Drug-induced neutropenia accounts for more than 70% of all neutropenias encountered in clinical practice [1]. A myriad of pharmacological agents is described in the literature as potential inducers of neutropenia, most notable being chemotherapeutic drugs, such as busulfan, methotrexate, platinum analogs, doxorubicin, cyclophosphamide, etc. [2] [3] [4]. In addition, antithyroid agents (propylthiouracil, thiocyanate), anticonvulsants (carbamazepine, valproic acid, phenytoin), antipsychotics (clozapine, phenothiazines), antimicrobials (trimethoprim-sulfamethoxazole, beta-lactams, chloramphenicol, vancomycin, several antiretrovirals,), anti-inflammatory drugs (aspirin, indomethacin, mesalazine), but also antiplatelet and several cardiovascular agents are some of the more commonly mentioned causes of drug-induced neutropenia [1] [2] [3] [4] [5] [6]. The pathogenesis may stem from direct toxic effects of the drugs and/or the formation of drug-dependent antibodies targeted against glycoproteins located in the cell membrane of neutrophils [4] [5]. In any case, the clinical presentation is distinguished by the appearance of localized infections, and in more severe neutropenia, systemic signs (fever, malaise, weight loss, night sweats, hypotension, and poor general condition) [4] [7]. In most cases, throat and mucous membrane infections develop first, presenting with oral ulcerations and a sore throat, whereas a range of skin lesions (ulcers, abscesses and delayed healing of wounds) is a typical finding in cutaneous infections [1] [4]. However, pneumonia, gastrointestinal and genitourinary infections, but also systemic infections that lead to life-threatening sepsis and substantial morbidity/mortality may be seen [1] [4]. In fact, about 10% of patients who suffer from drug-induced neutropenia after the use of cytotoxic drugs develop a toxic-shock-like syndrome, comprising of fever, skin desquamation, hypotension and respiratory distress, with mortality rates of up to 30% [4].

• Fever

  Patients typically experience acute, severe neutropenia, or agranulocytosis ( 9 neutrophils/L) and symptoms of fever, chills, sore throat, and muscle and joint pain. [ncbi.nlm.nih.gov]

  In severe neutropenia, the patient is likely to develop periodontal disease, oral and rectal ulcers, fever, and bacterial pneumonia. Fever recurring every 19-30 days suggests cyclical neutropenia. [medical-dictionary.thefreedictionary.com]

  The patient suffered continuous high-grade fever and maculopapular rash, therefore IL-1Ra therapy was started (100 mg/day). [em-consulte.com]

  During hospitalization, these very elderly patients had the same clinical pictures as the group 75 years with: isolated fever (15.4 %); documented pneumonia (46.2 %), and other documented infections (39.4 %). [link.springer.com]

  In any case, the clinical presentation is distinguished by the appearance of localized infections, and in more severe neutropenia, systemic signs (fever, malaise, weight loss, night sweats, hypotension, and poor general condition). [symptoma.com]

• Malaise

  […] circulating blood by cell changes that trap them in the lungs and spleen. neutropenia [ noo″tro-pe ne-ah ] diminished numbers of neutrophils in the blood. cyclic neutropenia a chronic form marked by regular, periodic episodic recurrences, associated with malaise [medical-dictionary.thefreedictionary.com]

  In any case, the clinical presentation is distinguished by the appearance of localized infections, and in more severe neutropenia, systemic signs (fever, malaise, weight loss, night sweats, hypotension, and poor general condition). [symptoma.com]

  Clinical Manifestations in Elderlies Patients with idiopathic drug-induced agranulocytosis or deep neutropenia usually present, at diagnosis or during their follow-up: high fever, sore throat, stomatitis, diarrhea and a general sensation of malaise, including [omicsonline.org]

  Two weeks after discharge from hospital, the patient referred malaise and fever. No ocular symptoms were referred. Gliclazide had been reintroduced by his general practitioner 2 weeks earlier. WBC was 1630 with 608 neutrophils. [nature.com]

  Signs of infection include: Infections must be treated as soon as they are recognized. high fever or low temperature chills and sweating flu-like symptoms malaise mucositis, a painful inflammation and ulceration of the mucous membranes of the digestive [medicalnewstoday.com]

• Chills

  Patients typically experience acute, severe neutropenia, or agranulocytosis ( 9 neutrophils/L) and symptoms of fever, chills, sore throat, and muscle and joint pain. [ncbi.nlm.nih.gov]

  Case 043: Fever, chills, gum pain, sore throat. [medicine-on-line.com]

  Manifestations in Elderlies Patients with idiopathic drug-induced agranulocytosis or deep neutropenia usually present, at diagnosis or during their follow-up: high fever, sore throat, stomatitis, diarrhea and a general sensation of malaise, including headache, chills [omicsonline.org]

  Signs of infection include: Infections must be treated as soon as they are recognized. high fever or low temperature chills and sweating flu-like symptoms malaise mucositis, a painful inflammation and ulceration of the mucous membranes of the digestive [medicalnewstoday.com]

  Signs & Symptoms The first symptoms of acquired agranulocytosis are usually those associated with a bacterial infection such as general weakness, chills, fever, and/or extreme exhaustion. [rarediseases.org]

• Rigor

  The idiosyncratic nature of IDIN, the lack of mouse models and diagnostic testing, and its low overall incidence make rigorous studies to elucidate possible mechanisms exceptionally difficult. [ncbi.nlm.nih.gov]

  His hyperthyroid symptoms improved when he was reviewed in the out-patient clinic 6 weeks later but he presented to his doctor another month later with a 2 day history of swinging fever, chills and rigor, gum pain, sore throat, and epigastric pain. [medicine-on-line.com]

• Hypoxemia

  The addition of IL-1Ra (100 mg/day) had a dramatic efficacy: on day 3, fever and hypoxemia had markedly decreased, CRP, ASAT and ALAT had felt to 15 mg/L, 8 and 14 UNL, respectively, and TP had risen to 72%. [em-consulte.com]

• Respiratory Insufficiency

  insufficiency ( n 4, 6.5 %); systemic disorder like rheumatoid arthritis ( n 1, 1.6 %). 3.2 Causative Drugs A single drug was documented as “likely causative” or “very likely causative” in all except four cases (93.4 %), for which two to four drugs were [link.springer.com]

• Aphthous Ulceration

  It lasts for approximately 10 days; during this time, gingival inflammation and aphthous ulcer occur. Cyclic neutropenia. neutropenia a diminished number of neutrophils in the blood. cyclic neutropenia periodic neutropenia. [medical-dictionary.thefreedictionary.com]

  Keeping in mind the previous history of occasional small ulcers which the patient had been experiencing since the last five to seven years, we formulated a provisional diagnosis of Recurrent Aphthous Ulcers of Major type. [jiaomr.in]

• Coated Tongue

  There was no bleeding from the ulcers and a coated tongue was seen [Figure 3]. [jiaomr.in]

The development of infections after the use of any of the above-mentioned drugs should prompt the physician to conduct a thorough investigation. One of the first steps in the diagnostic workup is the identification of the exact drugs that were administered, and determination of whether the infections appear in a recurrent fashion, which may provide vital clues for a presumptive diagnosis [7] [8]. A complete blood count will reveal a reduced neutrophil count (and normal hemoglobin and platelet counts) [7] [8] [9]. Based on the severity of neutropenia, it is classified as mild (1000–1500 cells/mm3), moderate (500–1000 cells/mm3), or severe (<500 cells/mm3) [4]. Additional tests that are recommended in patients with confirmed neutropenia include a peripheral blood smear (which can exclude myelodysplastic disorders or hematological malignancies), bone marrow aspiration and subsequent cytologic analysis, as well as human immunodeficiency virus (HIV) testing (if risk factors are present) [7]. Blood cultures (or sampling of other tissues, such as bronchoalveolar aspirate, urine, or feces for microbiological investigation) are a vital component of the workup as well, especially in patients who suffer from systemic infections [7] [8]. Staphylococcus aureus, Streptococcus viridans, gram-negative Enterobacteriaceae, Enterococcus faecalis, E. faecium and fungal agents (Candida and Aspergillus spp.) are pathogens isolated from drug-induced neutropenic patients [4].

• Rectal Ulcer

  In severe neutropenia, the patient is likely to develop periodontal disease, oral and rectal ulcers, fever, and bacterial pneumonia. Fever recurring every 19-30 days suggests cyclical neutropenia. [medical-dictionary.thefreedictionary.com]

• HLA-B27

  For a few drugs, specific risk factors have been identified such as histocompatiblity antigens (HLA): HLA B27 and levamizole, HLAB38 and clozapine [ 1, 10 ]. [omicsonline.org]

1. Garbe E. Non-chemotherapy drug-induced agranulocytosis. Expert Opin Drug Saf. 2007;6(3):323-335.
2. Moore DC. Drug-Induced Neutropenia: A Focus on Rituximab-Induced Late-Onset Neutropenia. P T. 2016;41(12):765-768.
3. Andersohn F, Konzen C, Garbe E. Systematic review: agranulocytosis induced by nonchemotherapy drugs. Ann Intern Med. 2007;146:657–665.
4. Bhatt V, Saleem A. Review: Drug-induced neutropenia--pathophysiology, clinical features, and management. Ann Clin Lab Sci. 2004;34(2):131-137.
5. Curtis BR. Drug-induced immune neutropenia/agranulocytosis. Immunohematology. 2014;30(2):95-101.
6. Sun MT, Tsai CH, Shih KC. Antithyroid drug-induced agranulocytosis. J Chin Med Assoc. 2009;72(8):438-441.
7. Munshi HG, Montgomery RB. Severe neutropenia: a diagnostic approach. West J Med. 2000;172(4):248-252.
8. Hashmi HRT, Jabbour R, Schreiber Z, Khaja M. Benazepril-Induced Agranulocytosis: A Case Report and Review of the Literature. Am J Case Rep. 2016;17:425-428.
9. 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(8):529-535.