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 Table of Contents  
REVIEW ARTICLE
Year : 2015  |  Volume : 40  |  Issue : 3  |  Page : 109-112

How to approach drug-induced agranulocytosis in ICU


1 Department of General Medicine, RKDF Medical College Hospital & Research Center, Bhopal, Madhya Pradesh, India
2 Department of Radiodiagnosis, RKDF Medical College Hospital & Research Center, Bhopal, Madhya Pradesh, India
3 Department of Pathology, PCMS and Research Center, Bhopal, Madhya Pradesh, India

Date of Submission13-Oct-2014
Date of Acceptance21-Nov-2014
Date of Web Publication8-Sep-2015

Correspondence Address:
Seema Mahant
A 312, Old Minal Residency, Bhopal 462023, Madhya Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-1067.164724

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  Abstract 

Many drugs can cause agranulocytosis and neutropenia by bone marrow suppression. Drug-induced agranulocytosis (DIA) is a relatively rare, but life-threatening disorder that frequently occurs as an adverse reaction to drugs. The overall incidence of DIA ranges from 2.4 to 15.4 cases/million patients exposed to drugs per year. DIA remains a serious adverse event because of the occurrence of severe sepsis with severe deep infections (such as pneumonia), septicemia, and septic shock in around two thirds of patients. In this setting, older age (>65 years), septicemia or shock, metabolic disorders such as renal failure, and a neutrophil count below 0.1×10 9 /l are poor prognostic factors. The severity of neutropenia (<0.1×10 9 /l) and its duration (>10 days) may also impact negatively on the outcome. Commonly used drugs such as antibiotics (b-lactam and cotrimoxazole), antiplatelet agents (ticlopidine), antithyroid drugs, sulfasalazine, neuroleptics (clozapine), antiepileptic agents (carbamazepine), nonsteroidal anti-inflammatory agents, and dipyrone are the most common causes of neutropenia and agranulocytosis. Recent investigations suggest that there are at least three mechanisms by which it can be produced, namely, differences in drug pharmacokinetics, abnormal sensitivity of myeloid precursors, and adverse immune responses to drug administration. Genetic factors are important and could act by any of the above mechanism. In management, use of hematopoietic growth factors, such as granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor, reduced mortality rate from 21.5 to 5%. Now a days, physicians use many drugs to increased life expectancy, as well as the development of new agents, should be aware of this complication and its management.

Keywords: drug-induced agranulocytosis, human granulocyte colony-stimulating factor, neutropenia-related infections


How to cite this article:
Mahant S, Mahant PD, Shobhane U. How to approach drug-induced agranulocytosis in ICU. Egypt J Haematol 2015;40:109-12

How to cite this URL:
Mahant S, Mahant PD, Shobhane U. How to approach drug-induced agranulocytosis in ICU. Egypt J Haematol [serial online] 2015 [cited 2017 Dec 11];40:109-12. Available from: http://www.ehj.eg.net/text.asp?2015/40/3/109/164724


  Introduction Top


Agranulocytosis is a group of pathologic disorders characterized by severe leukopenia (leukocyte count <1.5 × 10 9 /l) with neutropenia, leading to high susceptibility to bacterial and fungal infections [1] .

The term agranulocytosis was first used by Schultz in 1922 in patients with a severe sore throat, extreme reduction, or even complete disappearance of granulocytes from the peripheral blood and in rapid succession, sepsis, and death.

Neutropenia can be graded as mild, moderate, and severe, corresponding, respectively, to ANC values of 1000-1500, 500-1000, and <500 cells/mm 3 , and the outcome is linked to severity [2] .

Drug-induced agranulocytosis (DIA) is usually a self-limiting condition (provided that toxic drugs are withdrawn) with complete resolution within 2 weeks. However, the mortality rate during the acute phase is high, and therefore, prompt supportive therapy with isolation and broad-spectrum antibiotics for infection are mandatory during periods of severe neutropenia [3] .

Many studies show that the use of hematopoietic growth factors results in significantly faster recovery of the peripheral blood granulocytes compared with previously published studies. At the same time, a significantly lower mortality rate ranging from 21.5 to 5% was observed.

Incidence

The overall incidence of DIA ranges from 2.4 to 15.4 cases/million patients exposed to drugs per year. Drug-induced neutropenia is most common in women and the elderly, probably because of more frequent use of medications. Genetic and physiological traits may also contribute toward the higher incidence [4] .

Drugs often reported to be involved in drug-induced agranulocytosis

  1. Common drugs - phenothiazine, antithyroid drugs (thiouracil and propylthiouracil) aminopyrine, phenylbutazone, chloramphenicol, sulfonamides.
  2. Analgesics - acetaminophen, aminopyrine, dipyrone.
  3. Cardiovascular drugs - captopril, hydralazine, methyldopa, pindolol, procainamide, propranolol, quinidine.
  4. Antibiotics - cephalosporins, clindamycin, chloramphenicol, doxycycline, gentamicin, griseofulvin, isoniazid, metronidazole, nitrofurantoin, penicillins, rifampin, streptomycin sulfonamides, vancomycin.
  5. Diuretics - acetazolamide, bumetanide, chlorothiazide, hydrochlorothiazide,chlorthalidone methazolamide, spironolactone.
  6. Anticonvulsants - carbamazepine, mephenytoin, phenytoin, primidone, trimethadione.
  7. Hypoglycemic agents - chlorpropamide, tolbutamide.
  8. Antihistamines - brompheniramine, cimetidine, tripelennamine, ranitidine, thenalidine.
  9. Phenothiazines - chlorpromazine, clozapine, desipramine, prochlorperazine, promazine thioridazine, trifluoperazine, trimeprazine.
  10. Anti-inflammatory drugs - fenoprofen, gold salts, ibuprofen, indomethacin, phenylbutazone.
  11. Neuropharmacologic agents - chlordiazepoxide, clozapine, desipramine, meprobamate metoclopramide, prochlorperazine, promazine.
  12. Antithyroid agents - carbimazole, methylthiouracil, propylthiouracil.
  13. Antimalarials - amodiaquine, dapsone, hydroxychloroquine, pyrimethamine, quinine.
  14. Miscellaneous drugs - allopurinol, colchicine, d-penicillamine, ethanol, levamisole, levodopa.


Mechanisms of action

This form of neutropenia is rapid in onset, taking a few hours to 1-2 days, especially in patients with previous exposure to the drug. Several mechanisms are related to immune-mediated actions:

Hapten

Some drugs act as haptens to induce antibody formation against neutrophils, leading to their destruction. The continuous presence of the drug is required for the destruction of neutrophils. Drugs such as aminopyrine, penicillin, and gold compounds appear to act as haptens [4],[5] .

Apoptosis

Neutrophils are destined to undergo apoptosis, with a life span in the circulation of 8-20 h. Clozapine accelerates the process of apoptosis, as shown by in-vitro studies. Clozapine undergoes bioactivation by P450 and peroxidase enzymes to form the toxic and reactive nitrenium ion. This unstable metabolite covalently binds to cellular proteins, depletes intracellular glutathione, and leads to polymorphonuclear and mononuclear cell toxicity in vitro ([Figure 1]).
Figure 1 Clozapine is converted into a toxic metabolite. NADPH oxidase-generated superoxide is converted into hypochlorous acid by superoxide dismutase-dependent and myeloperoxidase-dependent reactions. This acid oxidizes clozapine (and other drugs) into metabolites (e.g. the nitrenium ion in case of clozapine), which interacts with sulfhydryl groups in the glutathione cycle. This may lead to the formation of haptens or to the depletion of the neutrophil of ATP. This leads to apoptosis and eventually to neutropenia. Adapted from [6,7]. Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.



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Immune complexes

Circulating immune complexes may be formed, which bind to neutrophils and lead to their destruction. These complexes do not require the continuous presence of the drug, which is evident in vitro by the presence of antineutrophilic antibodies even in the absence of the inducing drug [4] .

Complement-mediated mechanism

This mechanism was reported recently in a patient with Grave's disease who developed neutropenia and antineutrophil cytoplasmic antibodies after treatment with propylthiouracil. Antineutrophil cytoplasmic antibodies disappeared after withdrawal of the drug.

Dose-dependent inhibition of granulopoiesis

This is encountered with the use of drugs such as b-lactam antibiotics, carbamazepine, and valproic acid. At high concentrations, these drugs induce inhibition of colony-forming units of granulocytes and macrophages in all bone marrow samples, but produce variable results at low concentrations.

Direct toxicity for myeloid precursors

Reversible direct cytotoxity of ticlopidine for pluripotent or bipotent hemopoietic progenitor stem cells was noted by Symeonidis et al. [8] Many case reports show that life-threatening bone marrow suppression may develop with the use of busulfan, methotrexate, methimazole, doxorubicin, cyclophosphamide, and cis-diamminedichloroplatinum.

Symptoms of agranulocytosis

The list of signs and symptoms reported in various sources for agranulocytosis includes the following six symptoms: fever (92%), sore throat (85%), painful mouth ulcer (15%), anal ulcer (8%), reduced immune response, susceptibility to bacterial infections.

Clinical features

The main signs are ulcerative-necrotic changes in the mucous membranes of the URT, GIT, and ulcerative-necrotic tonsillitis. Agranulocytosis may be acute or subacute, with fever, regional lymphadenopathy, and complications (fungal infections). In severe cases, jaundice, hematuria, and cylinduria may be observed in patients with agranulocytosis.

The pathogens that cause these infections are mainly bacteria and fungi. Common organisms are - Gram-negative bacilli, such as  Escherichia More Details coli, Klebsiella spp., and Pseudomonas spp., and Gram-positive organisms such as Staphylococcus, Streptococcus viridans, and Staphylococcus aureus. Almost 10% of these infected patients develop a syndrome resembling toxic shock, with fever, hypotension, diffuse rash, desquamation, and adult respiratory distress syndrome, leading to about 30% mortality [9] .

Fungal infections have increased in the past 30 years, and are a common cause of morbidity and mortality in patients. Most of these patients develop systemic yeast infections (oral and gastro intestinal tract) because of Candida albicans, although the most frequent clinical manifestation of aspergillosis is pneumonia.

Investigations

  1. Complete blood cell: leukopenia (<2×109/l), granulocytes 1-4%, relative lymphocytosis (until 90%). For example, red blood cell - 3.8×10 12 /l, Hb - 121 g/l, CI - 0.95, thrombocytes - 179×10 9 /l, WBC - 0.9×10 9 /l: stab cells - 2, segmented cells - 3, lymphocytes - 93, monocytes - 2, ESR - 21 mm/h.
  2. Myelogram: partial or full hypoplasia of granulocytic lines.
  3. Immunologic studies: presence of Ig against WBC and dysimmunoglobulinemia.


Laboratory studies

A complete blood cell assessment should be performed, including manual differential (In case of agranulocytosis we should examine by cell counter as well as manual by microscope) for the evaluation of cases of agranulocytosis. Careful evaluation of the peripheral blood smear provides information on red blood cell and platelet morphology.

Bone marrow smears and biopsy samples should be examined using techniques including flow cytometry.

Microbiologic cultures of blood, wounds, and body fluids are indicated in febrile patients ([Figure 2] and [Figure 3]).
Figure 2 Peripheral smear of agranulocytosis.



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Figure 3 Hypocellular bone marrow smear.



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Imaging studies

No specific imaging study establishes the diagnosis of agranulocytosis.

As part of the workup for localization of infection, appropriate radiographs (e.g. chest images) are indicated. Other imaging studies can be carried out on the basis of the specific indications of each case.

Histologic findings

The peripheral blood smear shows a marked decrease or absence of neutrophils. The bone marrow may show myeloid hypoplasia or absence of myeloid precursors. In many cases, the bone marrow is cellular, with a maturation arrest at the promyelocyte stage. On occasion, the marrow may be hypercellular.

Management

  1. All early drug prescriptions should be discontinued and possible causes of agranulocytosis should be eliminated.
  2. Empiric antibiotics - specific antibiotic therapy should be initiated to combat infections. This often involves the use of third-generation cephalosporins or equivalents.
  3. Antifungals and antiviral agents should be administered (taking into account).
  4. Areas of stomatitis and skin infections should be treated with local cleaning, antisepsis, and dental care. These infections should be managed by professionals with experience in the treatment of infections in neutropenic patients.
  5. Oral and gingival lesion pain should be controlled with saline and hydrogen peroxide rinses and local anesthetic gels and gargles [9] .


Filgrastim (neupogen)-colony-stimulating factor

Recombinant human granulocyte colony-stimulating factor (rG-CSF). Granulocyte colony-stimulating factor (G-CSF) is the major cytokine that stimulates the growth and development of neutrophils in the bone marrow. A recombinant form of G-CSF (filgrastim; r-metHuG-CSF) is commercially available. Filgrastim increases the activation, proliferation, and differentiation of neutrophil progenitor cells and enhances the function of mature neutrophils. It results in increased granulopoiesis without reducing the half-life of neutrophils. The single-use prefilled syringes contain either 300 or 480 mcg Filgrastim at a fill volume of 0.5 or 0.8 ml, respectively. Signs of an allergic reaction include hives; difficulty breathing; and swelling of the face, lips, tongue, or throat. Side effects may include stomach pain, shortness of breath, diarrhea, constipation, bone pain, muscle aches, hair loss, headache, tiredness, mild skin rash, or itching, swelling, or redness at the site of injection [10],[11] .

Surgical care

Surgical care is generally not indicated for patients with agranulocytosis.

Consultations

  1. Agranulocytosis is a serious illness, and several consultations are indicated.
  2. A hematologist reviews the bone marrow slides and peripheral blood smears to confirm the diagnosis and to enable G-CSF dosing and evaluation.
  3. An infectious disease specialist advises and assists in the selection of appropriate antibiotics.


Diet

  1. All foods must be cooked thoroughly. Raw fruits and vegetables may contain large numbers of bacteria and should be avoided.
  2. In patients with periodontitis and stomatitis, a soft or a full liquid diet is indicated. Spicy and acidic foods should be avoided until recovery is complete.


Activity

Patient activity is permitted as tolerated.


  Acknowledgements Top


The author is very grateful to Prof Dr U.B. Shah, Dean RKDF Medical College, for encouragement for writing and publication. The author is also grateful to Prof Dr P.D. Mahant for his help with writing the manuscript.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Council for International Organizations of Medical Sciences. Standardization of definitions and criteria of assessment of adverse drug reactions: Drug-induced cytopenia. Int J Clin Pharmacol Ther Toxicol 1991; 29 :75-81.  Back to cited text no. 1
    
2.
Papadaki HA, Pontikoglou C. Pathophysiologic mechanisms, clinical features and treatment of idiopathic neutropenia. Expert Rev Hematol 2008; 1 :217-229.  Back to cited text no. 2
    
3.
Palmblad JE, von dem Borne AE. Idiopathic, immune, infectious, and idiosyncratic neutropenias. Semin Hematol 2002; 39 :113-120.  Back to cited text no. 3
    
4.
Andrès E, Zimmer J, Mecili M, Weitten T, Alt M, Maloisel F. Clinical presentation and management of drug-induced agranulocytosis. Expert Rev Hematol 2011; 4:143-51.  Back to cited text no. 4
    
5.
Watts RG. Neutropenia. In: Lee GR, Foerster J, Lukens J, editors. Wintrobe′s clinical hematology. 10th ed. Baltimore: Williams and Wilkins; 1999; 2 :1860-1888.  Back to cited text no. 5
    
6.
Muroi K, Ito M, Sasaki R, et al. Treatment of drug induced agranulocytosis with granulocyte colony stimulating factor. Lancet 1989;2:55.  Back to cited text no. 6
    
7.
S Vento, F Cainelli. Infections in patients with cancer undergoing chemotherapy: aetiology, prevention, and treatment. Lancet Oncol 2003; 4 :595-604.  Back to cited text no. 7
    
8.
Symeonidis A, Kouraklis-Symeonidis A, Seimeni U, et al. Ticlopidine-Induced aplastic anemia: two new case reports, review, and meta-analysis of 55 additional cases. Am J Haematol 2002; 71 :24-32.  Back to cited text no. 8
    
9.
S Vento, F Cainelli. Infections in patients with cancer undergoing chemotherapy: aetiology, prevention, and treatment. Lancet Oncol 2003; 4:595-604.  Back to cited text no. 9
    
10.
David D. Current management of chemotherapy-induced neutropenia: the role of colony-stimulating factors. Semin Oncol 2003; 30(Suppl 13) :3-9.  Back to cited text no. 10
    
11.
Muroi K, Ito M, Sasaki R, et al. Treatment of drug induced agranulocytosis with granulocyte colony stimulating factor. Lancet 1989; 2 :55.  Back to cited text no. 11
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]



 

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