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Systematic Review: Agranulocytosis Induced by Nonchemotherapy Drugs

Frank Andersohn, MD; Christine Konzen, MD; and Edeltraut Garbe, MD, PhD
[+] Article and Author Information

From Charité—Universitaetsmedizin Berlin, Berlin, Germany, and Bremen Institute for Prevention Research and Social Medicine, Bremen, Germany.


Potential Financial Conflicts of Interest: None disclosed.

Request for Single Reprints: Frank Andersohn, MD, Department of Clinical Pharmacology and Toxicology, Charité—Universitaetsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; e-mail, frank.andersohn@charite.de.

Current Author Addresses: Drs. Andersohn and Konzen: Department of Clinical Pharmacology and Toxicology, Charité—Universitaetsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.

Dr. Garbe: Department of Clinical Epidemiology, Bremen Institute for Prevention Research and Social Medicine, Linzer Strasse 10, 28539 Bremen, Germany.


Ann Intern Med. 2007;146(9):657-665. doi:10.7326/0003-4819-146-9-200705010-00009
Text Size: A A A

Background: Nonchemotherapy drug–induced agranulocytosis is a rare adverse reaction that is characterized by a decrease in peripheral neutrophil count to less than 0.5 × 109 cells/L due to immunologic or cytotoxic mechanisms.

Purpose: To systematically review case reports of drugs that are definitely or probably related to agranulocytosis.

Data Sources: English-language and German-language reports in MEDLINE (1966 to 2006) or EMBASE (1989 to 2006) and in bibliographies of retrieved articles.

Study Selection: Published case reports of patients with nonchemotherapy drug–induced agranulocytosis.

Data Extraction: One reviewer abstracted details about cases and assessed causality between drug intake and agranulocytosis by using World Health Organization assessment criteria.

Data Synthesis: Causality assessments of 980 reported cases of agranulocytosis were definite in 56 (6%), probable in 436 (44%), possible in 481 (49%), and unlikely in 7 (1%). A total of 125 drugs were definitely or probably related to agranulocytosis. Drugs for which more than 10 reports were available (carbimazole, clozapine, dapsone, dipyrone, methimazole, penicillin G, procainamide, propylthiouracil, rituximab, sulfasalazine, and ticlopidine) accounted for more than 50% of definite or probable reports. Proportions of fatal cases decreased between 1966 and 2006. More patients with a neutrophil count nadir less than 0.1 × 109 cells/L had fatal complications than did those with a neutrophil count nadir of 0.1 × 109 cells/L or greater (10% vs. 3%; P < 0.001). Patients treated with hematopoietic growth factors had a shorter median duration of neutropenia (8 days vs. 9 days; P = 0.015) and, among asymptomatic patients at diagnosis, had a lower proportion of infectious or fatal complications (14% vs. 29%; P = 0.030) than patients without such treatment.

Limitations: Case reports cannot provide rates of drug-induced complications, sometimes incompletely assess or describe important details, and sometimes emphasize atypical features and outcomes.

Conclusions: Many drugs can cause nonchemotherapy drug–induced agranulocytosis. Case fatality may be decreasing over time with the availability of better treatment.

Figures

Grahic Jump Location
Figure 2.
Median duration of treatment and neutropenia.

Only drugs with more than 3 definite or probable reports of the time between onset of acute agranulocytosis and normalization of neutrophil count and the duration of treatment before onset of acute agranulocytosis were considered. Patients treated with hematopoietic growth factors were excluded in the calculation of the median duration of neutropenia. *For rituximab, the white bar represents the median number of infusions before onset of agranulocytosis.

Grahic Jump Location
Grahic Jump Location
Figure 3.
Proportion of fatal cases over time and treatment with granulocyte colony-stimulating factor (G-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF)

P < 0.001 for trends over time for 1966 to 1980, 1981 to 1990, and 1991 to 2006. Patients who were treated and those who were not treated with hematopoietic growth factors were included. Error bars represent 95% CIs. *Fisher exact test.

Grahic Jump Location

Tables

References

Letters

NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Comments

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Ganciclovir induced neutropenia
Posted on May 1, 2007
Sherif B. Mossad
Cleveland Clinic
Conflict of Interest: None Declared

To the editors:

I read with interest the report by Andersohn et al (1). I expected to see ganciclovir or its prodrug valganciclovir on the list of drugs with definite or probable causality for agranulocytosis. I conducted a MEDLINE search for published reports from 1950 to April 2007 using Medical Subject Heading terms "agranulocytosis" and "ganciclovir". I found several reports describing this association, both in allogeneic marrow transplant recipients (2) and AIDS patients (3). Prevention (4) or treatment (5) with hematopoietic growth factors is also effective in these patient populations.

References:

1. Andersohn F, Konzen C, Garbe E. Systematic review: agranulocytosis induced by nonchemotherapy drugs. Ann Intern Med 2007;146:657-65.

2. Salzberger B, Bowden RA, Hackman RC, Davis C, Boeckh M. Neutropenia in allogeneic marrow transplant recipients receiving ganciclovir for prevention of cytomegalovirus disease: risk factors and outcome. Blood 1997;90:2502-8.

3. Anonymous. Morbidity and toxic effects associated with ganciclovir or foscarnet therapy in a randomized cytomegalovirus retinitis trial. Studies of ocular complications of AIDS Research Group, in collaboration with the AIDS Clinical Trials Group. Arch Intern Med 1995;155:65-74.

4. Reynoso Gomez E, Duenas Gonzalez A, Miranda Lopez E, et al. Prevention of myelotoxicity in a case of bone marrow transplantation using granulocyte-macrophage colony-stimulating factor along with ganciclovir. Revista de Investigacion Clinica 1996;48:55-8.

5. Dubreuil-Lemaire ML, Gori A, Vittecoq D. GCS 309 European Study Group. Lenograstim for the treatment of neutropenia in patients receiving ganciclovir for cytomegalovirus infection: a randomised, placebo- controlled trial in AIDS patients. Eur J Haematol 2000;65:337-43.

Conflict of Interest:

None declared

SYSTEMATIC REVIEW: AGRANULOCYTOSIS INDUCED BY NONCHEMOTHERAPY DRUGS
Posted on May 14, 2007
Sridhar Mani
Albert Einstein College of Medicine
Conflict of Interest: None Declared

TO THE EDITOR: I would like to add to the discussion in this timely review conducted by Andersohn and colleagues (1). The review was conducted because of the clinical importance of this subject in the context of unclear effects of granulocyte colony-stimulating factor therapy ("¦"results on their effectiveness in nonchemotherapy drug-induced agranulocytosis are conflicting.") (1). Approximately 14 years ago, we published a case series on the incidence of nonchemotherapy drug induced agranulocytosis presenting at one hospital (1990-1992). Furthermore, during the analysis period, some patients received colony stimulating factors (and others did not) and we did a rough estimate of benefit (length of hospital stay and cost effectiveness) (2). We concluded that .." Treatment with granulocyte-colony stimulating factor was associated with a shorter duration of neutropenia and a decreased length of hospital stay, consistent with recent case reports. Despite the high cost of the drug, treatment with granulocyte-colony stimulating factor was found to be cost-effective for patients with uncomplicated drug-induced agranulocytosis." At that time, our paper was the first to analyze these parameters (2). The results of our paper are validated by the recent paper by Andersohn and colleagues and furthermore, underscore the need to include case series studied over a cross-section of time. At the very least, such data should be included in supplemental information.

Sridhar Mani MD* Associate Professor, Medicine

Current Affiliation: Albert Einstein College of Medicine 1300 Morris Park Ave Chanin 302D-1 Bronx, NY 10461 Tel: 718-430-2871 smani@montefiore.org

References:

1. Andersohn F, Konzen C, Garbe E. Systematic Review: Agranulocytosis Induced by Nonchemotherapy Drugs. Ann Intern Med 2007;146:657-665 2. Mani S, Barry M, Concato J. G-CSF therapy in drug induced agranulocytosis. Arch Intern Med 153:2500-2501, 1993.

Conflict of Interest:

None declared

Agranulocytosis induced by nonchemotherapy drugs.
Posted on May 17, 2007
Chaker Ben Salem
Faculty of Medicine of Sousse
Conflict of Interest: None Declared

Agranulocytosis induced by nonchemotherapy drugs.

In the excellent systematic review of agranulocytosis Induced by nonchemotherapy drugs, Andersohn et al (1) mention in Table 2 the drugs that can cause agranulocytosis. They classified them as definite or probable cause. The authors believe that they analyzed all published reports indexed by Medline from January 1966 to December 2006. They are limited to articles written in German or English. However, several German and English publications that report well-documented cases of drug-induced agranulocytosis and meet the criteria chosen by the authors are not included in the authors' list. Some of these publications are listed in Table 1.

We believe that a systematic review of drug-induced agranulocytosis should be extensive, exhaustive and comprehensive. The review should not be limited to English and German literature. French articles should also be included since many reviews, systematic reviews, epidemiological studies, and case reports provide reliable information (2-5). We believe the present list completes the article of Andershon et al, and provides additional information about drug-induced agranulocytosis, sometimes a challenging drug adverse event.

 

Table I: Additional published cases of drug-induced agranulocytosis

Drug

Drug causality

First Author

Reference

Carbutamide

Possible

Schneider H

Dtsch Gesundheitsw 1972 ;27:581-3.

Chlorpheniramine

Possible

Hardin AS

Ann Intern Med 1988;108: 770

Colchicine

Possible

Ducloux D

Nephrol Dial Transplant 1997;12:1541-2.

Finklestein M

Gastroenterology 1987;93:1231-5.

Erythromycin

Possible

Pastor E

DICP 1991;25:1136.

Etodolac

Possible

Cramer RL

Ann Pharmacother. 1994 ;28:458-60.

Fluconazole

Possible

Wong-Beringer A

Pharmacotherapy. 2000 ;20:484-6.

Gentamicin

Possible

Chang JC

JAMA. 1975; 232:1154-5.

Mefloquine

Possible

Hennequin C

Lancet. 1991; 337:984.

Methazolamide

Possible

Werblin TP

JAMA. 1979; 241:2817-8.

Nifedipine

Possible

Bonadonna A

Nephron. 1987;47:306-7.

Voth AJ

Ann Intern Med. 1983 ;99:882.

Phenindione

Possible

Gupta MC

J Indian Med Assoc. 1974 ;63:324-7.

Primidone

Possible

Laurenson IF

Lancet. 1994 ;344:332-3.

Propranolol

Possible

Nawabi IU

JAMA. 1973 ;223:1376-7.

Risperidone

Possible

Finkel B

Am J Psychiatry

Sertraline

Possible

Trescoli-Serrano C

Postgrad Med J. 1996 ;72:446.

Tamoxifen

Possible

Ching CK

Systematic review: agranulocytosis induced by non-chemotherapy drugs
Posted on May 31, 2007
Luisa Ibañez
Clinical Pharmacology Service,Vall d'Hebron Hospital (Barcelona), Universitat Autònoma (Barcelona)
Conflict of Interest: None Declared

To the Editor,

In their recent interesting article, Andershon and colleagues1 present a systematic review of case reports definitely or probably related to agranulocytosis. However, the definition of a plausible time relationship to drug administration includes the onset of acute agranulocytosis occurring within 1 month after drug withdrawal. This definition could lead to a misclassification of drug causality since agranulocytosis is mainly an immunological disorder and it is unlikely that a drug can induce it if it or its metabolites are not present in the body.2 This could have led to an overall misclassification of drug causality for an important number of drugs.

In table 2 they present several drugs with definite/probable causality categorised in level 2 evidence that have shown high risk estimations in case-control studies, (e.g.,ticlopidine, carbamazepine, omeprazol, sulphamides/sulphones, and beta-lactamic antibiotics). This may lead one to think of these drugs as less associated with agranulocytosis, with less risk, than those of level 1, when in fact several of them have high risk estimations (carbamazepine, ticlopidine), and other at least as high as several of those in level 1.3 These differences in drug risk estimation from epidemiological studies and the information provided by case reports may deserve further discussion. In addition, acetaminophen also appears as a definite/probable causality with level 2 evidence, based in only one case report of a patient who took an overdose of acetaminophen and developed hepatotoxicity and reactive plasmacytosis with thrombocytosis and agranulocytosis. This reaction is not usually seen with therapeutic doses and moreover the relationship of this drug with agranulocytosis is not supported by epidemiological estimations of risk.

Finally, the use of G-CSF has been reported to decrease fatality in patients with nonchemotherapy drug-induced agranulocytosis based on the comparison of information of case reports treated with these agents and the fatality rate from only one case series,4 therefore the influence of this treatment on lethality is still not known. They also conclude that their findings support previous recommendations to treat patients with a neutrophil count nadir less than 0.1x109 cells/L with hematopoietic growth factors, but this is only true for the published asymptomatic cases. Therefore, the conclusion could have been the opposite based on the results for the published symptomatic cases.

1-Andersohn F, Konzen C, Garbe E. Systematic review: Agranulocytosis induced by non-chemotherapy drugs. Ann Intern Med 2007;146:657-666.

2-Kaufman DW, Kelly JP, Levy M, Shapiro S. The drug etiology of agranulocytosis and aplastic anemia. New York, Oxford University Press, 1991.

3-Ibañez L, Vidal X, Ballarin E, Laporte JR. Population-based drug- induced agranulocytosis. Arch Intern Med 2005;165:869-874.

4-Beauchesne MF, Shalansky SJ. Nonchemotherapy drug-induced agranulocytosis: a review of 118 patients treated with colony-stimulating factors. Pharmacotherapy 1999;19:229-305.

Conflict of Interest:

None declared

Author reply
Posted on June 18, 2007
Frank Andersohn
Bremen Institute for Prevention Research and Social Medicine (BIPS)
Conflict of Interest: None Declared

Most of the case reports suggested by Salem et al. were already included in our review (N=10) (1). Six of the suggested reports were excluded because of use of cytotoxic drugs, pancytopenia or a neutrophil nadir >=0.5*109/L. Only 2 of the listed case reports (carbutamide, nifedipine) were not identified because they were not listed as case reports in the MEDLINE publication type field. As causality is "possible" in these reports, the inclusion of these cases during the next database update will not cause any change of table 2. We believe that especially the first report(s) of drug-induced agranulocytosis for a drug are most likely to be published in English speaking journals with high international impact and thus have been included in our review.

In contrast to Dr. Ibanez, we believe that there are important reasons to use the CIOMS time-relationship criteria (2). 1. If the time window is too narrow, a delay between onset of agranulocytosis and diagnosis might obscure the causative drug. 2. Some drugs associated with agranulocytosis have long half lifes and thus may be present in the body even more than one month after drug withdrawal. With respect to acetaminophen, an increased risk of agranulocytosis has been reported (3) and this side effect is also listed in the German SPC (4). We believe that treatment with G-CSF/GM-CSF is also of advantage for primary symptomatic patients: If we analyzed the duration of neutropenia in these patients, there was a borderline significant difference between treated and untreated patients, if the neutrophil nadir was <0.1*109/L (p=0.063), but not if it was >=0.1*109/L (p=0.77). If all primary symptomatic and asymptomatic patients were analyzed together, treated patients had a lower duration of neutropenia if the neutrophil nadir was <0.1*109/L (p=0.019), but not if it was >=0.1*109/L (p=0.199).

Like Dr. Mossad we also identified several case reports of ganciclovir induced bone marrow damage including agranulocytosis. However, nonchemotherapy agranulocytosis generelly refers to drugs causing agranulocytosis by non-cytotoxic, idiosyncratic mechanisms. This categorization was difficult for some drugs. In case of ganciclovir, the mechanism of action (inhibition of viral and human DNA polymerase), the high frequency of neutropenia listed in the SPC (>10%), and the bone marrow suppression after overdosing also mentioned in the SPC, suggest a non-idiosyncratic mechanism of neutropenia and agranulocytosis. It is important to note, that drugs like azathioprin, methotrexate or colchicin were also not included because of their known direct cytotoxic properties.

Frank Andersohn

Christine Konzen

Edeltraut Garbe

References

(1) http://www.adverse- effects.com/documents/case_reports_agranulocytosis.pdf. Accessed June 14, 2007.

(2) Benichou C, Solal CP. Standardization of definitions and criteria for causality assessment of adverse drug reactions. Drug-induced blood cytopenias: report of an international consensus meeting. Nouv Rev Fr Hematol. 1991;33:257-62.

(3) van der Klauw MM, Goudsmit R, Halie MR, van't Veer MB, Herings RM, Wilson JH, et al. A population-based case-cohort study of drug- associated agranulocytosis. Arch Intern Med. 1999;159:369-74.

(4) bene Arzneimittel GmbH. Fachinformation Benuron 500 mg Tabletten.

Conflict of Interest:

None declared

Usefulness of hematopoietic growth factors in idiosyncratic drug-induced agranulocytosis
Posted on July 31, 2007
Emmanuel ANDRES
University Hospital of Strasbourg, France
Conflict of Interest: None Declared

In idiosyncratic drug-induced agranulocytosis, the usefulness of hematopoietic growth factors: Granulocyte- and Granulocyte-Macrophage- Colony Stimulating factor (G-CSF and GM-CSF) has been previously reported [1]. Most of the data regarding the efficacy of these hematopoietic growth factors comes from case reports and case series with an historical comparison group [1]. Nevertheless to our opinion, it may be currently unethical to study the effect of these growth factors. In our experience, G-CSF and GM-CSF (at a mean dosage of 300 µg/day) were found useful in shortening the duration to blood count recovery without major toxicity or adverse effects, particularly in patients with poor prognostic factors [1,2]. In a multivariate analysis of all our patients with idiosyncratic drug-induced agranulocytosis patients (n = 91), we have demonstrated that G-CSF was an independent variable positively affecting the duration of hematological recovery [2]. We also demonstrate that the duration of antibiotic therapy hospitalization were significantly shorter under treatment with hematopoietic growth factors [3,4]. Only one study reported a lower mortality with this therapy [1]. However, it is to note that the only prospective randomized study available did not confirm the benefit of G-CSF [5]. A total of 24 patients with antithyroid-related drug-induced agranulocytosis were enrolled, and one may think that both the small size of the study and an inappropriate G-CSF dosing (100 to 200 µg/day) negatively impacted the results. In the previously mentioned cohort study, we have established the long-term (mean follow-up >52 months) safety of hematopoietic growth factors, with the absence of hematological adverse effects such myelodysplasia or hematological proliferative disorders [1].

1. Andrès E, Zimmer J, Affenberger S, Federici L, Alt M, Maloisel F. Idiosyncratic drug-induced agranulocytosis: update of an old disorder. Eur J Intern Med 2006; 17: 529-35.

2. Maloisel F, Andrès E, Kaltenbach G, Noel E. Prognostic factors of hematological recovery in nonchemotherapy drug-induced agranulocytosis. Haematologica 2003; 88: 470-1.

3. Andrès E, Kurtz JE, Martin-Hunyadi C, Kaltenbach G, Alt M, Weber JC, et al. Non-chemotherapy drug-induced agranulocytosis in elderly patients: the effects of Granulocyte Colony-Stimulating Factor. Am J Med 2002; 112: 460-4.

4. Andrès E, Kurtz JE, Perrin AE, Dufour P, Schlienger JL, Maloisel F. The use of haematopoietic growth factors in antithyroid-related drug-induced agranulocytosis: a report of 20 patients. Q J Med 2001; 94: 423-8.

5. Fukata S, Kuma K, Sugawara M. Granulocyte colony-stimulating factor (G- CSF) does not improve recovery from antithyroid drug-induced agranulocytosis: a prospective study. Thyroïd 1999; 9: 29-31.

Conflict of Interest:

None declared

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