**7. Clinical manifestations**

**5. Epidemiology and causative drugs**

190 Hematology - Latest Research and Clinical Advances

**Family drug Drugs**

Analgesics and nonsteroidal antiinflammatory drugs:

Antipsychotics, hypnosedatives and antidepressants:

Idiosyncratic agranulocytosis is a rare disorder. In Europe, the annual incidence of such events is between 1.6 and 9.2 cases per million populations [2, 4]. In the USA, reported ranges from 2.4 to 15.4 per million per year. In our experience, the incidence remains unchanged, despite the withdrawn of incriminated drugs (which carry a high-risk), and increased levels of medical awareness and pharmacovigilance [5]. Older patients are thought to be at greater

Almost all classes of drugs have been implicated as "causative," but for the majority, the risk appears to be very small (**Table 2**) [2, 5]. However, for drugs such as antithyroid drugs, ticlopidine, clozapine, phenothiazines, sulfasalazine, trimethoprim-sulfametoxazole (cotrimoxazole), and dipyrone or sulfasalazine, the risk may be higher. For antithyroid drugs (propyl-thiouracil and méthimazole), a risk of 3 per 10,000 users has been reported. For

olanzapine, phenothiazines, risperidone, tiapride, ziprasidone

spironolactone, thiazide diuretics, ticlopidine, vesnarinone Anti-infective agents: Abacavir, acyclovir, amodiaquine, atovaquone, cephalosporins, chloramphenicol,

sulfametoxazole (cotrimoxazole), vancomycin, zidovudine Miscellaneous drugs: Acetazolamide, acetylcysteine, allopurinol, aminoglutethimide, arsenic compounds,

thenalidine, tretinoid, tripelennamine

**Table 2.** Drugs implicated in the occurrence of idiosyncratic agranulocytosis.

Antiepileptic drugs: Carbamazepine, ethosuximide, phenytoin, trimethadione, valproic acid (sodium

Antithyroid drugs: Carbimazole, methimazole, potassium perchlorate, potassium thiocyanate,

Cardiovascular drugs: Acid acetylsalicylic, amiodarone, aprindine, bepridil, captopril, coumarins,

Acetaminophen, acid acetylsalicylic (aspirin), aminopyrine, benoxaprofen, diclofenac, diflunisal, dipyrone, fenoprofen, indomethacin, ibuprofen, naproxen, phenylbutazone,

Amoxapine, chlomipramine, chlorpromazine, chlordiazepoxide, clozapine, diazepam, fluoxetine, haloperidol, levopromazine, imipramine, indalpin, meprobamate, mianserin,

dipyridamole, digoxin, flurbiprofen, furosemide, hydralazine, lisinopril, methyldopa, nifedipine, phenindione, procainamide, propafenone, propanolol, quinidine, ramipril,

chloroguanine, chloroquine, ciprofloxacin, clindamycin, dapsone, ethambutol, flucytosine, fusidic acid, gentamicin, hydroxychloroquine, isoniazid, levamizole, lincomycin, linezolid, macrolids, mebendazole, mepacrine, metronidazole, minocycline, nitrofurantoin, norfloxacin, novobiocin, penicillins, pyrimethamine, quinine, rifampicin, streptomycin, terbinafine, tetracycline, thioacetazone, tinidazole, trimethoprim-

benzafibrate, brompheniramine, calcium dobesilate, chloropheniramine, cimetidine, colchicine, dapsone, deferiprone, famotidine, flutamide, gold, glucocorticoids, hydroxychloroquine, mesalazine, metapyrilène, methazolamide, metoclopramide, levodopa, olanzapine, omeprazole, oral hypoglycemic agents (glibenclamide), mercurial diuretics, penicillamine, ranitidine, riluzole, sulfasalazine, most sulfonamides, tamoxifen,

risk for to drug-induced neutropenia, probably because of increased medication use.

piroxicam, sulindac, tenoxicam, tolmetin

valproate)

propylthiouracil

Initially, symptomatic patients with idiosyncratic drug-induced severe neutropenia or agranulocytosis usually present with fever, which often is the earliest and sometimes the only sign during evolution. This later is often associated with general malaise, often including chills [2, 3]. In this setting, symptoms may appear either immediately or insidiously, depending on the time course of neutropenia development. Symptomatic patients are commonly present at discovery a non-specific sore throat, acute tonsillitis or sinusitis. More rarely, patients have first, as a not expected and brutal event, a severe deep and potentially life-threatening infection [2].

It is important to note that without medical intervention, particularly immediate antibiotics administration, natural history of agranulocytosis include severe and potentially life-threatening infections with often signs of general sepsis and septicemia (fever, chills, hypotension, etc.). During the evolution, documented pneumonia as well as anorectal, skin or oropharyngeal infections and septic shock were the most reported infections [2, 3]. To date, classical manifestations as necrotic tonsillitis and perinea gangrene or are exceptional.

In our experience (203 patients), the clinical manifestations include: isolated fever (unknown origin) (26.3%); septicemia (13.9%); documented pneumonia (13.4%); sore throat and acute tonsillitis (9.3%); and septic shock (6.7%) [5]. While in hospital 19.2% of the patients worsened clinically and exhibited features of severe sepsis, septic shock, or systemic inflammatory response syndrome (SIRS).

However, besides these "loud" clinical manifestations, clinicians must keep in mind that the signs of these infections may be sometimes crude and atypical because of the neutropenia (**Figure 1**). For practitioners, it is to note that pneumonia is often asymptomatic because of the lack of neutrophil cells. In this situation, thoracic CT-scan may be proposed with much better results than X-ray (**Figure 2**). Similarly, when antibiotics are administered prophylactically, or at the beginning of this adverse event, both the patient's complaints and the physical findings may be "masked," and fever is often the only clinical sign detected [2].

**8. Biological data**

neutrophil count of <0.5 × 109

**Figure 2.** CT-scan in a patient with absolute neutrophil count <0.1 × 109

documented later in the paper.

Theoretically, acute neutropenia is classically diagnosed in a blood sample, resulting in a

In this setting, bone marrow examination may not be required in for all patients but is pivotal to exclude an underlying pathology, particularly in the elderly to rule out myelodysplastic disorders and malignant hematological diseases [1, 2]. Bone marrow examination may be particularly required in case of associated anemia, thrombocytopenia or abnormal blood cells. In such patients with idiosyncratic drug-induced agranulocytosis, the bone marrow typically shows a lack of mature myeloid cells, whereas in other cases, immature cells from the myelocyte stage are preserved. This latter appearance is described as "myeloid maturation arrest" [2, 3].

In severe neutropenia, multiple microbiological specimens should be taken, as in the case of post-chemotherapy neutropenia. With such multiple microbial samples, a causative pathogen, typically Gram-negative bacilli or Gram-positive cocci (mainly Staphylococcus spp.), was isolated in 30% of cases [3]. Fungi are also involved as secondary infective agents (>10%), however, in a few percent of cases regarding neutropenia related to chemotherapy. To date, modern molecular techniques have further facilitated identification of microbial pathogens, allowing for aggressive interventions that appear to improve patient outcomes as

increased. In the majority of patients, the neutrophil count is under 0.1–0.2 × 109

/L [3, 5]. In this setting, monocyte and basophile counts may be

/L: Lung aspergillosis.

Idiosyncratic Drug-Induced Severe Neutropenia and Agranulocytosis: State of the Art

http://dx.doi.org/10.5772/intechopen.78769

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/L.

**Figure 1.** Chest radiography in a patient with absolute neutrophil count <0.1 × 109 /L: "Masked" pneumonia.

Idiosyncratic Drug-Induced Severe Neutropenia and Agranulocytosis: State of the Art http://dx.doi.org/10.5772/intechopen.78769 193

**Figure 2.** CT-scan in a patient with absolute neutrophil count <0.1 × 109 /L: Lung aspergillosis.
