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Andrès E, Mourot-Cottet R, Maloisel F. J Lung Health Dis (2018) 1(1): 31-38

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Diagnosis and management of idiopathic drug-induced and severe and agranulocytosis: What should the lung specialist know? Emmanuel Andrès1*, Rachel Mourot-Cottet1, Frédéric Maloisel2 1Departments of Internal Medicine B, University Hospital of Strasbourg, Strasbourg 67000, France 2Department of , Saint Anne’s Clinic, Strasbourg 67000, France

Article Info ABSTRACT

Article Notes In this paper, we report and discuss the diagnosis and management of severe Received: August 16, 2017 neutropenia and agranulocytosis ( count of <0.5 x 109/L) related to Accepted: January 18, 2018 non- drug intake, called “idiosyncratic”. Lung specialists may *Correspondence: be faced with these events. In fact, all classes of drugs have been implicated Pr. E. ANDRÈS, Service de Médecine Interne, Clinique (“causative”) and clinical manifestations may include or related Médicale B, Hôpital Civil, Hôpitaux Universitaires de disorders. Recently, several prognostic factors have been identified that may Strasbourg, 1 Porte de l’Hôpital, 67 091 Strasbourg Cedex, be helpful when identifying frailty patients. Old age (>65 years), septicemia or France; Telephone: 33-3-88-11-50-66; shock, metabolic disorders such as renal failure, and a neutrophil count below Fax: 33-3-88-11-62-62;; 0.1×109/L have been consensually accepted as poor prognostic factors for Email: [email protected] hematological recovery. In this potentially life-threatening disorder, modern © 2018 DAndrès E. This article is distributed under the terms of management with broad-spectrum antibiotics and hematopoietic growth the Creative Commons Attribution 4.0 International License. factors (particularly G-CSF), is likely to improve the prognosis. Thus, with appropriate management, the mortality rate of idiosyncratic drug-induced Keywords severe neutropenia and agranulocytosis is currently around 5%. Agranulocytosis Neutropenia Drugs Pneumonia Introduction Antibiotics Hematopoietic growth factor Severe neutropenia is characterized by a profound decrease of circulating , also called agranulocytosis in case of a neutrophil count of <0.5 x 109/L (associated or not with fever)1,2.

cases of acute and severe pharyngeal infections, associated with a lackSchultz of granulocytes first introduced in the the blood term in “agranulocytosis”relation with drug inintake. 1922, Such for

unpredictable event (named “idiosyncratic”)1,2. As in isneutropenia typically serious, related with around 50% of cases exhibiting severe and a mortality rate of 10-20% these twenty later years to chemotherapy, modern management of such event may reduce the -related mortality. All practitioners as the lung specialists may be informed and attentive of this potential life-threatening event, event in case of “daily” or “everyday” medication exposure, aggregationas: antibiotics inhibitors. (beta-lactams, cotrimoxazole), antithyroid drugs, neuroleptic, non-steroidal anti-inflammatory agents, and platelet In the present paper, we report and discuss the diagnosis and

neutropenia and agranulocytosis. management of idiopathic drug-induced (or drug-associated) severe

Page 31 of 38 Andrès E, Mourot-Cottet R, Maloisel F. J Lung Health Dis31-38 Journal of Lung Health and Diseases

Search strategy I per year7. In our experience (observational study in a PubMed n the USA, reported ranges from 2.4 to 15.4 per million database of the US National Library of Medicine and on A literature search was performed on the Scholar Google. We searched for articles published between French hospital), from 1996 to 2017, the annual incidence [of8 symptomatic idiosyncratic agranulocytosis remained stable, with approximately 6 cases per million population January 2010 and February 2017, using the following key ]. It’s important to note that the incidence remains words or associations: “drug-induced neutropenia”, “drug- unchanged, despite the withdrawn 2of incriminated drugs induced agranulocytosis”, “idiosyncratic neutropenia” and . This is in relation (which carry a high risk) and increased levels of medical “idiosyncratic agranulocytosis”; restrictions included: awareness and English- or French-language publications; published from induced by new drugs. trials, review articles or guidelines. All of the English and with the development of neutropenia and agranulocytosis Jan. 1, 2010, to Feb. 31, 2017; human subjects; clinical

French abstracts were reviewed by at least two senior publishedDifferences1,2. Geographic in the observed variability incidence in incidence may beis related due to researchersAmerican from Society our workof Hematology group. educational books, different methods/inclusion criteria used in the studies could also suggest genetic differences in susceptibility. to both differences in reporting and medication usage but alsotextbooks used. of Hematology and Internal medicine, and information gleaned from international meetings were drug-induced neutropenia, probably because of increased Definition Older patients 2 are. thought to be at greater risk for to Most, but not all cases of neutropenia and agranulocytosis medication use 9/L occur as a result of exposure to drugs [3 to educateAs we have all practitioners, shown below, including everyday thosemedication practicing can bein defined at least by a neutrophil count of <0.5 x 10 involved in such blood event. It is therefore very important ]. All drugs may be the hospitals or in the city. causative agents, particularly: chemotherapy, immune speciality as lung specialists, and pharmacists, those in modulator agents or biotherapies. Other daily drugs may Causative drugs be also more rarely incriminated. Such event1. Either is called the “idiosyncratic drug-induced” or “idiosyncratic drug- agent.associated” neutropenia and agranulocytosis For practitioners and pharmacists, it is important drug itself or one of its metabolites may be the causative to keep in mind that almost all classes1,2,9-11 of drugs. However, have forbeen drugs implicated such (“causative”), as antithyroid but fordrugs, the majorityticlopidine, the The recommended criteria for diagnosing blood risk appears to be very small (table 2) cytopenias2,4. andThese for implicatingcriteria are a outlineddrug as a incausative table 1.agent As , phenothiazines, sulfasalazine,10,11 trimethoprim- idiosyncraticin neutropenia severe are derived neutropenia from an and international agranulocytosis consensus are sulfametoxazole (cotrimoxazole), and dipyrone or life-threateningmeeting conditions, no patient was re-challenged sulfasalazine,per 10,000 users the has risk been may reported be higher1 . For antithyroid drugs (propyl-thiouracil and méthimazole),9. Clozapine a risk induces of 3 with the incriminated drug (“theoretical method of . For ticlopidine, the reference”).Epidemiology risk is more than 100-fold higher agranulocytosis in almost 1%11 of patients, particularly in Idiosyncratic severe neutropenia or agranulocytosis is a . the first three months of treatment, with older patients and rare disorder. In Europe, the annual incidence of such events females being at a higher risk 2,5,6. In our single center cohort (n=203), the most frequent is between 1.6 and 9.2Table cases 1: Criteria per million for idiosyncratic population drug-inducedcausative agranulocytosis drugs (adapted are: antibioticsfrom 1-3[ ]). (49.3%), especially Definition of agranulocytosis Criteria of drug imputability • Onset of agranulocytosis during treatment or within 7 days of exposure to the drug, with a complete recovery in neutrophil count of more than 1.5 x 109/L within one month of discon- tinuing the drug Neutrophil count <0.5 x 109/L ± exis- • Recurrence of agranulocytosis upon re-exposure to the drug (this is rarely observed, as the tence of a and/or any signs of high risk of mortality contra-indicates new administration of the drug) infection • Exclusion criteria: history of congenital neutropenia or immune mediated neutropenia, recent infectious disease (particularly recent viral infection), recent chemotherapy and/or radiothera- py and/or immunotherapy* and existence of an underlying haematological disease *Immunoglobulins, interferon, anti-TNF antibodies, anti-CD20 (rituximab)…

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Table 2: Drugs implicated in the occurrence of agranulocytosis [1-3]. Family drug Drugs Analgesics and nonsteroidal Acetaminophen, acid acetylsalicylic (aspirin), aminopyrine, benoxaprofen, diclofenac, diflunisal, dipyrone, anti-inflammatory drugs fenoprofen, indomethacin, ibuprofen, , , piroxicam, sulindac, tenoxicam, tolmetin , chlomipramine, chlorpromazine, chlordiazepoxide, clozapine, diazepam, fluoxetine, haloperi- , hypnoseda- dol, levopromazine, , , indalpin, meprobamate, , olanzapine, phenobarbi- tives and antidepressants tal, phenothiazines, risperidone, tiapride, ziprasidone Antiepileptic drugs , , , , , valproic acid (sodium ) Antithyroid drugs Carbimazole, methimazole, potassium perchlorate, potassium thiocyanate, propylthiouracil Acid acetylsalicylic, , aprindine, , captopril, coumarins, dipyridamole, digoxin, flurbipro- Cardiovascular drugs fen, furosemide, , lisinopril, , , phenindione, , propafenone, propanolol, , ramipril, , diuretics, ticlopidine, vesnarinone Abacavir, acyclovir, , , cephalosporins, , chloroguanine, chloro- quine, ciprofloxacin, , , ethambutol, , fusidic acid, ganciclovir, gentamicin, , , levamizole, lincomycin, , macrolids, , , Anti-infective agents , minocycline, nitrofurantoin, norfloxacin, novobiocin, penicillins, , , rifampicin, streptomycin, terbinafine, , thioacetazone, , trimethoprim-sulfametoxazole (cotrimoxazole), vancomycin, Acetazolamide, acetylcysteine, allopurinol, aminoglutethimide, arsenic compounds, benzafibrate, bromphe- niramine, calcium dobesilate, chloropheniramine, , , dapsone, deferiprone, mercurial diuretics, famotidine, flutamide, gold salts, glucocorticoids, glyburide, hydroxychloroquine, levodopa, mesal- Miscellaneous drugs azine, metapyrilène, methazolamide, , olanzapine, omeprazole, oral hypoglycemic agents (), penicillamine, prednisone, ranitidine, , sulfasalazine, most sulfonamides, sulfony- lureas ,3tamoxifen, thenalidine, tretinoid, tripelennamine

ß-lactams and cotrimoxazole; antithyroid drugs (16.7%); especiallyneuroleptic ticlopidine and anti-epileptic [8 agents (11.8%); antiviral agents (7.9%); and platelet aggregation inhibitors (6.9%), was observed, respectively.]. Since 1990Conversely, and 2000, nocases case of idiosyncraticnoramidopyrine- agranulocytosis and ticlopidine-induced associated agranulocytosiswith clozapine or antiviral agents were observed only since 200010,12. and 2005, respectively. These findings are similar to two recent reportsIn our that cohort incriminated study, twothe samethirds drug of familiespatients received drugmore responsible than two for drugs the agranulocytosis. with a mean In of this three cohort, drugs, no accounting for the difficulty in definitively8. No identifying inappropriate the Figure 1: Chest radiography in a patient with absolute neutrophil 9 over “self-medication” was documented count <0.39 x 10 /L: bilateral extensive pneumonia. prescribing, as the use of drug that pose more risk than benefit, the misuse of drugs by dose or duration, is also i identified.Recently, several new drugs have been listed as causative agents for severe neutropenia and agranulocytosis, e.g. nsidiously, depending on the time course of neutropenia development. Symptomatic patients commonly present ( andat discovery brutal event,a non-specific a severe sore deep throat, and acute potentially tonsillitis life- or acyclovir, ganciclovir, lamotrigine, terbinafine or deferiprone ). threateningsinusitis. More infection rarely, patients have first, as a not expected http://www.mhpharmacotherapy.com/0071800530/ Clinical manifestations 2 online_pdfs/24_Dipi_Web_Ch24_359-374.pdf . It’s important to note that without severemedical and intervention, potentially particularly life-threatening immediate infections antibiotics with drug-induced severe neutropenia and agranulocytosis administration, natural history of agranulocytosis includes usuallyInitially, present symptomatic with fever, which patients often with is the idiosyncratic earliest and hypotension…). often signs of general sepsis and septicemia (fever, , chillssometimes the only sign during evolution. This later is 1) as well as anorectal, skin or oropharyngeal infections often 1,2 associated with general malaise, often including During the evolution, documented pneumonia (figure . Symptoms may appear either immediately or Page 33 of 38 Andrès E, Mourot-Cottet R, Maloisel F. J Lung Health Dis31-38 Journal of Lung Health and Diseases

Figure 2: Chest radiography in a patient with absolute neutrophil count <0.1 x 109/L: “masked” pneumonia. Figure 3: CT-scan in a patient with absolute neutrophil count <0.1 x 9 . 10 /L: lung aspergillosis. 1,2,8 and septic shock were the most reported infections air crescent signs) open up a wide range of differential To date, classical manifestations as necrotic tonsillitis and perinea gangrene or are exceptional. Beside these “loud” diagnoses, such as invasive pulmonary aspergillosis, becausemanifestations, of the neutropenia. clinicians must keep in mind that the signs of these infections may be sometimes crude and atypical other types of pneumonia, hemorrhage, infiltration by the The clinical presentations recorded in our underlying malignancy, drug toxicity, alveolar proteinosis, or acute respiratory distress syndrome. High-resolution techniques or magnetic resonance imaging may provide aforementioned cohort study (n=203) mainly included intervention.further details to help distinguish inflammatory processes [8]: isolated fever (unknown origin) (26.3%); septicemia from processes that may not require an antimicrobial (13.9%); documented pneumonia (13.4%); and acuteexhibited tonsillitis features (9.3%); of severe and septic sepsis, shock septic (6.7%). shock, While or in hospital, 19.2% of the patients worsened clinically A causative pathogen, typically Gram-negative bacilli asor secondary Gram-positive infective cocci agents (mainly2 (>10%), Staphylococcus however spp.),in a systemic inflammatory response syndrome (SIRS). fewwas per isolated cent inof 30%cases ofin casesregard. Fungito neutropenia are also involved related For lung specialists, it is to note that pneumonia is observed only one case of invasive lung aspergillosis often asymptomatic because of the lack of neutrophil cells. to chemotherapy. In more than 200 patients, we have Thus, it is frequent to see despite a true lung infection: no 8 purulent sputum, few clinical sign on auscultation (few sinus and the lung . (figure 3) and one case of mucormycosis of the maxillary crackles),2 and no image on X-ray for pneumonia (figure 2) . In this situation, thoracic CT-scan may be proposed with much better results. It is notable that when antibiotics Modern molecular techniques, including expanded are administered prophylactically, or at the beginning of use of galactomannan testing, have further facilitated this adverse event, both the patient’s complaints and the identification of fungal pathogens, allowing for aggressive only clinical sign detected . It is worth noting, that in elderly patients, clinical physical findings may be 1,2“masked” and fever is often the interventions that appear to improve patient outcomes. or septic shock in at least two-thirds of patients in our Conventional chest radiographs frequently fail to detect experience,manifestations as werewe have generally previously more severe,published with septicemia. It is also lung infiltrates at an early stage, meaning that a normal 13 chest radiograph finding must be interpreted with caution. Thoracic CT scans provide a much higher yield and are the case in patients with associated morbidities as chronic therefore recommended in patients at risk for a complicated cardiac failure, chronic obstructive pulmonary disease, ground-glasspulmonary infection. opacities, Lungor cavitations infiltrates with documented or without by renal failure and immune. disorders. In our experience, CT scans (e.g., nodular infiltrates with or without a halo, the depth of the neutropenia2 impacts the severity of the clinical, manifestations

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At the opposite1. This side,supports some patientsthe case (<20%)for routine (not- underlyingIn our experience, pathology inbone the elderlymarrow2. Inexamination patients with may drug- not well identified characteristics or profile) remained be required for all patients, but is pivotal to exclude an asymptomatic . monitoring of blood counts in individuals receiving high-1,14 induced agranulocytosis, the bone marrow typically shows risk medications such as antithyroid drugs or ticlopidine a lack of mature myeloid cells, whereas in other cases, history,This also with supports fever asa notthe consensualsole sign)1. home management of immature2. cells from the myelocyte stage are preserved. such an event in certain patients (young, without medical This latter appearance is described as “myeloid maturation Differential diagnosis Prognosisarrest” and mortality rate Theoretically, acute neutropenia is classically diagnosed Drug-induced severe neutropenia and agranulocytosis count of <0.5 x 109/L,1,2 2 neutrophilin a blood count sample, is under resulting 0.1 x 10 in 9/L. an Thus, absolute the differential neutrophil usually resolves over time with supportive care and diagnosis of such acute and. In severe the majority neutropenia of patients, in adults the management of infection . The time to neutrophil recovery 2 has typically been reported to range8 from 4 to 24 days. In our aforementioned cohort study (n=203), outcome9/L) was is includes a limited number of conditions . In fact, the main favorable in 91.6% of subjects . The mean duration of neutropenia,differential diagnoses with an absoluteinclude myelodysplastic neutrophil count syndromes between hematological recovery9 (neutrophil count ≥1.5 x 10 1.5and acuteto 0.5 . x 109 All other conditions induced moderate 7.8 days (range: 2-20). The median duration for neutrophil neutropenia secondary to sepsis, particularly viral count ≥0.5 x 10 /L is 6.8 days (range: 1-24). /L. These conditions mainly includes: idiosyncratic agranulocytosis was 10-16% in European studiesOver1,2 .the However, past twenty this has years, recently the fallen mortality to 5% rate (range, for infections or bacterial infections (severe Gram negative2 infections with Salmonella sp.…, tuberculosis, Brucella sp.); rarer differential diagnoses include neutropenia secondary 2.5 to 10%). This is likely due to improved recognition, and neutropenia associated with hypersplenism . Other, management and treatment of the condition. The highest 2 . mortality rate is observed in frailty patients: older patients to nutritional deficiencies, Felty’s syndrome, systemic (>65 years), with poor performance status, as well2,15 as those lupusIn erythematosusthe literature, or Sjögren’ssevere syndromeneutropenia (absolute . neutrophil count < 0. 5 x 109/L) has been shown to be with several comorbidities as renal failure, chronic heart 1. Thus in failure; septicemia or shock at diagnosis (table 3) practice, drug-induced neutropenia or agranulocytosis attributable to drugs in 70 to 90% of cases We have recently confirmed indirectly these findings by performing a uni- and multivariate analysis8 . In of should be discussed routinely (considered in first) even if factors affecting the hematological recovery, duration there is a context moving towards another condition. In this wasof hospitalization not found to be and associated outcome with in our a delayed cohort studyrecovery. context, the clinician must keep in mind that in all cases, this study, bone marrow showing a lack of myeloid cells the patient’s 1,2medication. history must be carefully obtained in chronological order so that the suspected agent(s) may Previously, we have demonstrated that several variables be identified Table 3: Impact factors for the prognosis* of idiosyncraticwere drug-induced significantly agranulocytosis associated (adapted with from a longer[9,21]. neutrophil • Age: >65 years Negative impact on duration of hematological recovery**, duration of hospitalization and antibiotherapy

• Neutrophil count at diagnosis: ≤0.1 x 109/L Negative impact on duration of hematological recovery, duration of hospitalization and antibiotherapy

• Clinical status: Deep severe infections or bacteremia or septic Negative impact on duration of hospitalization and shock (versus isolated fever) antibiotherapy and of mortality

• Severe underlying disease or severe co-morbidity: Renal failure, Negative impact on duration of hematological recovery and cardiac or respiratory failure, systemic auto-inflammatory hospitalization diseases

• Management with pre-established procedures and Positive impact on duration of hematological recovery, duration hematopoietic growth factor for use in severe conditions of hospitalization and of mortality

* Prognosis: hematological recovery, duration of hospitalization and antibiotherapy, mortality) * * Hematological recovery: absolute neutrophil count >1.5 x 109/L.

Page 35 of 38 Andrès E, Mourot-Cottet R, Maloisel F. J Lung Health Dis31-38 Journal of Lung Health and Diseases

9/L), as: an absolute neutrophil agranulocytosis but are based on the evidence based- count of <0.1 x 109 recoveryand/or shock time16 (>1.5. x 10 . /L at diagnosis, as well as septicemia medicine recommendations for the management 2,3 of Supportive management ofchemotherapy-induced concentrates neutropenia should (field only of be oncology) used in It’s also important to keep in mind that transfusion induced severe neutropenia and agranulocytosis begins life-threatening infections with antibiotic resistance - such In practice, the management of idiosyncratic drug- asexceptional perineal gangrenecircumstances,. and only then for the control of . Thus, the 2 with the immediate withdrawal of any1,2 medications, Antimicrobial therapy inwhich chronological may potentially order so be that responsible the suspected agent(s) patient’s medication history must be carefully obtained The occurrence of sepsis requires prompt management,. In our suchmay as be clozapine, identified. ticlopidine In our opinion, and antithyroid routine drugs monitoring. All without any delay, including the administration1,2 of for agranulocytosis is required in some high-risk drugs,1,2 broad-spectrum intravenous antibiotic therapy . hospital, we commonly combine in first line therapy, new cases of drug-induced neutropenia2 must be notified to the cephalosporins and quinolones or aminoglycosides [8]. pharmacovigilance center Of course ureidopenicillins beta-lactam/beta-lactamase without any delay . It should be noted that as a result of inhibitor combinations, as carbapenems, or imipenem All febrile patients2 should be admitted to hospital, can be safely used in these antibiotic combinations. The addition of intravenous vancomycin or teicoplanin is neutrophil deficiency, both the patient’s symptoms and only clinical sign lineconsidered of antibiotics in patients with atat highleast risk cephalosporins of serious gram-positive. the physical findings1,2 may be altered, and fever may be the infections or after 48 hours of continued fever1,2 despite first . Important. prognostic factors resulting When an antibiotic is suspected of being the causative in an increased risk of2,16 serious complications must be systematicallyPatients with searched a low risk of infection, with none of the the potential for antibody cross-reactivity, and therefore agent resulting in neutropenia, one should keep in mind be considered very carefully1. bad factors of prognosis and good performance status, the choice of further antibiotics to be administered should should also usually be treated in hospital,1. Nevertheless unless adequate to date, In patients with a persistent fever despite broad- and comprehensive medical follow-up can be provided in an ambulatory setting or at home several not frailty patients are managed in home with spectrum antibiotics against Gram-negative bacilli or Gram- intensive supervision and monitoring! positive cocci or systematically after 1 week of persistent fever, the addition of empirical antifungal agents should Concomitant measures include realization of multiple caspofunginbe considered,. as or related derivates (e.g. asmicrobial well assamples the prevention(blood, urine, of stool secondary and sputum infections cultures). liposomal preparation2 of amphotericin) and voriconazol or and aggressive treatment of confirmed or potential sepsis,1,2 Usefulness of hematopoietic growth factor fungal infections, using Aspergillus antigen sandwich Since 1985, two-thirds of reported cases of Sequential nonculture-based monitoring for invasive idiosyncratic agranulocytosis have been treated with enzyme-linked immunosorbent assay, and panfungal or . We do not use or Aspergillus-specific polymerase chain reaction, may add hematopoietic growth factors, especially17 Granulocyte- important tools in the early identification of patients who Colony Stimulating Factor (G-CSF) may benefit from systemic antifungal treatment. recommend Granulocyte -Colony Stimulating control, paying particular attention to high-risk areas such Factor (GM-CSF), because of lower efficiency and reported Preventive measures include good1 hygiene and infection . Patient isolation and the side effects as pulmonary . To our knowledge, use of prophylactic antibiotics (e.g. for the gastrointestinal no data is available with pegylated G-CSF. The most recent,18- as the mouth, skin and perineum major studies on hematopoietic growth factors use in 22drug-induced agranulocytosis are described in table 4 tract) have been proposed, but their usefulness in limiting has not been clinically proven . . In our aforementioned cohort, a faster hematological the risk of infection has not been2 documented or at least, non significantly recovery (neutrophil count >1.5 x 109/L) was observed in the hematopoietic growth factors The occurrence of sepsis requires prompt management, group: 2.1 days (p=0.057) [8]. Nevertheless, we observed without any delay, including the administration1,2 of broad- relatingno other to duration improvements of antibiotherapy in these patientsand hospitalization. associated spectrum intravenous antibiotic therapy . It’s importantr with hematopoietic growth factors therapy, particularly to note that these recommendations are not validated specifically for idiosyncratic severe neutropenia o These results do not go in the same direction as those Page 36 of 38 Andrès E, Mourot-Cottet R, Maloisel F. J Lung Health Dis31-38 Journal of Lung Health and Diseases

Table 4: Recent studies on the use of hematopoietic growth factors in idiosyncratic drug-induced agranulocytosis (adapted from [17-22]). Type of study and target population Main results - All patients with idiosyncratic drug-induced agran- ulocytosisSystematic review of all published cases (n=492); neutrophilTreatment withcount hematopoietic <0.1 x 109/L growth factors was associated with a statistical ly significantly lower rate of infectious and fatal complications, in cases with a - recovery (neutrophil count >0.5 x 109 cratic drug-induced agranulocytosis G-CSF or GM-CSF (100 to 6009 µg/day) reduced the mean time to neutrophil Meta-analysis (n=118); All patients with idiosyn neutrophil count <0.1 x 10 /L) from 10 to 7.7 days, in cases with a patients with idiosyncratic drug-induced agranulo- /L, and reduced the mortality rate from 16 to 4.2% cytosisCase control study, retrospective analysis (n=70); All 10G-CSF9/L and GM-CSF (100 to 600 µg/day) reduced the recovery of neutrophil count from 7 to 4 days, particularly in patients with a neutrophil count <0.1 x with idiosyncratic drug-induced agranulocytosis Cohort study, retrospective analysis (n=54); Patients >65 years of age, with poor prognostic factors G-CSF (300 µg/day) significantly reduced the mean duration for hematological recovery from 8.8 to 6.6 days (p <0.04). G-CSF reduced the global cost with antithyroid drug-induced agranulocytosis and G-CSF (300 µg/day) significantly reduced the mean durations of hematological poorCohort prognostic study, retrospective factors analysis (n=20); Patients globalrecovery, cost antibiotic therapy and hospitalization from: 11.6 to 6.8 days, 12 to 7.5 days and 13 to 7.3 days, respectively (p <0.05 in all cases). G-CSF reduced the patients with idiosyncratic drug-induced agranulo- cytosisCohort study, retrospective analysis (n=145); All G-CSF shortens time to recovery in patients with agranulocytosis patients with idiosyncratic drug-induced agranulo- Cohort study, retrospective analysis (n=201); All cytosis G-CSF (300 µg/day) reduced the mean durations of hematological recovery for 2.1 days (p=0.057). with antithyroid drug-induced agranulocytosis G-CSF:Prospective Granulocyte-Colony randomized study Stimulating (n=24); factor.All patients GM-CSF: G-CSF Granulocyte--Colony (100 to 200 µg/day) did not Stimulating significantly factor. reduce the mean duration for hematological recovery we had previously reported , but are consistent with 2 growth factors therapy in idiosyncratic agranulocytosis hematological recovery; duration of hospitalization and patientsthose reported1 in recent larger studies of hematopoietic the outcome; and (iv) supportive management, broad- spectrum antibiotics in case of any sepsis sign and in such patients.. Thus, forTo certainsupport Hematologistthis view, the theonly usefulness available hematopoietic growth factors as G-CSF is likely to improve of hematopoietic growth factors remains controversy Fundingthe prognosis, and with Conflict a currently of interest mortality rate around 5%. No sources of funding were used to assist the preparation prospective randomized study (based on 24 patients with antithyroid-related23 agranulocytosis) did not confirm the. In benefit of G-CSF . Nevertheless, this negative result may2 be of this manuscript. The authors have no conflicts of interest related to inappropriate G-CSF doses (100-200 µg/day) that are directly relevant of the content of this manuscript. our cohort study, we have established the long-term (mean E. Andrès is recipient of a grant from CHUGAI, AMGEN, follow-up >52 months) safety of hematopoietic growth ROCHE, GSK, NOVARTIS but these sponsors had no part disordersfactors, in .the absence of hematological adverse events in the research or writing of the present manuscript. F. such as myelodysplasia24 and hematological proliferative Maloisel is recipient of a grant from CHUGAI, AMGEN, Conclusions ROCHE, SHIRE, GSK but these sponsors had no part in the researchReferences or writing of the present manuscript. 1. In conclusion, for practitioners and pharmacists, 2007Andersohn F, Konzen C, Garbe E. Non-chemotherapy drug-induced especially for lung specialists, it is important to keep in agranulocytosis: A systematic review of case reports. Ann Intern Med. mind that: (i) all drugs may be causative for idiosyncratic ; 146: 657-65. agranulocytosis, but mainly antibiotics (beta-lactams and 2. Andr2011ès E, Zimmer J, Mecili M, et al. Clinical presentation and cotrimoxazole), carbimazole, clozapine and ticlopidine; (ii) management of drug-induced agranulocytosis. Expert Rev Hematol. ; 4: 143-151. idiosyncratic agranulocytosis remains a potentially serious adverse event due to the frequency of severe sepsis, with 3. DrugPatton Safety. WN, 1994 Duffull SB. Idiosyncratic drug-induced haematological abnormalities: incidence, pathogenosis, management and avoidance. pneumonia, septicemia, and septic shockities in suchtwo-thirds as renal of ; 11: 445-62. all hospitalized patients; (iii): old age, poor performance failure, and a neutrophil count below 0.1×109/L have 4. Bénichou C, Solal-Celigny P. Standardization of definitions and criteria status, septicemia or shock, comorbid for causality assessment1993 of adverse drug reactions. Drug-induced blood cytopenias: report of an international consensus meeting. Nouv been consensually accepted as factors that impact the Rev Fr Hematol. ; 33: 257-62. 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5. 15. case-cohort study of drug-associated agranulocytosis. Arch Intern 1991 VMed.an der 1999 Klauw MM, Goudsmit R, Halie MR, et al. A population-based Julia A, Olona M, Bueno J, et al. Drug-induced agranulocytosis: prognostic factors in a series of 168 episodes. Br J Hematol. ; 6. ; 159: 369-74. 16. 79: 366-72. 2003 Van Staa TP, Boulton F, Cooper C, et al. Neutropenia and agranulocytosis Maloisel F, Andrès E, Kaltenbach2003 G, et al. Prognostic factors of in England and Wales: incidence and risk factors. Am J Hematol. ; hematological recovery in nonchemotherapy drug-induced 72: 248-54. agranulocytosis. Haematologica. ; 88: 470-1. agranulocytosis. Arch Intern Med. 1992 7. Strom BL, Carson JL, Schinnar R, et al. Descriptive epidemiology of 17. Andrès E, Maloisel F, Zimmer J.2010 The role of haematopoietic growth 8. ; 152: 1475-80. factors G-CSF and GM-CSF in the management of drug-induced induced neutropenia & agranulocytosis. QJM. 2017 18. agranulocytosis. Br J Haematol. ; 150: 3-8. Andrès E, Mourot-Cottet R, Maloisel F, et al. Idiosyncratic drug- induced agranulocytosis in elderly patients: the effects of Granulocyte 9. ; 110: 299-305. Andrès E, Kurtz JE, Martin-Hunyadi C,2002 et al. Non-chemotherapy drug-

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