**9. Prognosis and mortality rate**

Idiosyncratic drug-induced severe neutropenia usually resolves over time, with supportive care and management of infection [2, 3]. The time to neutrophil recovery has typically been reported to range from 4 to 24 days.

At the opposite side, some patients (<20%) (not-well identified characteristics or profile) remained asymptomatic [3]. This supports the case for routine monitoring of blood counts in individuals receiving high-risk medications such as, for example, antithyroid drugs [2, 3]. This also supports not consensual home management of such an event in certain patients (young,

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The management of idiosyncratic drug-induced severe neutropenia and agranulocytosis begins with the immediate withdrawal of any medications, which may potentially be responsible [2, 3]. Thus, the patient's medication history must be carefully obtained in chronological

For experts, routine monitoring for agranulocytosis is required in some high-risk drugs, such as clozapine, ticlopidine, and antithyroid drugs [2, 3]. All cases of drug-induced neutropenia must be notified to the pharmacovigilance center. All febrile patients should be admitted to

Concomitant measures include realization of multiple microbial samples (blood, urine, stool, and sputum cultures) and aggressive treatment of confirmed or potential sepsis, as well as the prevention of secondary infections. It should be noted that as a result of neutrophil deficiency, both the patient's symptoms and the physical findings may be altered, and fever may be the only clinical sign [3]. Preventive measures include good hygiene and infection control, paying

Patients with a low-risk of infection, and good performance status may be managed in home with intensive supervision and monitoring! The occurrence of sepsis requires prompt management, without any delay, including the administration of broad-spectrum intravenous

In case of fever or for "frailty" patients, prompt hospitalization without delay may be required [2, 3]. In this setting, patient isolation and the use of prophylactic antibiotics (e.g., for the gastrointestinal tract) have been proposed, but their usefulness in limiting the risk of infection

In case of sepsis, we commonly combine in first-line therapy, new cephalosporins and quinolones or aminoglycosides. It is important to note that a great part of these recommendations is adapted from the evidence-based medicine recommendations for the management of chemotherapy-induced neutropenia (field of oncology) [3]. Of course ureidopenicillins betalactam/beta-lactamase inhibitor combinations, as carbapenems, or imipenem can be safely used in these antibiotic combinations. The addition of intravenous vancomycin or teicoplanin

particular attention to high-risk areas such as the mouth, skin, and perineum [2, 3].

has not been documented or at least, has not been clinically proven [3].

without medical history, and with fever as the sole sign) [3].

order so that the suspected agent(s) may be identified.

**10. General management**

hospital, without any delay [2, 3].

antibiotic therapy [2, 3].

**11. Antimicrobial therapy**

In our aforementioned cohort study (n = 203), the mean duration of hematological recovery (neutrophil count ≥1.5 × 10<sup>9</sup> /L) is 7.8 days (range: 2–20) [5]. The median duration for neutrophil count ≥0.5 × 10<sup>9</sup> /L is 6.8 days (range: 1–24).

In this context, the mortality rate for idiosyncratic agranulocytosis has recently fallen from 10 to 16 to 5% (range 2.5–10%) [2, 3]. This is likely due to improved recognition, management, and treatment of the condition. The highest mortality rate is observed in "frailty" patients: older patients (>65 years), with poor performance status, as well as those with several comorbidities as renal failure (defined as serum creatinine level > 120 μmol/L), chronic heart failure; bacteremia septicemia at diagnosis; or shock at diagnosis (**Table 3**); or low neutrophil count levels [2, 6].

Previously, we have found demonstrated that several variables were significantly associated with a longer neutrophil recovery time (>1.5 × 109 /L), as: that an absolute neutrophil count of <0.1 × 109 /L at diagnosis, as well as septicemia and/or shock [7], were variables that were significantly associated with a longer neutrophil recovery time. In our cohort, bone marrow showing a lack of myeloid cells was not found to be associated with a delayed recovery (using uni- and multivariate analysis) [5].

It is worth noting, that in elderly patients, clinical manifestations were generally more severe, with septicemia or septic shock in at least two-thirds of patients, as we have previously published [8]. It is also the case in patients with associated morbidities as chronic cardiac failure, chronic obstructive pulmonary disease, renal failure and immune disorders. In our experience, the depth of the neutropenia impacts the severity of the clinical, manifestations [7].


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

**Table 3.** Impact factors for the prognosis\* of idiosyncratic drug-induced agranulocytosis.

At the opposite side, some patients (<20%) (not-well identified characteristics or profile) remained asymptomatic [3]. This supports the case for routine monitoring of blood counts in individuals receiving high-risk medications such as, for example, antithyroid drugs [2, 3]. This also supports not consensual home management of such an event in certain patients (young, without medical history, and with fever as the sole sign) [3].
