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]

In Neutropenia: Causes, Signs, Symptoms and Treatment (pp. 29-42). Nova Science Publishers, Inc.. Drug-induced neutropenia. / Nedved, Adrienne N.; Akhtari, Mojtaba. Neutropenia: Causes, Signs, Symptoms and Treatment. [nebraska.pure.elsevier.com]

The outcome was favorable in all cases with a combination of granulocyte colony-stimulating factor and conventional treatment. [ncbi.nlm.nih.gov]

Treatment Treatment of neutropenia depends on the underlying cause. Medications Patients with fever and other signs of infection are treated for seven to 10 days with antibiotics. [medical-dictionary.thefreedictionary.com]

In our experience, modern management with pre-established procedures, intravenous broad-spectrum antibiotics and hematopoietic growth factors (particularly G-CSF) is likely to improve the prognosis. [ncbi.nlm.nih.gov]

Prognosis The prognosis for mild or chronic neutropenia is excellent. Recovery from acute neutropenia depends on the severity of the patient's infection and the promptness of treatment. Resources Books Linker, Charles A. "Blood." [medical-dictionary.thefreedictionary.com]

Prognosis and Mortality Rate Until the last decade, the mortality rate for idiosyncratic druginduced agranulocytosis was 10% to 16% in European studies [ 1, 2 ], but it has recently dropped to less than 10% (Ë 5% in our cohort study [ 6 ]), probably due [omicsonline.org]

Thus, in patients with these factors, the empirical use of hematopoietic growth factors, glucocorticosteroid and/or broad-spectrum antibiotics may positively impact the prognosis [ 18 ]. [journals.plos.org]

Notably, our data suggests that, despite the population’s frailty and severity of the clinical manifestations, appropriate management of septic complications of IDIA, especially using broad-spectrum antibiotic therapy and HGF, may improve the prognosis [link.springer.com]

Use Additional Use Additional Help Certain conditions have both an underlying etiology and multiple body system manifestations due to the underlying etiology. [icd10data.com]

Koul Nivas, Ist Cross, D main, Harikrishna layout, Ramamurthy Nagar, Bangalore India Source of Support: None, Conflict of Interest: None DOI: 10.4103/0972-1363.57890 Abstract As dental practitioners, we often come across oral ulcerations of varied etiology [jiaomr.in]

The etiology of neutropenia can conceptually be viewed in two broad ways, by mechanism or etiologic category. The mechanisms that cause neutropenia are varied and not completely understood. [emedicine.medscape.com]

Discussion AOSD and SS are inflammatory diseases of unknown etiology, which share several clinical characteristics (high-grade fever, neutrophilic urticarial dermatosis and osteo-articular involvement) [ 6 ]. [em-consulte.com]

If acute neutropenia is suspected to be drug- or toxin-induced, all potentially etiologic agents are stopped. [merckmanuals.com]

Operational definitions for blood dyscrasias have allowed us to create an epidemiological database on this rare side effect of psychotropic medications. [ncbi.nlm.nih.gov]

Epidemiology Neutropenia is considered a rare side effect of vancomycin therapy. The incidence of vancomycin-induced neutropenia has been estimated to be 2-8% based on retrospective analyses in hospitalized patients ( 1, 2 ). [antimicrobe.org]

Strom BL, Carson JL, Schinnar R, SnyderES, Shaw M(1992) Descriptive epidemiology of agranulocytosis. [omicsonline.org]

Silliman CC, Boshkov LK, Mehdizadehkashi Z, Elzi DJ, Dickey WO, Podlosky L, Clarke G, Ambruso DR (2003) Transfusion-related acute lung injury: epidemiology and a prospective analysis of etiologic factors. [link.springer.com]

The exact pathophysiology of lamotrigine-induced neutropenia is unknown (4). A literature review produced several reports of lamotrigine-induced neutropenia that reversed upon drug discontinuation (5–7). [ww1.cpa-apc.org]

Review was limited to articles focusing on leukopenia, neutropenia, agranulocytosis, bicytopenia, and underlying pathophysiological mechanisms. [dovepress.com]

Pathophysiologic mechanisms, clinical features and treatment of idiopathic neutropenia. Expert Rev Hematol 2008; 1 :217-229. 3. Palmblad JE, von dem Borne AE. Idiopathic, immune, infectious, and idiosyncratic neutropenias. [ehj.eg.net]

Semple JW (2002) Immune pathophysiology of autoimmune thrombocytopenic purpura. Blood Rev 16: 9–12 PubMed CrossRef 49. Smith MA, Smith JG (2001) The use of granulocyte colony-stimulating factor for treatment of autoimmune neutropenia. [springermedizin.de]

Now in its second edition, this popular and essential comprehensive resource provides a detailed analysis of how to identify, prevent, and manage drug-induced diseases. Edited by James E. Tisdale and Douglas A. [books.google.com]

The identification of risk factors associated with mortality along with the knowledge of local susceptibility may lead to a better management in terms of preventive and therapeutic measures. [medworm.com]

Preventive measures require good hygiene maintenance with special attention to high-risk areas such as the mouth, skin and perineum [ 1 ]. [omicsonline.org]

Hematology involves the comprehensive study of the diagnosis, treatment, outcome, and prevention of blood diseases. [bcw.edu]

Lyme disease was first widely recognized in 1975 in […] September 20, 2018 According to a recent report published by the Centers for Disease Control and Prevention in the United States, insect-borne diseases in the US tripled during the […] [www4ro.dr-rath-foundation.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.