receptor. Patients whose condition responds clinically to G-CSF are treated for life.

Some patients with other forms of SCN appear to have mutations in GFI1, a zinc-finger transcriptional repressor gene involved in hematopoietic stem cell function and lineage commitment decisions.

Cyclic neutropenia (CN) is characterized by periodic bouts of neutropenia associated with infection, followed by peripheral neutrophil count recovery. Its periodicity is about 21 days (range, 12-35 d). Granulocyte precursors disappear from the marrow before each neutrophil nadir in the cycle because of the accelerated apoptosis of myeloid progenitor cells. [1] Some cases may be genetically determined with an autosomal recessive inheritance. Other cases may be due to an autosomal dominant inheritance. In some sporadic cases of CN, patients have mutations in ELA2.

People with CN typically present as infants or children, though acquired forms of CN in adulthood exist. The prognosis is good, with a benign course; however, 10% of patients can experience life-threatening infections. The treatment for cyclic neutropenia is daily G-CSF.

Chronic benign neutropenia

Familial chronic benign neutropenia, or benign ethnic neutropenia, is a disorder with an autosomal dominant pattern of inheritance observed in African, Yemenite Jewish, Ethiopian Jewish, Arab, Caribbean, and West Indian descent. In populations of African and Yemenite Jewish ancestry, genetic studies show a strong association with a single-nucleotide polymorphism in the DARC gene. Patients are typically asymptomatic, and the infections are mild. Affected individuals with chronic benign neutropenia do no thave an increased risk of infection and no specific therapy is required for this condition. [29]

In nonfamilial chronic benign neutropenias, mild infections with a benign course typify this disorder. The ANC, however, does respond to stress, such as infection, corticosteroids, and catecholamines.

Idiopathic chronic severe neutropenia

Idiopathic chronic severe neutropenia is a diagnosis of exclusion. Affected patients exhibit infections and severe neutropenia.

Neutropenia associated with phenotypic abnormalities

Shwachman syndrome (Shwachman-Diamond) has an autosomal recessive inheritance pattern. The neutropenia is moderate to severe, with a mortality rate of 15-25%, and the syndrome presents in infancy, with recurrent infections, diarrhea, and difficulty in feeding. Dwarfism, chondrodysplasia, and pancreatic exocrine insufficiency can occur.

Shwachman-Diamond syndrome and X-linked dyskeratosis congenita (DC), cartilage-hair hypoplasia (CHH), and Diamond-Blackfan anemia (DBA) all appear to share common gene defects involved in ribosome synthesis. Most cases of Shwachman-Diamond syndrome are caused by mutations in the SBDS gene. [30] The precise function of this gene is still being elucidated; however, it is involved in ribosome synthesis and RNA processing reactions. The treatment is G-CSF.

In CHH, the inheritance pattern is autosomal recessive on chromosome 9, and it is observed in Amish and Finnish families. CHH is caused by mutations in the RMRP gene, which encodes the RNA component of the ribonuclease mitochondrial RNA processing (RNase MRP) complex. The neutropenia is moderate to severe. CHH presents with cell-mediated immunity defects, macrocytic anemia, gastrointestinal disease, and dwarfism. It also shows a predisposition to cancer, especially lymphoma. The treatment is bone marrow transplantation.

Dyskeratosis congenita (Zinsser-Cole-Engman syndrome) presents with intellectual disability, pancytopenia, and defective cell-mediated immunity. Dyskeratosis congenita is more common in men as compared to women and is hematologically similar to Fanconi anemia. Dyskeratosis congenita is usually X-linked recessive, although autosomal dominant and autosomal recessive forms are also present.

The X-linked recessive form of the disorder has been linked to mutations in DKC1, which encodes dyskerin, a nucleolar protein associated with ribonucleoprotein particles. The autosomal dominant form is associated with mutations in another gene, TERC, which is part of telomerase. Telomerase has both a protein and RNA component, and TERC codes the RNA component. Patients with this disorder have shorter telomeres than normal. The treatment is G-CSF, granulocyte-macrophage colony-stimulating factor (GM-CSF), and bone marrow transplantation.

Barth syndrome is an X-linked recessive disorder presenting with cardiomyopathy in infancy, skeletal myopathy, recurrent infections, dwarfism, and moderate to severe neutropenia.

Chediak-Higashi syndrome is an autosomal recessive disorder with recurrent infections, mental slowing, photophobia, nystagmus, oculo-cutaneous albinism, neuropathy, bleeding disorders, gingivitis, and lysosomal granules in various cells. The neutropenia is moderate to severe, and the treatment is bone marrow transplantation.

Thrombocytopenia with absent radii syndrome (TAR) is an autosomal recessive disorder characterized by bilateral radial dysplasia and hyper megakaryocytic thrombocytopenia

Myelokathexis

Myelokathexis presents in infancy as moderate neutropenia and is associated with recurrent infections. The condition is due to accelerated apoptosis and decreased expression of bcl-x in neutrophil precursors. Neutrophils have an abnormal nuclear appearance, with hypersegmentation with nuclear strands, pyknosis, and cytoplasmic vacuolization. The treatment is G-CSF and GM-CSF.

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a severe congenital neutropenia caused by an autosomal dominant gain-of-function mutation in the CXCR4 gene encoding chemokine receptor type 4**.** Management includes treatment of infections and warts, correction of neutropenia with G-CSF, and supplementing immunoglobulin deficiency when present. Allogeneic hematopoietic stem cell transplantation has provided cures. CXCR4 blocking agents are undergoing clinical trials. [31]

Lazy leukocyte syndrome

Lazy leukocyte syndrome is a severe neutropenia with associated abnormal neutrophil motility. The etiology is unknown, and the treatment is generally supportive.

Metabolic disorders

These are chronic neutropenias with variable ANCs. They include glycogen storage disease type 1b and various acidemias, such as isovaleric, propionic, and methylmalonic. In glycogen storage disease type 1b, the treatment is G-CSF and GM-CSF.

Acquired neutropenias

Intrinsic bone marrow diseases that may cause neutropenia include the following:

Immune-mediated neutropenia

A drug may act as a hapten and induce antibody formation. This mechanism operates in cases due to gold, aminopyrine, and antithyroid drugs. The antibodies destroy the granulocytes and may not require the continued presence of the drug for their action. Alternatively, the drug may form immune complexes that attach to the neutrophils. This mechanism operates with quinidine.

Drug immune-mediated neutropenia may be caused by the following:

Autoimmune neutropenia is the neutrophil analog of autoimmune hemolytic anemia and idiopathic thrombocytopenic neutropenia. It should be considered in the absence of any of the common causes. Antineutrophil antibodies have been demonstrated in these patients. Autoimmune neutropenia may be associated with the following:

In isoimmune neonatal neutropenia, the mother produces IgG antineutrophil antibodies to fetal neutrophil antigens that are recognized as nonself. This occurs in 3% of live births. The disorder manifests as neonatal fever, urinary tract infection, cellulitis, pneumonia, and sepsis. The duration of the neutropenia is typically 7 weeks.

Chronic autoimmune neutropenia is observed in adults and has no age predilection. As many as 36% of patients will exhibit serum antineutrophil antibodies, and the clinical course is usually less severe. Patients can have this disorder in association with systemic lupus erythematosus, rheumatoid arthritis, Wegener granulomatosis, and chronic hepatitis.

If chronic autoimmune neutropenia is associated with these diseases, corticosteroids are indicated as treatment. In neonates and children, this disorder is associated with a lower risk of infection and milder infections involving the middle ear, gastrointestinal tract, and skin.

T-gamma lymphocytosis, or lymphoproliferative disorder, is a clonal disease of CD3+ T lymphocytes or CD3- natural killer (NK) cells that infiltrate the bone marrow and tissues. Also known as leukemia of large granular lymphocytes (LGL-leukemia), T-gamma lymphocytosis can be associated with rheumatoid arthritis and is associated with high-titer antineutrophil antibodies. The neutropenia is persistent and severe. The treatment is often supportive in nature, but it is also directed at eliminating the clonal population.

Infections

Infections are the most common form of acquired neutropenia. Infections that may cause neutropenia include, but are not limited to, the following:

The most commonly involved organisms are from endogenous flora, such as Staphylococcus aureus in cases of skin infections. Gram-negative organisms are observed in infections of the urinary and gastrointestinal tracts, particularly Escherichia coli and Pseudomonas species. Candida albicans infections may also occur. Mixed flora may be found in the oral cavity.

Viral infections often lead to mild or moderate neutropenia. Agranulocytosis is uncommon but may occur. The most common organisms are Epstein-Barr virus, hepatitis B virus, yellow fever virus, cytomegalovirus, and influenza. Many overwhelming infections, both viral and bacterial, may cause severe neutropenia.

Nutritional deficiency

Nutritional deficiencies that can cause neutropenia include vitamin B-12, folate, and copper deficiency.

Drugs and chemicals, excluding cytotoxic chemotherapy

Numerous drugs have been associated with neutropenia. Drug-induced neutropenia usually occurs within 6 months of starting the offending drug. Once the offending agent is stopped, neutrophil counts tend to recover within 1 week. Some drugs with a significantly high risk of neutropenia require weekly blood counts for monitoring (eg, clozapine, sulfasalazine). Other highest-risk categories include antithyroid medications, macrolides, and procainamides.

As stated above, many drugs act by an immune-mediated mechanism. However, some drugs appear to have direct toxic effects on marrow stem cells or neutrophil precursors in the mitotic compartment. For example, drugs such as antipsychotics, antidepressants, and chloramphenicol may act as direct toxins in some individuals, based on metabolism and sensitivity in this manner. Other drugs may have a combination of immune and nonimmune mechanisms or may have unknown mechanisms of action.

Antimicrobials include penicillin, cephalosporins, vancomycin, chloramphenicol, gentamicin, clindamycin, doxycycline, flucytosine, nitrofurantoin, novobiocin, minocycline, griseofulvin, lincomycin, metronidazole, rifampin, isoniazid, streptomycin, thiacetazone, mebendazole, pyrimethamine, levamisole, ristocetin, sulfonamides, chloroquine, hydroxychloroquine, quinacrine, ethambutol, dapsone, ciprofloxacin, trimethoprim, imipenem/cilastatin, zidovudine, fludarabine, acyclovir, and terbinafine. [32]

Analgesics and anti-inflammatory agents include indomethacin, ibuprofen, acetylsalicylic acid, diflunisal, sulindac, tolmetin, benoxaprofen, barbiturates, mesalazine, and quinine. Aminopyrine and dipyrone have been withdrawn from the market in many countries due to the risk of agranulocytosis.

Antipsychotics, antidepressants, and neuropharmacological agents include phenothiazines (chlorpromazine, methylpromazine, mepazine, promazine, thioridazine, prochlorperazine, trifluoperazine, trimeprazine), clozapine, risperidone, imipramine, desipramine, diazepam, chlordiazepoxide, amoxapine, meprobamate, thiothixene, and haloperidol.

Anticonvulsants include valproic acid, phenytoin, trimethadione, mephenytoin (Mesantoin), ethosuximide, and carbamazepine.

Antithyroid drugs include thiouracil, propylthiouracil, methimazole, carbimazole, potassium perchlorate, and thiocyanate.

Cardiovascular drugs include procainamide, captopril, aprindine, propranolol, hydralazine, methyldopa, quinidine, diazoxide, nifedipine, propafenone, ticlopidine, and vesnarinone.

Antihistamines include cimetidine, ranitidine, tripelennamine (Pyribenzamine), methaphenilene, thenalidine, brompheniramine, and mianserin.

Diuretics include acetazolamide, bumetanide, chlorothiazide, hydrochlorothiazide, chlorthalidone, methazolamide, and spironolactone.

Hypoglycemic agents include chlorpropamide and tolbutamide.

Antimalarial drugs include amodiaquine, dapsone, hydroxychloroquine, pyrimethamine, and quinine.

Miscellaneous drugs include allopurinol, colchicine, aminoglutethimide, famotidine, bezafibrate, flutamide, tamoxifen, penicillamine, retinoic acid, metoclopramide, phenindione, dinitrophenol, ethacrynic acid, dichlorodiphenyltrichloroethane (DDT), cinchophen, antimony, pyrithyldione, rauwolfia, ethanol, chlorpropamide, tolbutamide, thiazides, spironolactone, methazolamide, acetazolamide, IVIG, and levodopa.

Heavy metals include gold, arsenic, and mercury.

Exposure to drugs or chemicals is the most common cause of agranulocytosis: about one-half of patients have a history of medication or chemical exposure. Any chemical or drug that can depress the bone marrow and cause hypoplasia or aplasia is capable of causing agranulocytosis. Some drugs do this to everyone if they are administered in large enough doses. Other agents seem to cause idiosyncratic reactions that affect only certain susceptible individuals.

Some agents (eg, valproic acid, carbamazepine, and beta-lactam antibiotics) act by direct inhibition of myelopoiesis. In bone marrow cultures, these agents inhibit granulocyte colony formation in a dose-related fashion. Direct damage to the bone marrow microenvironment or myeloid precursors plays a role in most other cases.

Many drugs associated with agranulocytosis have been reported to the US Food and Drug Administration (FDA) under its adverse reactions reporting requirement. Many agents are also reported to a registry maintained by the American Medical Association (AMA). The reported drugs were used alone, in combination with another drug known to be potentially toxic, or with another drug without known toxicity. Several drugs are particularly salient because of their high frequency of association with agranulocytosis. They include the following:

Miscellaneous immunologic neutropenias

Immunologic neutropenias may occur after bone marrow transplantation and blood product transfusions.

Felty syndrome is a syndrome of rheumatoid arthritis, splenomegaly, and neutropenia. Splenectomy produces an initial response, but neutropenia may recur in 10-20% of patients. Treatment is directed toward rheumatoid arthritis.

In complement activation–mediated neutropenia, hemodialysis, cardiopulmonary bypass, and extracorporeal membrane oxygenation (ECMO) expose blood to artificial membranes and can cause complement activation with subsequent neutropenia.

In splenic sequestration, the degree of neutropenia resulting from this process is proportional to the severity of the splenomegaly and the bone marrow’s ability to compensate for the reduction in circulating bands and neutrophils.

Eosinopenia and basophilopenia

Eosinopenia may be associated with the following:

Decreased circulating basophils may be associated with the following:

Go to Pediatric Autoimmune Neutropenia for complete information on this topic.