Drug-induced neutropenia and agranulocytosis

INTRODUCTION — Most cases of neutropenia in adults are acquired and are due to decreased granulocyte production or increased destruction. Neutropenia can be predictable and dose related, as in the case of cytotoxic chemotherapy, or an idiosyncratic reaction. The mechanisms of the neutropenia are varied and the propensity to infection depends upon the adequacy of bone marrow reserve.

Drug-induced neutropenia and agranulocytosis will be reviewed here. Others causes of acquired neutropenia, such as primary immune mechanisms, chemotherapy, and infections, as well as congenital neutropenia in children are discussed separately. (See "Immune neutropenia" and "Infectious causes of neutropenia" and "Congenital neutropenia" and "Overview of neutropenic fever syndromes".)

The overall approach to the patient with neutropenia is discussed separately. (See "Overview of neutropenia in children and adolescents" and "Approach to the adult with unexplained neutropenia".)

DEFINITIONS — Neutropenia is defined as an absolute neutrophil count (ANC) <1500/microL. The ANC is numerically equal to the product of the white blood cell count (WBC) and the fraction of polymorphonuclear cells (PMNs) and band forms noted on the differential analysis (calculator 1):

As an example, a patient with a total WBC of 3500/microL, 30 percent PMNs and 1 percent bands would have an ANC = (3500 x [30 + 1]) ÷ 100 = 1085/microL.

Neutrophilic metamyelocytes and younger forms are not included in this calculation. The risk of infection increases when the ANC falls to less than 1000/microL, and is most clinically significant when the ANC is <500/microL (table 1).

The terms leukopenia and granulocytopenia are generally used interchangeably with neutropenia, although they are somewhat different. Leukopenia refers specifically to a low WBC due to any cause, while granulocytopenia refers to a reduced number of granulocytes.

Agranulocytosis literally means the absence of granulocytes (ie, ANC of zero), although the term is often used loosely to indicate severe degrees of neutropenia (ie, ANC <100, <200 or even <500/microL) [1].

DRUG-INDUCED NEUTROPENIA

Epidemiology — Idiosyncratic drug reactions (IDR) have an estimated incidence of 1/10,000 to 1/100,000 [2]. However, since many drugs have associated idiosyncratic drug reactions, the overall risk is higher. While the risk is independent of dose, they are more common in drugs given at high dose and very rarely seen if the dose is less than 10 mg/day.

Implicated agents — A number of medications have been implicated as potential causes of severe neutropenia or agranulocytosis. Evidence for such a relationship is based upon an accumulation of case reports, spontaneous reports to registries, cohort studies, and population and case control studies. Drugs can be classified as definite, probable, or possible causes of neutropenia based upon the available evidence.

There are a number of medications that are considered to have a high risk for agranulocytosis based upon definite and unequivocal evidence (table 2) [3-6]. This list excludes agents that produce agranulocytosis on the basis of bone marrow suppression (eg, methotrexate, cyclophosphamide, colchicine, azathioprine, ganciclovir).

Among the agents that are more commonly associated with agranulocytosis are clozapine, the thionamides (antithyroid drugs), sulfasalazine, and ticlopidine. Other classes of agents with multiple reports of agranulocytosis include other antibiotics [7], ACE inhibitors [4,8,9], H2 blockers [10-12], nonsteroidal antiinflammatory drugs [13-19], amodiaquine [20,21], antiarrhythmic drugs such as tocainide, procainamide, and flecainide [22-25], aminoglutethimide (no longer available) [26,27], dapsone [28], and deferiprone [29,30].

In a systematic literature review of English- and German-language reports of patients with non-chemotherapy drug-induced agranulocytosis, the following 11 drugs accounted for more than 50 percent of definite or probable reports: carbimazole, clozapine, dapsone, dipyrone, methimazole, penicillin G, procainamide, propylthiouracil, rituximab, sulfasalazine, and ticlopidine [1]. A listing of all case reports of agranulocytosis included in this 2007 systematic review is available at: www.adverse-effects.com/agranulocytosis/case_reports.html [31].

The relative and absolute risks of drug-induced agranulocytosis were evaluated in a study of all patients hospitalized in the Netherlands for a diagnosis of agranulocytosis (defined as an ANC <500/microL) during the years 1987 through 1990. The following results were found [6]:

●The highest relative risks for development of agranulocytosis were found for antithyroid drugs, sulfasalazine, trimethoprim-sulfamethoxazole, dipyrone combined with analgesics, clomipramine, and carbimazole.

●Three drugs (methimazole, sulfasalazine, and trimethoprim-sulfamethoxazole) were responsible for 42 percent of all cases, with excess risks (cases of agranulocytosis per million users following 10 days of exposure) of 10.1, 3.6, and 1.2, respectively.

●Calcium dobesilate (Doxium), a veno-tonic drug widely prescribed in Europe, Latin America, Asia, and the Middle East, has been associated with a high incidence of agranulocytosis [32].

Psychotropic drugs and anticonvulsants — Many psychotropic agents, such as clozapine, the phenothiazines and the tri- and tetra-cyclic antidepressants, have been associated with neutropenia and/or agranulocytosis. Similarly, many of the commonly used anticonvulsants can cause hypersensitivity reactions (eg, carbamazepine, phenytoin, phenobarbital) and are associated with neutropenia. Clinicians need to be aware of this possibility and either monitor blood counts in patients taking such agents on a regular basis or alert the patient to the possibility that fever and/or infection may be signs of this toxicity. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Carbamazepine'.)

Clozapine — Clozapine, an atypical antipsychotic agent, is used only for schizophrenia unresponsive to other therapies due to the risk of agranulocytosis [3,5,33]. The cumulative risk of agranulocytosis is approximately 0.8 to 1.5 percent at one year [3,33], with little further increase over time [3]. The majority of cases (84 percent) occur within the first three months of therapy, which constitutes the rationale for monitoring the white blood cell count, especially soon after therapy has been instituted. (See 'Prevention and screening' below and "Second-generation antipsychotic medications: Pharmacology, administration, and side effects".)

Olanzapine — Olanzapine, related structurally to clozapine, has been recommended as an antipsychotic agent for patients with clozapine-induced granulocytopenia or agranulocytosis. However, the safety of this approach is uncertain due in part to the following observations:

●Metabolites of olanzapine were toxic in vitro to neutrophils from two patients with a history of clozapine-induced agranulocytosis [34].

●One patient developed agranulocytosis following treatment with olanzapine; he had been treated previously with clozapine without hematologic complications [35].

●Another patient with clozapine-induced neutropenia developed reversible neutropenia after being switched to olanzapine [36].

Deferiprone — Deferiprone is an oral iron-chelating agent that has been in use since the 1990s [29]. It has been available in many European countries for a number of years [29,30] and was approved for use in the United States in 2011 [37]. Agranulocytosis has been reported in 0.5 to 3.6 percent of patients in various studies [29]. An ANC of less than 0.2 x 10⁹/L was seen in 0.2/100 patient years and 0.5 to 1500 x 10⁹/L in 2.8 per 100 patient years [30]. The onset of agranulocytosis or neutropenia can occur between zero and 19 months or zero and 70 months, respectively, but usually occurs in the first year after starting the drug.

Both neutropenia and agranulocytosis are reversible after stopping the drug. While some patients with neutropenia have done well after restarting the drug, it is recommended that patients will full agranulocytosis not be rechallenged with this agent. There have been reported deaths from sepsis due to agranulocytosis. At close inspection of these cases, the physicians and patients were not aware of the possibility of this side effect and therefore did not respond properly when fever developed. Because of this risk, it is recommended that monitoring of the ANC be performed in all patients taking the medication, and they be instructed to stop the drug and seek medical attention if there is any development of fever [29,37,38].

A report of fatal aplasia in a patient with Diamond-Blackfan anemia [39] has led to concern regarding the use of this agent in patients with marrow failure syndromes. The mechanism of the agranulocytosis is unclear, though it is likely different from that of milder neutropenia. Bone marrow examination has shown early myeloid arrest at the progranulocyte stage [40], as well as more global aplasia [39].

Thionamides — The prevalence of agranulocytosis with thionamide therapy (eg, methimazole [MMI], propylthiouracil [PTU], or carbimazole, a drug available in Europe that is completely metabolized to MMI) ranges from 0.2 to 0.5 percent [41-47]. In one study, agranulocytosis was more frequent in older adult patients taking MMI in doses >40 mg/day; in comparison, the prevalence with PTU was dose-independent [46]. In another report, most cases occurred within three months after treatment was begun [44]. However, these findings are not uniform as a Japanese study found that the development of thionamide-induced agranulocytosis was independent of dose, age, duration of treatment, or second exposure to the thionamide [47]. Controversy exists as to the value of monitoring white blood cell counts in patients taking these medications. (See 'Prevention and screening' below.)

Sulfasalazine — Sulfasalazine, an agent that is reduced by the bacterial enzyme azoreductase to sulfapyridine and 5-aminosalicylic acid, is used in the treatment of inflammatory bowel disease and rheumatoid arthritis. (See "Sulfasalazine and 5-aminosalicylates in the treatment of inflammatory bowel disease" and "Sulfasalazine: Pharmacology, administration, and adverse effects in the treatment of rheumatoid arthritis".)

Most episodes of neutropenia, which occur in 1 to 2 percent of patients treated with sulfasalazine, are mild and transient, although life-threatening agranulocytosis can occur [48-51]. The estimated frequency of agranulocytosis is 0.6 percent in patients with arthritis and 0.06 percent in those with inflammatory bowel disease [49]. In this review, there were no cases of agranulocytosis following the use of mesalamine, a related 5-aminosalicylic acid derivative. Serious episodes of agranulocytosis are usually observed within the first three months of therapy and often within the first six weeks [51].

The adverse effect of sulfasalazine on white cells may be either idiosyncratic or dose-dependent. Distinguishing the different mechanisms is clinically important. Agranulocytosis caused by a hypersensitivity reaction requires drug discontinuation without rechallenge; by comparison, some investigators feel that benign neutropenia can be treated with dose reduction.

Other sulfa drugs, such as trimethoprim-sulfamethoxazole, also are common causes of agranulocytosis [6,52,53].

Ticlopidine — Ticlopidine is a thienopyridine antiplatelet drug that is effective in stroke patients and in preventing coronary stent thrombosis after coronary stenting. However, it causes neutropenia at a rate of approximately 2.4 percent, usually within the first three months of therapy [54-56]. Fatal agranulocytosis with thrombocytopenia has been seen as early as three to four weeks after starting ticlopidine [57,58]. Data from the Food and Drug Administration's MedWatch program collected between 1992 and 1997 revealed 116 cases of agranulocytosis associated with ticlopidine, with 22 deaths [59].

Because of the above risks, which are not seen or seen much less often with clopidogrel, clopidogrel has become the thienopyridine of choice. When ticlopidine is used, it is essential to obtain a complete blood count with platelet count and white cell differential every two weeks for four months after the initiation of therapy.

Rituximab — Neutropenia has been observed following use of the chimeric anti-CD20 monoclonal antibody rituximab for both malignant (eg, lymphoproliferative) and non-malignant (eg, rheumatic) disease [60,61]. It may be severe (grades III-IV), is associated with the period of B cell depletion, with fever and infection in about 17 percent of the cases, and occurs a median of 38 to 175 days following the last rituximab dose, with a median duration of 5 to 77 days [60,62]. Retreatment with rituximab may result in recurrent episodes. The mechanism behind “late onset neutropenia” is unknown, although direct toxicity is thought to be unlikely [63,64]. Myeloid maturation arrest has been noted in some cases [60].

Polymorphisms in FCGR3A (FcgammaRIIIa), a low-affinity receptor capable of binding to the Fc portion of complexed but not monomeric IgG, have been implicated in this process [65,66]. This issue was evaluated in a retrospective analysis of 115 patients with diffuse large B cell lymphoma treated with CHOP plus rituximab chemotherapy, following which 6 percent developed LON [67]. LON developed in 50, 7, and 2 percent of those with the VV, VF, and FF FCGR3A polymorphisms, respectively.

Of interest, in a review of 92 patients who developed late onset neutropenia, all except one had achieved a complete remission from their underlying lymphoproliferative disorder [68]. Rituximab was discontinued from further chemotherapy regimens in many of these patients with no negative impact on their final outcome.

The role of growth factors once late onset neutropenia appears is ill-defined and the decision to use them should be made on a case-by-case basis. In the series of 11 patients with rheumatologic disease who developed late onset neutropenia following treatment with rituximab, the median duration of neutropenia was nine days (range: 4 to 20 days), with nadir absolute neutrophil counts ranging from 100 to 1200/microL (median 700/microL) [60]. Seven of the 11 patients were hospitalized, six with sepsis and one with febrile neutropenia; all required treatment with intravenous antibiotics and six of the seven received treatment with G-CSF. While the neutrophil count recovered in all cases, sustained neutropenia lasting 19 to 20 days was observed in three of the patients who did not receive treatment with G-CSF.

Other biotherapies (alemtuzumab, anakinra, canakinumab, tocilizumab, adalimumab, etanercept infliximab) have also been implicated as causing neutropenia [69].

Quinine — Quinine, which is occasionally used to treat malaria or leg cramps and is an ingredient in certain beverages, is occasionally implicated in causing neutropenia. When it occurs, neutropenia is often accompanied by other organ-system findings that may include thrombocytopenia, microangiopathic hemolytic anemia, rash, acute kidney injury, fever/chills, and others. The mechanism in many cases appears to be an acute, immune-mediated reaction to the drug. Evidence to support these associations was evaluated in a 2016 systematic review of published reports, which found neutropenia in 24 (17 percent) of the 142 patients who had an immune-mediated quinine reaction.

Of quinine reactions, drug-induced thrombotic microangiopathy (DITMA) and drug-induced immune thrombocytopenia (DITP) are more common than drug-induced neutropenia. Additional information about sources of quinine and typical findings in individuals with an adverse drug reaction to quinine is presented separately. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Quinine' and "Drug-induced immune thrombocytopenia", section on 'Medication review/temporal relationship'.)

Cocaine and heroin — The use of heroin and cocaine has been associated with agranulocytosis, likely because these illicit agents were adulterated with levamisole [70-73]. (See "Cocaine: Acute intoxication", section on 'Levamisole'.)

Miscellaneous agents — Along with the antimicrobial agents noted in the table (table 2), oseltamivir has now been associated with neutropenia in adults and children and the antihistamine chlorpheniramine has been associated with neutropenia and agranulocytosis [74].

PATHOGENESIS — There are two basic mechanisms by which drugs cause neutropenia and/or agranulocytosis:

●Immune mediated destruction of circulating neutrophils by drug-dependent or drug-induced antibodies

●Direct toxic effects upon marrow granulocytic precursors.

Idiosyncratic drug reactions are thought to be immune mediated. The onset is usually delayed and can occur as much as a month after the drug has been stopped. As might be expected, the onset of reaction with re-challenge can be much shorter [2].

Both mechanisms appear to be mediated by reactive metabolites [75]. The enzyme system most likely responsible for the formation of reactive metabolites is the NADPH oxidase/myeloperoxidase system found in neutrophils and monocytes [2]. Drugs that are known to be oxidized to reactive metabolites by this system, and which have been associated with agranulocytosis, include clozapine, sulfonamides, dapsone, indomethacin, and amodiaquine [2].

Immune-mediated destruction — The current hypothesis of immune-mediated drug-induced agranulocytosis suggests that the drug, or more commonly a reactive metabolite of the drug, irreversibly binds to the neutrophil membrane. In some cases, the reactive metabolite results in the production of antibodies or T cells directed against the altered membrane structure; in others, true antineutrophil autoantibodies are produced that do not require the presence of the drug [76].

Examples of drugs that bind to the neutrophil membrane and act as haptens in the production of autoantibodies are propylthiouracil (PTU), the antimalarial drug amodiaquine and one of its major metabolites, mono-desethyl amodiaquine, and flecainide [2,20,21,25,42].

With PTU, highly reactive oxidative products are generated using activated neutrophil myeloperoxidase/hydrogen peroxide/chloride. The products, propyl-thioester, sulfinic acid, and sulfonic acid are all thought to be reactive and form macromolecules that bind covalently to the neutrophil membrane [2]. This macromolecular complex can then induce antibodies capable of binding to the haptenized membrane, leading to the phagocytic destruction of the sensitized cell. Cytotoxicity in one patient was demonstrated to be mediated by a complement-dependent IgM antibody [42].

Dipyrone, a pyrazolone analgesic, can also induce the production of antineutrophil antibodies [77]. The drug was banned by the United States FDA in 1977 because of a high risk of agranulocytosis, but is still available in some countries [6,77,78].

Antineutrophil antibodies can be demonstrated by a variety of techniques in most cases of immune-mediated drug-induced agranulocytosis [79]. Laboratory demonstration of antibody binding to target cells often requires the presence of the suspect drug or its metabolites [2].

Direct and indirect toxicity — Some drugs can directly damage myeloid precursors. As an example, detoxification of many nonpolar compounds requires conversion to a chemically reactive intermediate that may bind to nuclear material or cytoplasmic proteins, causing direct toxicity [75]. This mechanism has been described with phenothiazines, in particular chlorpromazine and procainamide [24,80], clozapine, and dapsone [81-83].

●Clozapine is oxidized by granulocytes to a nitrenium ion formed by chlorination of the nitrogen bridge between the two aromatic rings [81]. This metabolite binds covalently and irreversibly to, and is toxic to, neutrophils and their bone marrow precursors [82].

●Dapsone is metabolized to a highly reactive hydroxylamine which is toxic to bone marrow myeloid cells [83]. In one study over a 17-year period, agranulocytosis was estimated to develop in 1 of 240 to 425 patients receiving dapsone therapy [28].

Specific drug-induced reductions in the number and growth of colony forming units can be seen by culture of bone marrow aspirates from affected patients with and without the drug in the medium [84].

CLINICAL PRESENTATION — Most cases of severe neutropenia or agranulocytosis present within the first six months and usually within the first three months after beginning the offending drug [1,3,28,44,48,51,85]. As an example, a review of the literature concerning vancomycin-induced neutropenia indicated that most cases occurred after a minimum of seven days of treatment, with the majority occurring at least 20 days after initiation of treatment [86]. Many patients are asymptomatic at the time that severe neutropenia is detected, particularly if the patient is being monitored for early detection [44].

The clinical presentation is usually oral ulcerations with or without fever. As the onset of agranulocytosis can be abrupt, sepsis can be the presentation [39,40]. Thus, it is critical that all patients taking drugs that can cause agranulocytosis be counseled about this complication and instructed to stop the medication and seek medical attention immediately if such symptoms occur.

Propensity to infection in neutropenic patients is related to adequacy of the marrow reserve pool, and, in patients with decreased reserve, to the ANC (calculator 1) and the duration of neutropenia. In a systematic review of patients with severe neutropenia induced by nonchemotherapy drugs, fatal complications were more frequent in patients with absolute neutrophil counts of <100 compared with 100 to 500 cells/microL (10 versus 3 percent) [1]. (See "Overview of neutropenia in children and adolescents".)

The clinical presentation depends in part upon the etiology and pathogenesis of drug-induced neutropenia or agranulocytosis. (See "Overview of neutropenia in children and adolescents".) The duration of the process before onset of symptoms may depend in part on the mechanism of the neutropenia:

●Immune-mediated destruction may present days to weeks after beginning the drug, often with acute and explosive symptoms. Rechallenge, or inadvertent subsequent administration, is associated with a prompt recurrence even with low doses.

●When direct or indirect toxicity is the operative mechanism, the presentation may be delayed for months. The neutropenia is often asymptomatic or presents with an insidious onset. Rechallenge requires both a latent period and high drug doses before recurrence is observed.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis in a patient in whom the predominant abnormality is neutropenia or agranulocytosis includes other causes of acquired neutropenia. The diagnosis may be suspected from the history and is established by bone marrow examination and, when relevant, other tests. (See "Overview of neutropenia in children and adolescents" and "Approach to the adult with unexplained neutropenia", section on 'Causes of neutropenia'.)

Among neutropenic patients who present with infection, it may not be clear whether the infection is due to, or the cause of, the neutropenia. This may be a very important distinction to make, particularly if the medication is critical to the patient’s care. As certain viral infections can be associated with neutropenia, it would be problematic to permanently discontinue use of an important drug on the mistaken assumption that it is the cause of the neutropenia. Bone marrow examination can be particularly helpful in this case. If the marrow cellularity is normal with a late myeloid arrest, the danger from neutropenia is likely much less, and re-challenge or even continuation with careful monitoring may be possible. (See "Infectious causes of neutropenia".)

PREVENTION AND SCREENING

Overview — There is no effective way to detect the rare patient at high risk for drug-induced severe neutropenia or agranulocytosis. Monitoring of the white blood cell count and white cell differential in order to permit early detection has been used for several drug regimens, such as clozapine and thionamides [3,44].

However, the benefit of monitoring is uncertain. Routine use remains controversial due to the low incidence of agranulocytosis and the expense of repeated white blood cell and differential counts.

In favor of such programs are several studies indicating detection of a large number of patients prior to the development of symptomatic infection, thereby reducing morbidity and mortality. Also in favor of screening is the rapid resolution of neutropenia, often within one to two weeks, once the drug has been discontinued (see 'Treatment' below).

Prophylactic monitoring of the white blood cell count and differential has been evaluated primarily with drugs associated with the highest risk of agranulocytosis, namely clozapine and thionamides.

Clozapine screening programs — The efficacy of prospectively monitoring the white blood cell count during clozapine therapy has been evaluated in two large series:

●After clozapine became available in the United States, weekly monitoring of the white blood cell count and differential was required for continued therapy [3]. At 1.5 years, the cumulative incidence of agranulocytosis was 0.9 percent. Two of the 73 patients who developed this complication died of infectious causes.

●In 4061 Australian patients who were prospectively monitored, the overall incidence of agranulocytosis or neutropenia was 2.6 percent, while the incidence of agranulocytosis was 0.9 percent [87]. There were no deaths from complications of neutropenia or agranulocytosis.

Weekly monitoring of the white blood cell count and differential during the first six months is required in the United States for all patients taking this agent. Details concerning frequency of monitoring and when to interrupt or discontinue this medication are presented separately. (See "Schizophrenia in adults: Guidelines for prescribing clozapine", section on 'Neutrophil count'.)

Deferiprone screening — Complete blood counts at 7 to 10-day intervals are currently recommended for all patients taking deferiprone, and the FDA approval requires that all physicians prescribing this medication counsel patients regarding its use and the risks of fever and neutropenia. Most experienced clinicians agree with this at least for the first year of treatment, although the efficacy of such monitoring has been questioned [40].

Thionamides — A study from Japan evaluated the efficacy of routine monitoring of the white blood cell count in 15,398 patients with Graves' disease receiving thionamide therapy over a 12-year period [44]. An ANC ≤500/microL occurred in 55 patients (0.4 percent), and was detected in the absence of infection in 43, 14 of whom became symptomatic several days after withdrawal of the drug despite antimicrobial therapy.

Most clinicians in the United States do not recommend periodic monitoring of the white blood cell count during thionamide therapy. Instead, we advise patients taking a thionamide to have a white blood cell count with differential at the earliest sign of a sore throat or other infection, and to discontinue the drug until the result is available. (See "Thionamides: Side effects and toxicities".)

TREATMENT

Withdrawal of the offending agent — Once severe neutropenia or agranulocytosis is documented in association with a putative offending drug, the drug should be withdrawn regardless of whether the patient is symptomatic. However, some patients will be taking multiple drugs and identifying the possible offending agent may be difficult [1,88].

Neutropenia usually resolves within one to three weeks after cessation of the offending drug, but there is substantial interpatient variability [85,88,89].

●In one study of 63 episodes in 61 patients, for example, the mean time to recovery was 12 days with a range of 3 to 56 days [88].

●In another series of 10 patients with thionamide-induced agranulocytosis, the median recovery time was 15 days with a range of 5 to 31 days [89].

Treatment of associated infection — Bone marrow aspiration and biopsy may be helpful, although an isolated agranulocytosis in a patient taking a high-risk drug may, in some cases, be treated without bone marrow examination. If the patient is febrile, cultures of blood, urine, sputum, and other suspected sites of infection should be taken and the patient should be started on broad-spectrum intravenous antibiotics. (See "Diagnostic approach to the adult cancer patient with neutropenic fever" and "Overview of neutropenic fever syndromes".)

Older age, sepsis, shock, and renal failure are poor prognostic factors [90].

Granulocyte colony-stimulating factor — Treatment of drug-induced agranulocytosis with granulocyte colony-stimulating factor (G-CSF) is generally associated with shorter recovery times, less antibiotic use, and shorter length of hospitalization compared with historic or concurrent controls, based on small uncontrolled studies [8,79,91-97]. A small, randomized trial found no significant differences in recovery time, but it used subtherapeutic doses of G-CSF.

●In one report, recovery to an absolute neutrophil count (ANC) >1000/microL occurred within one to 15 days (median four days) after initiation of G-CSF in doses of 4 to 10 mcg/kg per day [79]. Seven of the 22 patients had received aggressive antibiotic and/or antifungal treatment for seven or more days before initiation of G-CSF. Two deaths occurred from causes unrelated to G-CSF use. Complete recovery occurred in the remaining 20 patients, with clinical improvement coincident with normalization of the ANC.

●A second study evaluated the effects of G-CSF on recovery at four and 24 hours after injection in 37 patients [92]. In 29 patients (25 with mild neutropenia, ie, ANC 500 to 1000/microL), recovery from granulocytopenia occurred within four hours and remained normal thereafter. In the remaining eight patients, daily G-CSF injections were required for 2 to 11 days. Recovery within four hours suggests that bone marrow suppression was not present, but rather that neutrophils were being released by G-CSF from a storage pool in the marrow.

●A trial that randomized 24 patients with drug-induced neutropenia to G-CSF versus no treatment reported no difference in time to recovery of ANC to >500/microL, but it used subtherapeutic doses of G-CSF (100 to 250 mcg subcutaneously daily) [98].

Although their efficacy is not conclusively proven, growth factors have minimal toxicity in this setting. In spite of the lack of evidence of their efficacy in drug-induced neutropenia outside of the oncology setting [75], it seems likely that most patients with agranulocytosis will receive these drugs. G-CSF can be given (at the recommended dose of 5 mcg/kg per day) subcutaneously, empirically, to patients with significant drug-induced neutropenia who are ill and suspected of having reduced marrow reserve. (See "Overview of neutropenia in children and adolescents".) Treatment with G-CSF can be discontinued when the total white blood cell count exceeds 10,000/microL [97].

Availability of longer-lasting pegylated G-CSF (pegfilgrastim) provides similar benefits as filgrastim with a simpler, less frequent, dosing regimen. However, such agents may be associated with increased bone pain and significant leukocytosis in patients who have a short duration of neutropenia. (See "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation" and "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation", section on 'Long-acting agents'.)

AGRANULOCYTOSIS — Agranulocytosis is a rare condition with a reported incidence ranging from 1 to 5 cases per million population per year [99-105]. An association with medication use can be found in about 70 percent of cases [101].

Risk factors — Specific risk factors for agranulocytosis were evaluated in a prospective survey performed by the International Aplastic Anemia and Agranulocytosis Study (IAAAS) in Europe and Israel from 1980 to 1986 [106,107]. The following findings were noted:

●The incidence rose sharply with age; only 10 percent of cases occurred in children and young adults, while more than 50 percent of cases occurred in patients over age 50.

●Agranulocytosis was almost twice as frequent in females, accounting for approximately 70 percent of cases. The sex difference may be due in part to greater consumption of medications at higher risk of causing neutropenia by adult females. This hypothesis is supported by the lack of preponderance of agranulocytosis in female children [108]. There may, however, be a true increase in incidence in females. In a study of 11,555 patients receiving the atypical antipsychotic agent clozapine, the risk of agranulocytosis was significantly higher among females [3].

Other risk factors for agranulocytosis include [79]:

●A possible increase in risk in patients with infectious mononucleosis [109].

●Impaired drug excretion in the urine due to renal failure or the concomitant use of probenecid in patients taking captopril [110].

●Underlying autoimmune disease.

●Combination therapy with an angiotensin converting enzyme inhibitor and interferon may be associated with a particularly high risk of severe neutropenia. In a series of patients with mixed cryoglobulinemia who were treated with interferon, severe neutropenia developed within a few days in all three patients also receiving an ACE inhibitor but in none of 35 patients treated with interferon alone [4].

There is evidence for genetic susceptibility in certain populations.

●The HLA-B38 phenotype and the combined alleles DR4 and DQw3, which occur frequently in Ashkenazi Jews, occur with increased frequency in patients with clozapine-induced agranulocytosis [5]. The associated gene within the MHC region appears to be marked by variants of the heat shock protein 70 gene [111].

●Among Japanese patients with Graves' disease, the HLA DRB1*08032 allele appears to be strongly associated with susceptibility to methimazole-induced agranulocytosis [41].

●Agranulocytosis secondary to treatment with levamisole, an agent no longer available in North America for human use, has been associated with presence of HLA-B27 [70]. This agent has reappeared as a cause of agranulocytosis or severe neutropenia as a result of its being added to cocaine and heroin, perhaps to potentiate its euphoric effects [71,72,112]. (See 'Cocaine and heroin' above.)

Prognosis — A number of adverse prognostic factors have been reported for patients with agranulocytosis. These include [1,2,97]:

●Age >65 years

●Absolute neutrophil count at the time of diagnosis <100/microL

●Development of severe intercurrent infection (eg, septicemia, septic shock)

●Pre-existing comorbidities (eg, renal, cardiac, respiratory, systemic inflammatory diseases)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neutropenic fever in adults with cancer".)

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topics (see "Patient education: Neutropenia (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Definitions:

•Neutropenia – Absolute neutrophil count (ANC) <1500/microL; calculated using white blood cell count (WBC) and percentage of polymorphonuclear cells (PMNs) and bands (calculator 1):

ANC = (WBC/microL] x percent [PMNs + bands]) ÷ 100

•Agranulocytosis – Absence of granulocytes (ie, ANC = 0), but the term is often used loosely to indicate severe neutropenia (ie, ANC <100, <200/microL).

●Drug-induced agranulocytosis – Idiosyncratic drug reactions (IDR) are uncommon (eg, 1/10,000 to 1/100,000).

Drugs that are associated with high risk for agranulocytosis (table 2) include:

•Clozapine

•Antithyroid drugs

•Sulfasalazine

•Ticlopidine

•Other – Antibiotics, angiotensin-converting enzyme (ACE) inhibitors, H2 blockers, nonsteroidal anti-inflammatory drugs (NSAIDS), amodiaquine, antiarrhythmic drugs, dapsone, and deferiprone.

●Mechanisms – There are two basic mechanisms of drug-induced neutropenia:

•Immune – Immune-mediated destruction of neutrophils (by drug-dependent or drug-induced antibodies).

•Toxicity – Direct toxic effects on marrow granulocytic precursors.

●Presentation – Most patients have oral ulcerations, with or without fever; if the onset is abrupt, the patient may present with a severe infection/sepsis. Neutropenia usually begins three to six months after beginning the offending drug, but the interval may vary with the cause (eg, days to weeks with immune-mediated, but months for direct toxicity).  

●Diagnosis – Suspected in a patient with fever or mouth sores with sudden and/or unexpected neutropenia weeks to months after beginning a drug.

Diagnosis is based on neutropenia in the proper clinical context; bone marrow examination is not required. The diagnosis is more likely with low/absent ANC without anemia or thrombocytopenia and when the ANC normalizes after withdrawal of the offending agent.

●Differential diagnosis – Concomitant viral infection, nutritional deficiency (eg, copper or vitamin B12 deficiency), other acquired and inherited disorders. (See "Overview of neutropenia in children and adolescents" and "Approach to the adult with unexplained neutropenia", section on 'Causes of neutropenia'.)

●Management

•Drug withdrawal – The suspected drug should be withdrawn, whether symptomatic or not. Neutropenia usually resolves within one to three weeks after drug cessation, but timing varies.

•Cytokine support – For symptomatic neutropenia, we generally administer granulocyte colony-stimulating factor (G-CSF) to shorten recovery time, reduce antibiotic use, and decrease length of hospitalization.

●Prevention/screening – Patients receiving a medication known to cause neutropenia should be instructed to stop the medication and seek immediate medical attention if they develop mouth sores/other mucosal ulcerations and/or fever.

For certain drugs (eg, clozapine, thionamides), monitoring the WBC count/differential permits early detection. (See 'Prevention and screening' above.)

●Agranulocytosis – A rare condition (eg, 1 to 5 cases per million population/year); suspected drugs are identified in two-thirds of patients. (See 'Agranulocytosis' above.)

•Risk factors – Incidence increases with age, in females, and in association with autoimmune conditions and certain human leukocyte antigen (HLA) genotypes. (See 'Risk factors' above.)

•Prognostic factors – Worse outcomes are associated with age >65 years, ANC <100/microL at diagnosis, severe intercurrent infection, and comorbid conditions.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges the late Laurence A Boxer, MD, for his previous role as a section editor for this topic.