OUTLINEBAB IPENDAHULUANNeutropenia dapat terjadi akibat gangguan pembentukan neutrofil, pergeseran neutrofil ke jaringan, meningkatnya konsumsi neutrofil, serta meningkatnya destruksi neutrofil di sirkulasi. Gangguan pembentukan neutrofil dapat terjadi akibat infiltrasi sel ganas dan efek mielosupresif kemoterapi. Kondisi neutropenia juga dapat disebabkan oleh defisiensi imun akibat perjalanan penyakit keganasan, efek samping kemoterapi ataupun reaksi transfusi. Infiltrasi keganasan dapat terjadi secara primer (leukemia) maupun sekunder (limfoma maligna, neuroblastoma, retinoblastoma, rabdomiosarkoma). Infeksi yang terkait dengan neutropenia pasca kemoterapi merupakan salah satu penyebab morbiditas dan mortalitas yang cukup sering pada pasien kanker. Neutropenia pasca kemoterapi selain akan memperpanjang lama rawat dan meningkatkan risiko infeksi, juga menyebabkan tertundanya pemberian kemoterapi dan pengurangan dosis kemoterapi. Hematopoietic growth-stimulating factor adalah sitokin yang mengatur proliferasi, diferensiasi dan fungsi sel hematopoietik. Penggunaan granulocyte colony-stimulating factor (G-CSF) dan granulocytemacrophage colony-stimulating foctor(GM-CSF) saat ini banyak diteliti pada pasien kanker yang berisikomengalami neutropenia. Pemberian G-CSF pada manusia menyebabkan peningkatan neutrofil yang bersirkulasi karena berkurangnya masa transit dari sel induk menjadi neutrofil matur, oleh karenanya zat ini sering dipakai untuk mengatasi neutropenia. Tujuan penulisan referat ini untuk mengetahui kegunaannya pada pasien keganaasan yang mengalami neutropenia.

BAB IITINJAUAN PUSTAKA

Hematopoietic growth-stimulating factor adalah sitokin yang mengatur proliferasi, diferensiasi dan fungsi sel hematopoietik. Granulosit macrophage colony stimulating factor ( GM - CSF) , juga dikenal sebagai colony stimulating factor 2 ( CSF2 ) , adalah glikoprotein monomer yang disekresikan oleh makrofag , sel T , sel mast , sel NK , sel-sel endotel dan fibroblas yang berfungsi sebagai sitokin yang untuk menghasilkan granulosit (neutrofil, eosinofil, dan basofil) dan monosit batang. Monosit keluar sirkulasi dan bermigrasi ke dalam jaringan yang akan menjadi makrofag dan sel dendritik. GM-CSF juga berperan dalam perkembangan embrio dengan berfungsi sebagai embryokine dihasilkan oleh saluran reproduksi.Penggunaan medisGM-CSF diproduksi menggunakan teknologi DNA rekombinan dan dipasarkan sebagai protein yang disebut molgramostim terapeutik atau, sargramostim. Hal ini digunakan sebagai obat untuk merangsang produksi sel darah putih dan dengan demikian mencegah neutropenia setelah kemoterapi. Contohnya : sargramostim.Granulosit-colony stimulating factor (G-CSF atau GCSF), juga dikenal sebagai colony-stimulating factor 3 (CSF 3), adalah glikoprotein yang merangsang sumsum tulang untuk menghasilkan granulosit dan sel batang dan melepaskan mereka ke dalam aliran darah. Secara fungsional, itu adalah sitokin dan hormon, jenis colony-stimulating factor, dan diproduksi oleh sejumlah jaringan yang berbeda. Para analog farmasi alami G-CSF disebut filgrastim dan lenograstim. G-CSF adalah jenis faktor pertumbuhan yang membuat tubuh memproduksi sel-sel darah putih untuk mengurangi risiko infeksi setelah beberapa jenis pengobatan kanker. G-CSF juga merangsang kelangsungan hidup, proliferasi, diferensiasi, dan fungsi prekursor neutrofil dan neutrofil matang. G-CSF mengatur mereka menggunakan Janus kinase (JAK) / sinyal transduser dan penggerak transkripsi (STAT) dan Ras / mitogen-activated protein kinase (MAPK) dan phosphatidylinositol 3-kinase (PI3K) / protein kinase B (Akt) jalur transduksi sinyal

Neutropenia is a decrease in circulating neutrophils in the nonmarginal pool, which constitutes 4-5% of total body neutrophil stores.[1]Most of the neutrophils are contained in the bone marrow, either as mitotically active (one third) or postmitotic mature cells (two thirds).[2, 3, 4]Granulocytopenia is defined as a reduced number of blood granulocytes, namely neutrophils, eosinophils, and basophils. However, the term granulocytopenia is often used synonymously with neutropenia and, in that sense, is again confined to the neutrophil lineage alone.The risk of serious infection increases as the absolute neutrophil count (ANC) falls to the severely neutropenic range (< 500/L). The duration and severity of neutropenia directly correlate with the total incidence of all infections and of those infections that are life threatening. Tuberculosis (see the image below) is one type of infection that may cause neutropenia.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.Signs and symptomsCommon presenting symptoms of neutropenia include the following: Low-grade fever Sore mouth Odynophagia Gingival pain and swelling Skin abscesses Recurrent sinusitis and otitis Symptoms of pneumonia (eg, cough, dyspnea) Perirectal pain and irritationPatients with agranulocytosis usually present with the following: Sudden onset of malaise Sudden onset of fever, possibly with chills and prostration Stomatitis and periodontitis accompanied by pain Pharyngitis, with difficulty swallowingLung infections are usually bacterial or fungal pneumonias. Physical findings on examination of a patient with neutropenia may include the following: Fever Stomatitis Periodontal infection Cervical lymphadenopathy Skin infection: The skin examination focuses on rashes, ulcers, or abscesses Splenomegaly Associated petechial bleeding Perirectal infection Growth retardation in childrenIn agranulocytosis, the following may be present: Fever (often 40C or higher) Rapid pulse and respiration Hypotension and signs of septic shock if infection has been present Painful aphthous ulcers in the oral cavity Swollen and tender gumsSeeClinical Presentationfor more detail.DiagnosisPrevious to a major workup, rule out infectious and drug-induced causes of neutropenia; then, obtain the following laboratory studies: Complete blood count: Including a manual differential in evaluating cases of agranulocytosis Differential white blood cell count Peripheral smear review by a pathologistThe following studies are applicable in some patients with neutropenia: Antinuclear antibody Rheumatoid factor Serum immunoglobulin studies[5] Liver function tests Peripheral blood flow cytometry T-cell gene rearrangement for T-cell clonality Paroxysmal nocturnal hemoglobinuria testing: By high-sensitivity or fluorescent aerolysin (FLAER)based flow cytometry Antineutrophil antibodies: Tests for antineutrophil antibodies should be performed in patients with a history suggestive of autoimmune neutropenia and in those with no other obvious explanation for agranulocytosisConcurrent anemia, thrombocytopenia, and/or an abnormal result on a peripheral blood smear from a patient with neutropenia suggest an underlying hematologic disorder. In this setting, immediately perform a bone marrow aspiration and obtain a biopsy from the posterior iliac crest. Cytogenetic analysis and cell-flow analysis of the aspirate may be indicated.SeeWorkupfor more detail.ManagementGeneral measures to be taken in patients with neutropenia include the following: Remove any offending drugs or agents in cases involving drug exposure: If the identity of the causative agent is not known, stop administration of all drugs until the etiology is established Use careful oral hygiene to prevent infections of the mucosa and teeth Avoid rectal temperature measurements and rectal examinations Administer stool softeners for constipation Use good skin care for wounds and abrasions: Skin infections should be managed by someone with experience in the treatment of infection in neutropenic patientsAntibioticsStart specific antibiotic therapy to combat infections. This often involves the use of fourth-generation cephalosporins or equivalents. Fever may be treated as an infection, as follows[6, 7, 8, 4, 9, 10, 11, 12]: Cefepime, meropenem, imipenem-cilastatin, or piperacillin-tazobactam can be used empirically as a single agent Gentamicin or another aminoglycoside should be added if the neutropenic patients condition is unstable or the individual appears septic Vancomycin should be added if infection with methicillin-resistantStaphylococcus aureusor aCorynebacteriumspecies is suspectedA guideline from the American Society of Clinical Oncology (ASCO) recommends that physicians attempt to prevent infection in outpatients with "profound" neutropenia but no fever. It advises using antibacterial and antifungal prophylaxis if neutrophils are expected to remain below 100/L for more than 7 days. The guideline states that the preferable agent for antibacterial prophylaxis is an oral fluoroquinolone, while that for antifungal prophylaxis is an oral triazole.[13, 14]A priority of the new ASCO guideline is to help clinicians identify patients with febrile neutropenia who do not need to be fully hospitalized. The guideline therefore calls for complication risk in patients with febrile neutropenia to be assessed with the Multinational Association for Supportive Care in Cancer (MASCC) scoring system or with Talcott's rules.[13, 14]SplenectomyIn individuals with neutropenia and Felty syndrome who have recurrent, life-threatening bacterial infections, splenectomy is the treatment of choice, though the response is often short-lived. Systemic lupus associated with autoimmune agranulocytosis may also respond to splenectomy or to immunosuppressive therapy.[15]BackgroundNeutropenia is a decrease in circulating neutrophils in the nonmarginal pool, which constitutes 4-5% of total body neutrophil stores.[1]Most of the neutrophils are contained in the bone marrow, either as mitotically active (one third) or postmitotic mature cells (two thirds).[2, 3, 4]Granulocytopenia is defined as a reduced number of blood granulocytes, namely neutrophils, eosinophils, and basophils. However, the term granulocytopenia is often used synonymously with neutropenia and, in that sense, is again confined to the neutrophil lineage alone.Neutropenia is defined in terms of the absolute neutrophil count (ANC). The ANC is calculated by multiplying the total white blood cell (WBC) count by the percentage of neutrophils (segmented neutrophils or granulocytes) plus the band forms of neutrophils in the complete blood count (CBC) differential. See theAbsolute Neutrophil Countcalculator.Note that many modern automated instruments actually calculate and provide the ANC number in their reports. These instruments do not analyze separately bands from segmented neutrophils, and so the combined number is termed the absolute neutrophil count (ANC), representing both bands and more mature segmented neutrophils. If a band number is reported separately, usually by smear review, then one can divide the ANC into bands and segmented neutrophils by subtracting the absolute band number from the total ANC.The lower limit of the reference value for ANC in adults varies in different laboratories from 1.5-1.8 109/L or 1500-1800/L (mm3). For practical purposes, a value lower than 1500 cells/L is generally used to define neutropenia. Age, race, genetic background, environment, and other factors can influence the neutrophil count. For example, blacks may have a lower but normal ANC value of 1000 cells/L, with a normal total WBC count.Neutropenia is classified as mild, moderate, or severe, based on the ANC. Mild neutropenia is present when the ANC is 1000-1500 cells/L, moderate neutropenia is present with an ANC of 500-1000/L, and severe neutropenia refers to an ANC lower than 500 cells/L. The risk of bacterial infection is related to both the severity and duration of the neutropenia.The term agranulocytosis is used to describe a more severe subset of neutropenia. Agranulocytosis refers to a virtual absence of neutrophils in peripheral blood. It is usually applied to cases in which the ANC is lower than 100/L.[3, 16, 17, 18]The reduced number of neutrophils makes patients extremely vulnerable to infection.[3, 19]Cardinal symptoms include fever, sepsis, and other manifestations of infection. Causes can include drugs, chemicals, infective agents, ionizing radiation, immune mechanisms, primary bone marrow failure syndromes, and heritable genetic aberrations.This article is limited to discussing neutropenia (ANC < 1500/L) and agranulocytosis (ANC < 100/L). It does not address the transient neutropenia associated with cancer chemotherapy, nor does it consider agranulocytosis occurring as part of primary marrow-failure syndromes (eg,aplastic anemia, pancytopenia, acute leukemia, myelodysplastic syndromes)Mature neutrophils are produced by precursors in the bone marrow. The total body neutrophil content can be divided conceptually into the following three compartments: the bone marrow, the blood, and the tissues. In the marrow, the neutrophils exist in two divisions: the proliferative, or mitotic, compartment (myeloblasts, promyelocytes, myelocytes) and the maturation-storage compartment (metamyelocytes, bands, mature neutrophils, polymorphonuclear leukocytes ["polys"]).Neutrophils leave the marrow storage compartment and enter the blood without reentry into the marrow. In the blood, two compartments are also present, the marginal compartment and the circulating compartment. Some neutrophils do not circulate freely (marginal compartment), but are adherent to the vascular surface, and these constitute approximately half of the total neutrophils in the blood compartment.Neutrophils leave the blood pool in a random manner after 6-8 hours and enter the tissues, where they are destined for cellular action or death. Thus, if the process producing neutropenia is unknown, measurements of the blood neutrophil number, ANC, must often be supplemented by bone marrow examination to determine whether adequate production of neutrophils or increased destruction of neutrophils exists.Sites and mechanisms that cause neutropenia can be restricted to any of the three compartments or their subcomponents: bone marrow (mitotic or mature storage pools); blood (circulating and marginal pools); or tissues (sequestration). For example, benign congenital neutropenias are associated with a decrease in only the pool of circulating neutrophils; affected individuals have entirely normal marrow pools, marginal blood pools, and tissue neutrophils.Neutropenia can be caused by any of the following, alone or in combination: Insufficient or injured bone marrow stem cells Shifts in neutrophils from the circulating pool to the marginal blood or tissue pools Increased destruction in the circulationIntravascular stimulation of neutrophils by plasma-activated complement 5 (C5a) and endotoxin may cause increased margination along the vascular endothelium, decreasing the number of circulating neutrophils. Pseudoneutropenia refers to neutropenia caused by such increased margination.[2, 20, 21, 22, 23]Disorders of the pluripotent myeloid stem cells and committed myeloid progenitor cells, which cause decreased neutrophil production, include some congenital forms of neutropenia,aplastic anemia, acute leukemia, andmyelodysplastic syndromes. Other examples include bone marrow tumor infiltration, radiation, infection (especially viral), and bone marrow fibrosis. Cancer chemotherapy, other drugs, and toxins may damage hematopoietic precursors by directly affecting bone marrow.The clinical sequelae of neutropenia usually manifests as infections, most commonly of the mucous membranes. Skin is the second most common infection site, manifesting as ulcers, abscesses, rashes, and delays in wound healing. The genitalia and perirectum are also affected. However, the usual clinical signs of infection, including local warmth and swelling, may be absent, as these require the presence of significant numbers of neutrophils. Fever, however, is often present, and its presence requires urgent attention in the setting of severe neutropenia.The risk of serious infection increases as the ANC falls to the severely neutropenic range (< 500/L). The duration and severity of neutropenia directly correlate with the total incidence of all infections and those infections that are life threatening. When the ANC is persistently lower than 100 cells/L for longer than 3-4 weeks, the incidence of infection approaches 100%. In prolonged severe neutropenia, life-threatening gastrointestinal and pulmonary infections occur, as does sepsis. However, patients with neutropenia are not at increased risk for parasitic and viral infections, as these are defended by innate and lymphocyte-mediated immune mechanisms.Bacterial organisms most often cause fever and infection in neutropenic patients. Fungal organisms are also significant pathogens in the setting of neutropenia. Historically, gram-negative aerobic bacteria (eg,Escherichia coli,Klebsiellaspecies,Pseudomonas aeruginosa) have been most common in these patients. However, gram-positive cocci, especiallyStaphylococcusspecies andStreptococcus viridans, have emerged as the most common pathogens in fever and sepsis because of the increasing use of indwelling right atrial catheters.After neutropenic patients receive treatment with broad-spectrum antibiotics for several days, superinfection with fungi is common.Candidaspecies are the most frequently encountered organisms in this setting.The list for all the potential causes of neutropenia is not short. 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. Though this categorization may have limited clinical diagnostic utility, it can be useful to clearly separate hereditary causes of neutropenia from the panoply of acquired causes. In the setting of hereditary neutropenias, these disorders can be further described as associated with isolated neutropenia or with other defects, whether immune or phenotypic.Many hereditary disorders are due to mutations in the gene encoding neutrophil elastase,ELA2.Several alleles are involved. The most common mutations are intronic substitutions that inactivate a splice site in intron 4. Genes other thanELA2are also involved. The Table below lists some of the genetic conditions involved; these are uncommon conditions.Table 1. Genetic (Hereditary) Conditions in Agranulocytosis[24](Open Table in a new window)SyndromeInheritanceGeneClinical Features

Cyclic neutropeniaAutosomal dominantELA2Alternate 21-day cycling of neutrophils and monocytes

Kostmann syndromeAutosomal recessiveUnknownStable neutropenia, no MDS or AML

Severe congenital neutropeniaAutosomal dominantELA2(35-84%)Stable neutropenia, MDS or AML

Autosomal dominantGFI1Stable neutropenia, circulating myeloid progenitors, lymphopenia

Sex linkedWaspNeutropenic variant of Wiskott-Aldrich syndrome

Autosomal dominantG-CSFRG-CSFrefractory neutropenia, no AML or MDS

Hermansky-Pudlak syndrome type 2Autosomal recessiveAP3B1Severe congenital neutropenia, platelet dense-body defect, oculocutaneous albinism

Chediak-Higashi syndromeAutosomal recessiveLYSTNeutropenia, oculocutaneous albinism, giant lysosomes, impaired platelet function

Barth syndromeSex linkedTAZNeutropenia, often cyclic; cardiomyopathy, methylglutaconic aciduria

Cohen syndromeAutosomal recessiveCOH1Neutropenia, mental retardation, dysmorphism

Source: Modified from Berliner et al, 2004.[24]

AML = acute myeloid leukemia; G-CSF = granulocyte colony-stimulating factor; MDS = myelodysplastic syndrome.

Causes of acquired neutropenia are complex, but most are related to three major categories: infection, drugs (both direct toxic or immune mediated), and autoimmune. Chronic benign neutropenia, or chronic idiopathic neutropenia, appears to be an overlap disorder with hereditary and acquired forms, and is sometimes indistinguishable. Some neutropenic patients give a clear history and familial pattern, whereas others have no familial history, few blood test determinations, and an unknown duration of neutropenia. This group of patients could have hereditary or acquired neutropenia.[1, 25, 26, 27, 28]A brief summary of both congenital and acquired neutropenic disorders follows.Congenital neutropenia with associated immune defectsNeutropenia with abnormal immunoglobulins is observed in individuals withX-linked agammaglobulinemia, isolatedimmunoglobulin A (IgA) deficiency,X-linked hyperimmunoglobulin M (XHIGM) syndrome, and dysgammaglobulinemia type I.[29]In XHIGM, which is due to mutations in the CD40 ligand, patients can actually 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 isintravenous immunoglobulin (IVIG).Patients with reticular dysgenesis demonstrate severe neutropenia, no cell-mediated immunity, agammaglobulinemia, and lymphopenia.[29]Life-threatening infections occur that are refractory to granulocyte colony-stimulating factor (G-CSF).[30, 31, 32]Bone marrow transplantationis the treatment of choice.Congenital or chronic neutropeniasSevere congenital neutropenia (SCN), orKostmann syndrome, is most often caused by a recessive inheritance and found in remote, isolated populations with a high degree of consanguinity.[33]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 inELA2, 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. Risk of conversion tomyelodysplastic 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 inGFI1, 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 accelerated apoptosis of myeloid progenitor cells.[20]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 inELA2.People with CN typically present as infants or children, but acquired forms of CN in adulthood exist. The prognosis is good, with a benign course; however, 10% of patients will experience life-threatening infections. The treatment for cyclic neutropenia is daily G-CSF.Chronic benign neutropeniaAffected individuals with chronic benign neutropenia have an overall low risk of infection.Familial chronic benign neutropenia is a disorder with an autosomal dominant pattern of inheritance observed in western Europeans, Africans, and Jewish Yemenites. Patients are typically asymptomatic, and the infections are mild. No specific therapy is required.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 neutropeniaIdiopathic chronic severe neutropenia is a diagnosis of exclusion. Affected patients exhibit infections and severe neutropenia.Neutropenia associated with phenotypic abnormalitiesShwachman 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-linkeddyskeratosis 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 theSBDSgene.[34]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 theRMRPgene, 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 mental retardation, pancytopenia, and defective cell-mediated immunity. Dyskeratosis congenita is more common in men than in women and is hematologically similar toFanconi anemia. Dyskeratosis congenita is usually X-linked recessive, although autosomal dominant and autosomal recessive forms of this disorder exist.The X-linked recessive form of the disorder has been linked to mutations inDKC1,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, andTERCcodes 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 syndromeis an autosomal recessive disorder with recurrent infections, mental slowing, photophobia, nystagmus, oculocutaneous albinism, neuropathy, bleeding disorders, gingivitis, and lysosomal granules in various cells. The neutropenia is moderate to severe, and the treatment is bone marrow transplantation.MyelokathexisMyelokathexis presents in infancy with moderate neutropenia and is associated with recurrent infections. The condition is due to accelerated apoptosis and decreased expression ofbcl-xin neutrophil precursors. An abnormal nuclear appearance is observed, with hypersegmentation with nuclear strands, pyknosis, and cytoplasmic vacuolization. The treatment is G-CSF and GM-CSF.Lazy leukocyte syndromeLazy leukocyte syndrome is a severe neutropenia with associated abnormal neutrophil motility. The etiology is unknown, and the treatment is supportive in nature.Metabolic disordersThese 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 neutropenia caused by intrinsic bone marrow diseaseIntrinsic 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 MyelofibrosisImmune-mediated neutropeniaA 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: Aminopyrine Quinidine Cephalosporins Penicillins Sulfonamides Phenothiazines Hydralazine Other medications have been implicatedAutoimmune neutropenia is the neutrophil analogue of autoimmunehemolytic anemiaand 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) Sjgren syndrome Chronic, autoimmune hepatitis Hodgkin lymphoma Systemic lupus erythematosus Thymoma Goodpasture disease Granulomatosis with polyangiitis (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 withthymoma 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 leukemiaIn 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 infectionInfections 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 BabesiosisBilateral 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 aureusorganisms are found in cases of skin infections. Gram-negative organisms are observed in infections of the urinary and gastrointestinal tracts, particularlyEscherichia coliandPseudomonasspecies.Candida albicansinfections 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 areEpstein-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 deficiencyNutritional deficiencies that can cause neutropenia include vitamin B-12, folate, and copper deficiency.Acquired neutropenia caused by drugs and chemicals, excluding cytotoxic chemotherapyNumerous 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.[35]Analgesics and anti-inflammatory agents include aminopyrine, dipyrone, 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.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: Phenothiazine Antithyroid drugs (thiouracil and propylthiouracil) Aminopyrine Chloramphenicol SulfonamidesMiscellaneous immunologic neutropeniasImmunologic neutropenias may occur after bone marrow transplantation and blood product transfusions.Felty syndrome is a syndrome of rheumatoid arthritis, splenomegaly, and neutropenia. Splenectomy shows an initial response, but neutropenia may recur in 10-20% of patients. Treatment is directed toward rheumatoid arthritis.In complement activationmediated 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 marrows ability to compensate for the reduction in circulating bands and neutrophils.Eosinopenia and basophilopeniaEosinopenia may be associated with the following: Acute bacterial infection Glucocorticoid administration Hypogammaglobulinemia Physical stress ThymomaDecreased circulating basophils may be associated with the following: Anaphylaxis Acute infection Drug-induced hypersensitivity Congenital absence of basophils Hemorrhage Hyperthyroidism Ionizing radiation Neoplasia Ovulation Urticaria Drugs (eg, corticosteroid, adrenocorticotropic hormone [ACTH] therapy, chemotherapeutic agents, thyroid hormones)