(Agranulocytosis, granulocytopenia)

Under neutropenia is defined as a reduction of neutrophils in the blood. In severe cases, the risk and severity of bacterial and mycotic infections are increased. Local symptoms of infection may be missing, but most severe infections fever occurs. The diagnosis is made by the white blood cell count with differential distribution, but in addition, should look for the reason for neutropenia. Fever infection should be accepted; in this case an immediate, empirical use of a broad-spectrum antibiotic is required, especially in severe neutropenia. In some cases, the use of granulocyte colony-stimulating factor (G-CSF) may be useful. (Editor’s note: GM-CSF is not approved in Europe!)

The neutrophils (granulocytes) are the main defense of the body against bacterial and fungal infections. In the case of neutropenia inflammation reaction against such infections is ineffective. Light-skinned at the lower limit of the neutrophil count is (the product of the total number of white blood cells and the percentage of polynuclear rod and polymorphonuclear granulocytes) about 1500 / ul. Among blacks, this limit is slightly lower (about 1200 / ul).

Under neutropenia is defined as a reduction of neutrophils in the blood. In severe cases, the risk and severity of bacterial and mycotic infections are increased. Local symptoms of infection may be missing, but most severe infections fever occurs. The diagnosis is made by the white blood cell count with differential distribution, but in addition, should look for the reason for neutropenia. Fever infection should be accepted; in this case an immediate, empirical use of a broad-spectrum antibiotic is required, especially in severe neutropenia. In some cases, the use of granulocyte colony-stimulating factor (G-CSF) may be useful. (Editor’s note: GM-CSF is not approved in Europe!) Neutrophils (granulocytes) are the main defense of the body against bacterial and fungal infections are in case of neutropenia is the inflammatory response to such infections ineffective.. Light-skinned at the lower limit of the neutrophil count is (the product of the total number of white blood cells and the percentage of polynuclear rod and polymorphonuclear granulocytes) about 1500 / ul. Among blacks, this limit is slightly lower (about 1200 / ul). On the severity of neutropenia, the relative risk of infection depends on: Weak (1000-1500 / ul) default (500-1000 / ul) heavy (<500 / ul) sinking the neutrophils to values ??<500 / ul off, then the endogenous microbial Flora (z. B. in the mouth or gastrointestinal tract) cause infections. If the value drops to <200 / ul, the inflammatory response may fail entirely, and the usual signs of inflammation leukocytosis or leukocytes in urine or at the site of infection may not occur. Acute severe neutropenia can, especially if other factors (eg., Tumor diseases) are present, further weaken the immune system and lead to rapidly fatal infections. have an influence on the risk of infection beyond the integrity of the skin and mucous membranes, vessels in tissues and the nutritional status of the patient. Clinical Calculator: Absolute neutrophil count The infections most commonly occur in patients with severe neutropenia are cellulitis liver abscesses Furunculosis pneumonia septicemia vascular catheters and other puncture sites lead to additional risk of skin infections. The most widespread bacterial infections with coagulase-negative staphylococci and Staphylococcus aureus, other gram-positive and gram-negative infections are but also come on. Other common infections are stomatitis, gingivitis, perianal inflammation, colitis, sinusitis, onychitis and otitis media. Patients receiving long-neutropenic due to transplantation of blood-forming stem cells or chemotherapy and patients receiving high doses corticosteroids, are particularly vulnerable to fungal infections. Etiology Acute neutropenia, which can occur within hours or a few days, developed either by an increased consumption, destruction or impaired production of neutrophils. A chronic neutropenia, which may last for months or years, is usually caused by decreased production or increased sequestration of neutrophils in the spleen. Also neutropenia are divided into two categories. They are either the result of an intrinsic defect of the bone marrow precursor cells or are present as secondary neutropenia, d. H. due to an extrinsic factor, which acts on the bone marrow progenitor cells (see Table: Classification of neutropenia). Classification of the classification etiology neutropenia neutropenia by intrinsic defects of myeloid cells or their precursors Aplastic anemia Chronic idiopathic neutropenia, including benign neutropenia Cyclic neutropenia neutropenia in myelodysplasia dysgammaglobulinemia paroxysmal nocturnal hemoglobinuria Severe congenital neutropenia (Kostmann syndrome) syndrome-associated neutropenia, z. B. cartilage-hair hypoplasia, congenital dyskeratosis, glycogen storage disease type IB, Shwachman-Diamond syndrome Secondary neutropenia alcoholism autoimmune neutropenia, including chronic secondary neutropenia in AIDS marrow displacement (z. B. by cancer, myelofibrosis, granulomas or Gaucher cells) Cytotoxic Chemotherapy or radiation-induced neutropenia drug folic acid or vitamin B12 deficiency hypersplenism infection T-?-lymphoproliferative disease neutropenia by an intrinsic defect of myeloid cells and their precursors This Neutropenieform is rare, but when they occur, the most common causes are chronic idiopathic neutropenia Congenital neutropenia Cyclic neutropenia is a rare autosomal dominant disorder of Granulopoese and is usually caused by a mutation in the genes for neutrophil elastase, resulting in abnormal apoptosis. and characterized by regular, periodic fluctuations in peripheral neutrophil counts. The average oscillation time is 21 ± 3 days. The severe congenital neutropenia (Kostmann's syndrome) is a rare disease that occurs sporadically. It is characterized by growth arrest of myeloid cell line at the level of promyelocytes in the bone marrow and leads to absolute neutrophil count <200 / ul. Several genetic abnormalities that cause an increased Neutrophilapoptose have been identified. Chronic idiopathic neutropenia comprises a group of rare and little-studied diseases that affect myeloid determinate stem cells. The red line and platelet precursors are not affected. There is no splenomegaly. Chronic benign neutropenia is a subtype of chronic idiopathic neutropenia, in which the remaining functions of the immune system will probably remain preserved. Even with neutrophil count <200 / ul heavy infections usually occur. This is probably because, that are formed as a result of infection temporarily adequate neutrophil count. Neutropenia can also be the result of bone marrow failure due to rare syndromes such. B. cartilage-hair hypoplasia, Chediak-Higashi syndrome, congenital dyskeratosis, glycogen storage disease type IB, Shwachman-Diamond syndrome. Furthermore neutropenia may also be the clinical presentation of myelodysplasia: his (possibly accompanied by megaloblastic changes in the bone marrow) and aplastic anemia a (aplastic anemia) myelodysplastic syndromes (diagnosis). Even with a dysgammaglobulinaemia and paroxysmal nocturnal hemoglobinuria can neutropenia auftreten.Sekundäre neutropenia Secondary neutropenia various infections or immunological reactions be caused by various medications, a bone marrow infiltration or -verdrängung. The most common causes are: drugs to bone marrow infections processes the drug-induced neutropenia is the most common Neutropenieform. By drugs can either come to a decreased production of toxic or idiosyncratic processes or hypersensitivity reactions, or there is an increased peripheral consumption by immunological processes before. Only when toxic-induced neutropenia (eg., By phenothiazines) can be found a dose-dependent neutropenia. Idiosyncratic reactions are unpredictable and may occur at a variety of drugs, including homeopathic substances or extracts, and toxins. Hypersensitivity reactions are rare. They sometimes occur in connection with the use of anticonvulsant agents (eg., Phenytoin and phenobarbital). These reactions may last from a few days to several years. By hypersensitivity induced neutropenia nephritis, pneumonia or aplastic anemia are often of a hepatitis, accompanied. In the immune-mediated drug-induced neutropenia drugs act probably as haptens and thus stimulate antibody formation. This Neutropenieform usually persists for about 1 week after discontinuation of the drug. Observed it was after the administration of Aminopyrinen, propylthiouracil, penicillin or other antibiotics. Heavy dose dependent neutropenia occur regular way on after treatment with cytostatic antineoplastic or radiation therapy through suppression of bone marrow production. Even with a megaloblastic anemia due to vitamin B12 or folic acid deficiency can cause neutropenia due to insufficient bone marrow production. Here, mostly macrocytic anemia and parallel to it occasionally thrombocytopenia developed. A bone marrow infiltration by leukemic cells, myelomas, lymphomas or metastatic solid tumors (eg. As breast or prostate tumors) may affect production of neutrophils. A tumor-associated myelofibrosis may lead to a further strengthening of neutropenia. Myelofibrosis can also occur due to granulomatous infections of Gaucher disease or radiation therapy. A hypersplenism any cause can lead to a moderate neutropenia, thrombocytopenia and anemia. Infections result either by influencing the Neutrophilenproduktion, an immunologically mediated destruction or the increased consumption of neutrophils to neutropenia. Sepsis is a very serious cause. Neutropenia often occurs as a result of viral diseases in childhood within the first 1-2 days of illness on, however, lasts only 3-8 days. A redistribution of neutrophils from the circulating to the marginal pool can be caused by a viral infection or endotoxins and cause a temporary neutropenia. Alcohol also may lead to neutropenia by the inhibition of bone marrow response in certain infections (eg. B. pneumococcal pneumonia). HIV infection is often accompanied by a chronic neutropenia secondary to a decrease in production of neutrophils and increased destruction of neutrophils by antibodies. Autoimmunneutropenien can both acute and chronic or rekurrierend occur. Here antibodies can occur directly from circulating neutrophils or neutrophil precursor cells. You can also cytokines (eg., Gamma-interferon, tumor necrosis factor), concern that can lead to neutrophil apoptosis. Most patients with autoimmune neutropenia have an underlying autoimmune disease or a lymphoproliferative disease (z. B. SLE, Felty's syndrome). Symptoms and complaints Neutropenia itself is asymptomatic until the occurrence of infections. Fever is often the only indication of an existing infection. Local symptoms (eg., Oral ulcers) may occur, but are often very weak. In patients with drug-induced neutropenia due to a hypersensitivity reaction fever, rash and lymphadenopathy may occur as clinical signs. Some patients with chronic benign neutropenia and neutrophil count <200 / ul rarely develop a serious infection. Patients with cyclic neutropenia or severe congenital neutropenia often suffer from oral ulcers, stomatitis, pharyngitis, and lymphadenopathy in the phases of severe chronic neutropenia. Often occur pneumonia and septicemia. Diagnosis Clinical suspicion (repeated or unusual infections) confirmation by blood count with differential blood count clarification of infection with cultures and imaging identification of the underlying mechanism and the cause of neutropenia (In patients with frequent severe or unusual infections or in patients at risk for. Example, after administration of cytotoxic drugs or radiation) should be suspected neutropenia. Confirmation is through a blood count with differential blood count. Clarification of infection Most important is to determine whether the patient is currently suffering from an infection. As the infection signs are pronounced very low, under certain circumstances, a systematic physical examination is necessary in the most common places of origin are included to infection. These include the mucous membranes of the digestive tract (including gums, pharynx, anus), lungs, abdomen, urinary tract, skin and nails, lying vascular catheter and places where venipuncture was performed. Takes the neutropenia acute, laboratory tests should be carried out swiftly. Cultures are the cornerstone of clarification. In a patient with a fever at least 2 pairs should be investigated blood cultures for bacteria and fungi out. If an intravenous catheter is located, it is advisable to remove cultures from the catheter and additionally from a peripheral vein. Persistent or chronic occurring Sekretionmaterial should also be examined on fungi and atypical mycobacteria. The mucosal ulcers are swabbed and made a study on herpes simplex virus. At present skin lesions smears and biopsies for cytological and microbiological examination should be taken. Samples for urinalysis and urine cultures are taken from all patients. For diarrhea a stool examination for enteropathogenic germs and Clostridium difficile toxin is indicated. Imaging techniques are useful. A chest radiograph is done in all patients. Are clinical signs of sinusitis before (eg. As postural headache, pain in the upper jaw, facial swelling or rhinitis), a CT scan of the sinuses may be useful. A CT scan of the abdomen is usually when the symptoms (eg. As pain) or history (eg. As recent surgery) on an intra-abdominal infection hinweisen.Abklärung the cause then the reason for the neutropenia should be clarified. The history relates particularly to drugs, other substances and possible toxins, which has been exposed to the patient or he has taken. The physical examination should include evaluation for the presence of splenomegaly or sign of another underlying disease (eg. As arthritis, lymphadenopathy). The most important test is bone marrow examination by an examination of the bone marrow can be examined whether the neutropenia is decreased production in the bone marrow based or whether it is caused secondarily by increased destruction or increased consumption of cells (in this case the production in the bone marrow is normal or even increased). Furthermore, the bone marrow may under certain circumstances a specific reason for the show neutropenia (z. B. aplastic anemia, myelofibrosis, leukemia). As a complementary bone marrow examinations cytogenetic analysis, special staining and flow cytometry for the detection of leukemia and other malignant diseases and infections should be performed. Depending on the suspected diagnosis, further investigations are sometimes necessary to determine the cause of the neutropenia. In patients at risk for folic acid and vitamin B12 deficiency the appropriate levels should be determined. A test for antineutrophil antibodies is performed in cases of suspected immunologically induced neutropenia. The differentiation between antibiotic- and infection-induced neutropenia can sometimes be difficult. The white blood cell counts immediately before initiation of antibiotic therapy usually reflect the changes in the blood levels due to the infection. In patients who suffer or since childhood from a chronic neutropenia have in their medical history relapsing fever and chronic gingivitis leukocyte counts should be performed with differential distribution three times a week over a period of 6 weeks. This allows periodic fluctuations that are typical of a cyclic neutropenia, are detected. At the same platelet and reticulocyte counts should be performed. Often, the cycling of eosinophils, reticulocytes and platelets follow the neutrophil counts, whereas monocyte and lymphocyte values ??do not follow the cycle. Treatment Treatment of associated findings (z. B. infections, stomatitis) Uncommon Antibiotic prophylaxis myeloid growth factors discontinuation of probably causing substances (eg. As drugs) Occasionally corticosteroids Rarely splenectomy Acute neutropenia For suspected infection should be started immediately with a treatment. Fever or hypotension, a severe infection must be assumed and it should be done as soon as possible an empirical, high-dose, intravenous therapy with broad-spectrum antibiotics. The selection of the particular antibiotic depends on the microorganism may be most responsible for the type of infection, the pathogen spectrum of the clinic and the potential toxicity of the therapy. Due to the risk of developing resistance, vancomycin should be used only in cases of suspected infection with gram-positive bacteria, where resistance to other drugs is suspected. Lying vascular catheter can be left mostly even if bacteremia is suspected or has already been demonstrated. In infections with S. aureus, Bacillus sp., Corynebacterium sp. or Candida sp. and further positive blood cultures despite antibiotic therapy adequate removal of the catheter should, however, be considered. Infections caused by coagulase-negative staphylococci, usually speak well to antimicrobial therapy. In these patients also lying Foley catheter may favor infections; Therefore, a change or removal of the catheter should be considered in persistent urinary tract infections contemplated. When cultural detection of pathogens antibiotic therapy according to the resistance tests should be adjusted. Entfiebert the patient within 72 hours, antibiotic therapy for at least 7 days is or continued until the patient shows no symptoms of infection more. In a transient neutropenia (z. B. due to myelosuppressive chemotherapy), antibiotic therapy is usually continued until the neutrophil count has risen again to> 500 / ul. Termination of antibiotic therapy can be considered but with persistent neutropenia in selected patients when the clinical signs of infection have regressed and the cultures remain negative. If the fever in spite of antibiotic therapy for a period of 72 h addition, according to infections with resistant pathogens and superinfection by a second bacterium, inadequate serum or tissue levels or local infection (z. B. abscess) must be of non-bacterial infections, intended become. In neutropenic patients with persistent fever should periodically (every 2-4 days) are carried out a physical examination, microbiological cultures and a chest x-ray. the patient where clinically not deteriorated, despite fever the initial antibiotic regimen can be continued. Otherwise, a change of antibiotic therapy should be done. Fungal infections are the most common cause of persistent fever and clinical deterioration of the patient. Therefore, an antifungal treatment should be empirically supplemented if, despite the use of a broad-spectrum antibiotic for 3 to 4 days also unclear fever. The choice of specific Antimyotikums (z. B. fluconazole, caspofungin, voriconazole, posaconazole) depends on the nature of the risk from (z. B. duration and severity of neutropenia, past the fungal infection, persistent fever despite using an antifungal agent of the narrower spectrum) and should be made by a specialist in infectious diseases. If a patient after 3 weeks under empirical therapy (including two weeks of antifungal therapy) and is still not free from fever after the neutropenia, all antimicrobial drugs can be discontinued and the reason for the fever to be reexamined. In afebrile patients with neutropenia those going through one of the many chemotherapies, which often result in neutrophils ? 100 / ul for> 7 days, antibiotic prophylaxis with fluoroquinolones (levofloxacin, ciprofloxacin) administered. The prophylaxis is usually started by the treating oncologist. The antibiotics are continued until the neutrophil count at> 1500 / ul increases. An antifungal treatment is also in afebrile neutropenic patients with a higher risk for a fungal infection (eg., In transplantation of hematopoietic stem cells, intensive chemotherapy for acute myelogenous leukemia or myelodysplastic a disorder against fungal infections). The selection of the specific Antimyotikums should be guided by a specialist in infectious diseases. An antibiotic and antifungal prophylaxis is not recommended routinely for afebrile neutropenic patients without risk factors is believed due to their specific chemotherapy plan of which they remain neutropenic for <7 days. The myeloid growth factor G-CSF is often used to increase the neutrophil count, thus protecting patients with severe neutropenia from infection (eg., In transplantation of hematopoietic stem cells and intensive antineoplastic chemotherapy). (Editor's note: GM-CSF is not approved in Europe!) Such therapy is expensive. Nevertheless, growth factors are indicated when the risk of febrile neutropenia ? 30% (neutrophil count <500 / ul, infection during the previous cycle of chemotherapy, severe concomitant diseases, or age> 75 years). In general, the greatest clinical benefit when starting with the administration of the growth factor 24 hours of the end of chemotherapy. Patients with neutropenia, which was triggered by an idiosyncratic drug reaction may benefit from the use of myeloid growth factors. This is especially true when a delayed recovery in values ??is expected. The dose of G-CSF (Filgrastim) is 5 to 10 micrograms / kg s.c. 1 time / day, and the dose for pegylated G-CSF (Pegfilgrastim) is 6 mg s.c. 1 times per chemotherapy cycle. Glucocorticoids, anabolic steroids and vitamins not stimulate the production of neutrophils, but can affect their distribution and their degradation. There is suspicion of a drug-induced neutropenia or toxin, all potentially triggering substances should be discontinued immediately. Occurs neutropenia during treatment with a drug on, is known that it can cause neutropenia (z. B. chloramphenicol), the exchange of the antibiotic may be useful. The symptoms of stomatitis with oropharyngeal ulcerations can 2 to 3 times daily by gargling with hydrochloric or peroxide at a distance of a few hours, anesthetic lozenges (benzocaine 15 mg every 3-4 hours), or chlorhexidine mouthwashes (1% solution) be mitigated. An oral or esophageal candidiasis can nystatin mouthwashes (400,000 to 600,000 IU 4 times daily, at esophagitis flushing swallow), clotrimazole lozenges (10 mg 5 times daily, slowly in the mouth to dissolve) or systemic antifungal drugs (eg. B. fluconazole) are treated. Depending on the nature of the pain can be a semi-liquid or liquid diet during the period of acute stomatitis or esophagitis and topical analgesics (eg. As lidocaine gel) necessary sein.Chronische neutropenia The production of neutrophils can in congenital, cyclic or idiopathic neutropenia by administration of G-CSF at a dose of 1-10 micrograms / kg sc be increased once a day. This therapy can be effectively continued over a period of several months to years, daily or intermittent. Long-term administration of G-CSF is also used in other patients with chronic neutropenia, including in patients with myelodysplasia, HIV and other autoimmune diseases. Although neutrophil counts generally increase the clinical benefit is unclear, particularly in patients that do not have severe neutropenia. In patients with autoimmune diseases or patients who have received an organ transplant, cyclosporine can be a useful alternative. Corticosteroids (e.g., prednisone 0.5-1.0 mg / kg p.o. once daily) may occur in patients who have an increased destruction of neutrophils due to an autoimmune disease, lead to an increase of the peripheral values. This increase can often be maintained by the administration of G-CSF every other day. In patients with splenomegaly or sequestration of neutrophils in the spleen (z. B. Felty’s syndrome), a splenectomy may result in the increase in neutrophil counts. Splenectomy should be reserved for patients with severe neutropenia (d. E. <500 / ul) and repeated serious infections that have not responded to other treatments. Since splenectomy promotes infection by encapsulated organisms, patients should be vaccinated before and after splenectomy against infection with Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae. Summary The neutrophils represent the primary defense of the body against bacterial and fungal infections, the risk of infection is proportional to the severity of neutropenia. Patients with neutrophil counts <500 / ul are most at risk. Since the inflammatory response is limited, clinical findings may be absent, although mostly fever occurs. Febrile patients are treated empirically with broad spectrum antibiotics until the final identification of the infection. Antibiotic prophylaxis is indicated in high-risk patients.

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