However, the mortality rate during the acute phase is high, and therefore prompt supportive therapy with isolation and broadspectrum antibiotics for infection are mandatory during periods of severe neutropenia. Granulocytes, also known as neutrophils, are white blood cells that make up part of a persons immune system. Pharmacology and toxicology clozapine, agranulocytosis. Neutropenia and agranulocytosis can also result from antibody or compliment mediated damage to the stem cells.
The following article provides information about the various treatment options available for this condition. Agranulocytosis definition of agranulocytosis by the free. In research protocols, the definition excludes known cytotoxic agents or diseases that can cause neutropenia and requires that the offending drug be administered within four. Over the last 20 years, the incidence of idiosyncratic drug induced agranulocytosis or acute neutropenia has remained stable at 2. You may need to register to view the medical textbook, but registration is free. In the most common clinical picture, druginduced acute agranulocytosis, the bone marrow is either poor in cells or lacks granulopoietic precursor cells aplastic state, or shows a maturation block at the myeloblastpromyelocyte stage. In this article, we discuss its diagnosis and management and we consider the drugs most commonly involved and ways of minimising risk. L due to immunologic or cytotoxic mechanisms, allopurinol is primarily used to treat hyperuricemia and its complications, including chronic gout. After excluding patients with other possible causes, 67 patients were identified as having mmi or ptuinduced agranulocytosis. Initially this was done on a limited basis, but in 1969 the use of daily dapsone for this purpose was more widely. Idiosyncratic druginduced agranulocytosis or acute neutropenia. The prognostic value of 36 clinical and analytical parameters at diagnosis in patients with drug. Antineutrophil antibodies may be involved in mediating agranulocytosis.
Those with agranulocytosis exposed to metamizol had taken the drug for longer periods than the exposed controls. Acquired agranulocytosis is a rare, druginduced blood disorder that is characterized by a severe reduction in the number of white blood cells granulocytes in the circulating blood. Previous studies of levamisole, suggest that the human leukocyte antigen hlab27 confers a genetic. Compared with the cases recently reported from sweden. A study aimed to identify genetic variants associated with antithyroid druginduced agranulocytosis in a white european population using genomewide association studies concluded that druginduced agranulocytosis was associated with hlab27. Drug induced hematologic disorders can occur by two mechanisms. Neutropenia may occur in the con text of aplastic anemia or as an isolated event. Agranulocytosis, acquired nord national organization for rare. Nonchemotherapy druginduced neutropenia and agranulocytosis. The incidence of idiosyncratic druginduced agranulocytosis remains stable in the past twenty years. Agranulocytosis associated with dipyrone metamizol. Agranulocytosis is a rare but serious complication of antithyroid drug therapy, and an uptodate understanding of this topic is important. She was diagnosed with drug induced agranulocytosis presumably from antibiotics used with mild pneumonia and admitted to an isolated room.
An unexpected precipitous fall in peripheral leucocyte count may occur during treatment of certain sensitised individuals with drugs usually well tolerated by most people. Many drugs can cause agranulocytosis and neutropenia. Some major susceptibility loci have recently been identified, which may lead the diagnosis of agranulocytosis into a genomic era. This material is provided for educational purposes only and is not intended for medical advice, diagnosis or treatment. Numerous drugs that cause agranulocytosis are metabolized to reactive species by neutrophils that, in turn. The symptoms vary greatly among affected individuals, and the. Most of the neutrophils are contained in the bone marrow, either as mitotically active one third or postmitotic mature cells two thirds. Agranulocytosis was detected after vinpocetine therapy was started, and did not occure during a two year follow up without vinpocetine. Agranulocytosis is a condition which is characterized by decrease in the neutrophil count below 100ml of blood. Agranulocytosis definition of agranulocytosis by medical.
The drug etiology of agranulocytosis and aplastic anemia david w. Agranulocytosis can be treated in a number of ways. A study aimed to identify genetic variants associated with antithyroid drug induced agranulocytosis in a white european population using genomewide association studies concluded that drug induced agranulocytosis was associated with hlab27. Overview diagnosis and tests management and treatment prevention. Neutrophils are a type of white blood cell that your. See immune neutropenia and infectious causes of neutropenia. Agranulocytosis induced by drugs other than chemotherapy frank andersohn, md. Severe druginduced agranulocytosis successfully treated.
It is a severe lack of one major class of infectionfighting white blood cells. Antithyroid drugs induced agranulocytosis and multiple. Agranulocytosis and aplastic anemia as druginduced diseases, 5 3. Introduction druginduced neutropenia is a relatively uncommon clinical occurrence which typically resolves soon after the implicated drug is dis continued. Here, we report a case of spironolactoneinduced agranulocytosis. A patient with agranulocytosis induced by vinpocetine is presented. Data sources include ibm watson micromedex updated 10 apr 2020, cerner multum updated 6 apr. Pdf agranulocytosis induced by nonchemotherapy drugs.
Druginduced agranulocytosis drug and therapeutics bulletin. Oct 06, 2016 treatment if agranulocytosis has arisen from an underlying illness, that condition will be treated. Our case is the second mmiinduced agranulocytosis case reported in the literature that developed despite discontinuation of mmi treatment. Severe druginduced agranulocytosis successfully treated with. Druginduced hematologic disorders can occur by two mechanisms. Read more about symptoms, diagnosis, treatment, complications, causes and prognosis.
Agranulocytosis is a blood disorder characterized by a marked decrease in the level of granulocytes a type of white blood cell in the blood. Drug induced agranulocytosis is an idiosyncratic adverse drug reaction, and although its mechanism is not well understood, it is suspected to involve both metabolic reactive metabolites and immune components. Evidence for drug induction of aplastic anemia, 10 5. Apr 27, 2020 in the most common clinical picture, drug induced acute agranulocytosis, the bone marrow is either poor in cells or lacks granulopoietic precursor cells aplastic state, or shows a maturation block at the myeloblastpromyelocyte stage.
The no blood, no drug requirement for patients on clozapine, which can cause agranulocytosis, entails regular testing of patients wbc counts, the results of which are submitted by prescribing physicians into a computerized national patient registry. Mechanism of clozapineinduced agranulocytosis springerlink. In the present study, a case of atd induced agranulocytosis is presented that was seen following treatment with mmi, even though this had been discontinued for three weeks. In our hospital, we commonly combine cephalosporins such as cefotaxime or. Granulocytecolony stimulating factor gcsf therapy is recommended for the early recovery of agranulocytosis. State of art of idiosyncratic druginduced neutropenia or. Agranulocytosis management and treatment cleveland clinic. The monarch initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Thus, in practice, idiosyncratic druginduced neutropenia or agranulocytosis. Neutropenia is a decrease in circulating neutrophils in the nonmarginal pool, which constitutes 45% of total body neutrophil stores.
Candesartan, lansoprazole, amlodipine, and celecoxib were discontinued because they are also known to cause agranulocytosis. Clinical and hematologic characteristics of phenothiazineinduced agranulocytosis suggest that the mechanisms underlying the development of this condition are related to a possible suppressive effect of phenothiazines on cell division. Druginduced agranulocytosis is a recognized adverse drug event associated with serious infectious complications. Idiosyncratic druginduced neutropenia and agranulocytosis is seldom discussed in the literature, especially for new drugs such. The mechanism of clozapine induced agranulocytosis is not clear. Acquired agranulocytosis genetic and rare diseases. The quantification of the incidence of potentially druginduced agranulocytosis in general, and in particular its association with single drugs, requires studies on large populations and the use of strict epidemiological methodology to prevent reporting of grossly biased results. Resultsconclusions idiosyncratic druginduced agranulocytosis remains a potentially serious adverse event owing to the frequency of severe sepsis with severe deep tissue infections e.
The name granulocyte refers to grainlike bodies within the cell. This drug is to stimulate generation, proliferation and maturation of neutrophils. Numerous drugs that cause agranulocytosis are metabolized to reactive species by neutrophils that, in turn, covalently bind to the cells. Diagnosis and management of idiopathic druginduced severe. Currently, the standard treatment for druginduced agranulocytosis is discontinuation of the responsible agents, antibiotic treatment if the presence of infection is suspected, and proper use of granulocyte colonystimulating factor gcsf. Insights into the mechanism of druginduced agranulocytosis. Background leukoneutropenia is described in most of the summaries of the characteristics of the products of human intravenous immunoglobulins ivig. Untreated, it can lead to death from the blood infection called septicemia. One is characterised by sudden destruction of large numbers of leucocytes in peripheral blood by antibodies elicited in.
The primary treatment of druginduced hematologic disorders is removal of the drug in question and symptomatic support of the patient. Agranulocytosis, acquired nord national organization. However, several prognostic factors have recently been. While they may be the same in principle, they are used differently in different situations. One baczol formulation also contained metamizole or dipyrone, a nonsteroidal antiinflammatory drug formerly widely prescribed outside the united states under trade names including analgin, dipirona, novalgin, and optalgin as an analgesic and antipyretic, and banned by the fda in 1977 because of its association with agranulocytosis 6. These blood cells play a key role in the elimination of pathogens. Agranulocytosis, acquired nord national organization for. Clinical particularities of druginduced agranulocytosis or severe. Agranulocytosis induced by certain phenothiazine derivatives. Granulocytopenia is defined as a reduced number of blood granulocytes, namely neutrophils. Oct 25, 2012 clozapine is an atypical antipsychotic agent that has several advantages over conventional antipsychotics, not least of which is its superior efficacy. Drug induced agranulocytosis is a rare, potentially fatal idiosyncratic reaction that can occur unpredictably with a wide variety of drugs when taken in a conventional dose. Apparently promethazine and methdilazine do not cause agranulocytosis. Currently, acquired agranulocytosis may not be preventable, since in most cases, the disorder is associated with drugs used for serious health conditions.
The mortality rate from druginduced agranulocytosis is approximately 5 to 10 percent but decreases with early identification and treatment. In our hospital, we commonly combine in first line therapy, new cephalosporins and. Druginduced neutropenia and agranulocytosis uptodate. This side effect is uncommon and not usually described in paediatric populations. The doctor may tell you to stop taking the drug for a while to see if you improve. Stopping a medication that is believed to cause the disease. Eight deaths due to dapsoneinduced agranulocytosis have been reported recently. A great majority of cases are caused by sensitization to drugs or chemicals that affect the bone marrow and depress the. Di025 intravenous immunoglobulin induced agranulocytosis. The diagnosis of acquired agranulocytosis is made by combining a thorough. Usually, immunemediated agranulocytosis occurs within days to a few weeks after beginning the drug and is frequently acute, with explosive symptoms. Agranulocytosis associated with cocaine use four states.
Treatment if agranulocytosis has arisen from an underlying illness, that condition will be treated. If a drug needed for another condition causes agranulocytosis, your doctor may prescribe a substitute treatment. Pdf agranulocytosis associated with dipyrone metamizol. Side effects of antithyroid drugs are seen in 1 up to 10% of the patients as skin eruptions as macula or papula, dermatitis, urticaria, artralgia, hepatitis, jaundice, muscle pain, thrombocytopenia, abnormal hair loss, vomiting, loss of taste. Druginduced agranulocytosis is a severe complication that has been implicated with most classes of medications. Paris 181 short communication druginduced agranulocytosis. Both direct toxicity and immunemediated responses have been described as possible mechanisms. The drug etiology of agranulocytosis and aplastic anemia. Case report of agranulocytosis induced by vinpocetine. Drugs causing agranulocytosis or low white cell count.
The treatment for agranulocytosis depends upon whether the condition is acquired or congenital. Purpose the objective was to analyse the causes of two. However, the proportion of cocaine users exposed to levamisole who might develop levamisoleinduced agranulocytosis, is unknown. Clinical and hematologic characteristics of phenothiazine induced agranulocytosis suggest that the mechanisms underlying the development of this condition are related to a possible suppressive effect of phenothiazines on cell division.
Druginduced agranulocytosis cannot happen before first going through neutropenia. Dapsone agranulocytosis jama dermatology jama network. Druginduced agranulocytosis is a rare, potentially fatal idiosyncratic reaction that can occur unpredictably with a wide variety of drugs when taken in a conventional dose. The code is valid for the year 2020 for the submission of hipaacovered transactions. Relative lymphocytosis associated with granulocytopenia. Monarchs tools are designed to make it easier to compare the signs and symptoms. Annually, the incidence of druginduced agranulocytosis, excluding cytotoxic agents, is estimated to be approximately seven cases per one million people. Druginduced agranulocytosis, not associated with chemotherapy, is a rare adverse reaction characterized by decreased peripheral neutrophil counts to less than 0. In the present study, a case of atdinduced agranulocytosis is presented that was seen following treatment with mmi, even though this had been discontinued for three weeks. Medications such as clozapine, trimethoprimsulfamethoxazole and methimazole have been more commonly associated with agranulocytosis than other agents.
Medscape reference provides information on this topic. It results in a severe reduction of granulocytes in the peripheral blood with an absolute neutrophil count anc of under 0. Populationbased druginduced agranulocytosis hematology. However, the proportion of cocaine users exposed to levamisole who might develop levamisole induced agranulocytosis, is unknown. The risk disappeared after more than 10 days since the last dose of metamizol, and it increased with duration of use. Development of agranulocytosis after discontinuation of. The quantification of the incidence of potentially drug induced agranulocytosis in general, and in particular its association with single drugs, requires studies on large populations and the use of strict epidemiological methodology to prevent reporting of grossly biased results. Genetic determinants of cocaineassociated agranulocytosis. Others causes of acquired neutropenia, such as primary immune mechanisms, chemotherapy, and infections, as well as congenital neutropenia in children are discussed separately. Drug induced agranulocytosis is a severe complication that has been implicated with most classes of medications. Druginduced neutropenia or agranulocytosis occurs as an idiosyncratic reaction.
Evidence for drug induction of agranulocytosis, 6 4. We calculated the overall populationattributable risk by combining all exposures to individual drugs that showed a significant association as a. Pdf the etiology, epidemiology and management of idiosyncratic. Criteria for idiosyncratic druginduced agranulocytosis. Clinicians should be aware of the possible relationship between levamisoleassociated agranulocytosis and use of cocaine, and possibly heroin, and should obtain a drug history in all potential cases routinely. If youre taking several different drugs, you may need to stop taking them. Indeed, one drug might cause agranulocytosis by different mechanisms in different patients. It has been postulated that clozapine is metabolised to a nitrenium ion. It is a heterogeneous disorder in pathogenetic terms, not surprisingly in view of its idosyncratic nature. Agranulocytosis and aplastic anemia as drug induced diseases, 5 3. Resultsconclusions idiosyncratic drug induced agranulocytosis remains a potentially serious adverse event owing to the frequency of severe sepsis with severe deep tissue infections e. Three basic mechanisms for drug sensitivity have been found.
Agranulocytosis is a condition where the absolute neutrophil count is less than 100 per microliter of blood. Aplastic anemia was the leading cause of death followed by thrombocytopenia, agranulocytosis, and hemolytic anemia. Filgrastim for chronic or severe acquired agranulocytosis. What risk factors are associated with antithyroid drug.
Of these, 35 developed it while on a continuous course of the drug, while 22 had gaps in therapy that ranged from 5 months to 22 years. The differential diagnosis of pure agranulocytosis versus aplasias of several cell lines is outlined on. Criteria for idiosyncratic druginduced agranulocytosis adapted from 1 3. Acquired agranulocytosis is a rare, drug induced blood disorder that is characterized by a severe reduction in the number of white blood cells granulocytes in the circulating blood. Levamisole is an antihelminthic and immunomodulator withdrawn from north american markets in 2005 after reports of agranulocytosis. A collection of disease information resources and questions answered by our genetic and rare diseases information specialists for acquired agranulocytosis. Druginduced agranulocytosis is an idiosyncratic adverse drug reaction, and although its mechanism is not well understood, it is suspected to involve both metabolic reactive metabolites and immune components.
Idiosyncratic druginduced agranulocytosis diag is an adverse reaction to drugs due to abnormal susceptibility, peculiar to the individual. Since 1998, less than 200 cases have been reported in the literature. However, only four cases of spironolactoneinduced agranulocytosis have been previously reported 36, all of which were concurrently treated with furosemide. Granulocytes include basophils, eosinophils, and neutrophils. Many anti neoplastic drugs cause agranulocytosis and neutropenia by bone marrow suppression.
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