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Acquired neutropenia caused by intrinsic bone marrow disease
Intrinsic bone marrow diseases that may cause neutropenia include the following:
Aplastic anemia
Hematologic malignancy (eg, leukemia, lymphoma, myelodysplasia, myeloma)
Ionizing radiation
Tumor infiltration
Granulomatous infection
Myelofibrosis
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. As an alternative, 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:
Aminopyrine
Quinidine
Cephalosporins
Penicillins
Sulfonamides
Phenothiazines
Phenylbutazone
Hydralazine
Other medications have been implicated.
Autoimmune neutropenia is the neutrophil analogue of autoimmune hemolytic anemia and of 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:
Crohn disease
Rheumatoid arthritis (with or without Felty syndrome)
Sj o gren syndrome
Chronic, autoimmune hepatitis
Hodgkin lymphoma
Systemic lupus erythematosus
Thymoma
Goodpasture disease
Wegener granulomatosis
Pure red blood cell (RBC) aplasia, in which there is complete disappearance of granulocyte tissue from the bone marrow; pure RBC dysplasia is a rare disorder due to the presence of antibody-mediated, granulocyte-macrophage colony forming unit (GM-CFU) inhibitory activity, and it is often associated with thymoma
Transfusion reactions, which can be caused by the surface antigens of neutrophilia; recipients of repeated granulocyte transfusions could become alloimmunized
Large granular lymphocyte proliferation or leukemia
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.
Acquired neutropenia caused by infection
Infections are the most common form of acquired neutropenia. Infections that may cause neutropenia include, but are not limited to, the following:
Bacterial sepsis
Viral infections (eg, influenza, measles, Epstein Barr virus [EBV], cytomegalovirus [CMV], viral hepatitis, human immunodeficiency virus [HIV]-1) (see first image below)
Toxoplasmosis
Brucellosis
Typhoid
Tuberculosis (see second and third images below)
Malaria
Dengue fever
Rickettsial infection
Babesiosis
Bilateral interstitial infiltrates in a 31-year-old patient with influenza pneumonia.
Anteroposterior chest radiograph in a young ED patient presenting with cough and malaise. The radiograph shows a classic posterior segment right upper lobe density consistent with active tuberculosis. This woman was admitted to isolation and started empirically on a 4-drug regimen in the ED. Tuberculosis was confirmed on sputum testing. Image courtesy of Remote Medicine, remotemedicine.org.
Lateral chest radiograph in a 31-year-old patient with influenza pneumonia. Image courtesy of Remote Medicine, remotemedicine.org.
The most commonly involved organisms are from endogenous flora. Staphylococcus aureus organisms are found 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.
Acquired neutropenia caused by nutritional deficiency
Nutritional deficiencies that can cause neutropenia include vitamin B-12, folate, and copper deficiency.
Acquired neutropenia caused by drugs and chemicals, excluding cytotoxic chemotherapy
Numerous drugs have been associated with neutropenia. The highest risk categories are 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 the antipsychotics and 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.
Analgesics and anti-inflammatory agents include aminopyrine, dipyrone, phenylbutazone, indomethacin, ibuprofen, acetylsalicylic acid, diflunisal, sulindac, tolmetin, benoxaprofen, barbiturates, mesalazine, and quinine.
Antipsychotics, antidepressants, and neuropharmacologic 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.
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17.03.2012, 20:37
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