Immune neutropenia mediated by micafungin
Authors: Amir H. Ameri, Brian R. Curtis, David B. Sykes
Journal: American Journal of Hematology (2019)

A 70-year-old male with diabetes mellitus and coronary artery disease was found unresponsive at his home. Upon arrival to the hospital, he was confused and was noted to have a right-sided visual field deficit. Given the patient's cardiovascular risk factors, the patient's presentation with right-sided visual field deficit was most consistent with acute stroke. Other etiologies include an intracranial mass of malignant or infectious etiology, especially in the setting of underlying diabetes mellitus and resultant immunosuppression. The patient unfortunately presented outside the window for rtPA therapy. MRI of the brain demonstrated severe stenosis of the left internal carotid artery and a focus of decreased attenuation in the left occipital area, consistent with an acute ischemic stroke. He was started on atorvastatin and continued on aspirin. Also noted on the MRI was a nasopharyngeal mass with direct skull base invasion and external compression of the left proximal internal carotid artery. His chest radiograph was unremarkable. Testing for HIV was negative. Blood cultures grew S. pneumoniae. The differential for this nasopharyngeal mass included malignant and infectious etiologies. The patient's history of diabetes mellitus placed him at risk for the development of severe infection with microbes, such as Mucorales, Streptococcus pyogenes, Alternaria, Candida, and metastatic infection, among others. Given the suspicion of an underlying malignancy, the nasopharyngeal mass was biopsied and found to represent a fungal mass (Alternaria species). As the fungal mass involved critical vasculature, surgical resection was considered excessively risky and the patient was started on multiple antibiotic and antifungal therapies including cefepime, metronidazole, vancomycin, meropenem, amphotericin, micafungin, and caspofungin (Figure 1 ). The patient initially received cefepime, metronidazole, and vancomycin, and once blood cultures grew Streptococcus pneumoniae, he was narrowed to vancomycin. Multiple antifungal therapies were administered simultaneously given the patient's life-threatening infection with Alternaria. The patient's absolute neutrophil count (ANC) began to trend down to a nadir of 80 (Figure 1 ). His hemoglobin (9.3 g/dL) and platelet count (266 000/μL), as well as his absolute lymphocyte, monocyte, eosinophil and basophils counts, remained stable. The peripheral blood smear was unremarkable. Filgrastim was administered and the patient's ANC recovered. Drug induced neutropenia was suspected as the most likely etiology for this patient's decline in neutrophil count. Systemic infection was also considered but was felt to be less likely given the absence of other cytopenias. The stability of the patient's hemoglobin and platelet count argued against a process of general bone marrow suppression. A sample of the patient's serum was submitted to the Blood Center of Wisconsin to evaluate for immune neutropenia. Flow cytometric analysis revealed the presence of micafungin-dependent, neutrophil-reactive IgG antibodies, supporting a diagnosis of micafungin-induced immune neutropenia (Figure 2 ). Testing for vancomycin, caspofungin, amphotericin B, metronidazole, and meropenem-dependent IgG antibodies was negative (Figure 2 ) and testing for IgM antibodies to all medications was also negative (data not shown). The flow cytometry assay is performed by incubating the patient's serum with normal donor neutrophils in the presence and absence of each medication in question. Binding of the patient's antibody to the neutrophils is quantified using a fluorescent anti-IgG or anti-IgM polyclonal secondary antibody. A positive control serum with quinine drug-dependent neutrophil antibodies was included in each assay. A ratio of the median fluorescence intensity (MFI) in the presence of drug to the MFI in the absence of drug is determined, and values greater than 2.0 are designated as positive results (our patient demonstrated a ratio of 7.6 in the presence of micafungin).1, 2 The timing of micafungin administration, development of neutropenia and the strong IgG antibody response seems suggestive of a pre-formed antibody as it seems improbable that the patient developed a primary micafungin-dependent anti-neutrophil IgG response in only 2 days. The patient was not known to have had prior micafungin exposure. Other possibilities include prior immunization with a compound that crossreacts with micafungin. Neutropenia, defined as an ANC below 1500 cells/mm3, can result from decreased neutrophil production, increased neutrophil destruction, or neutrophilic tissue margination. Neutropenia arises commonly in the setting of pancytopenia which is often attributed to general bone marrow suppression secondary to adverse drug effects, viral infections, poor nutritional status and malignant infiltration of the bone marrow, among other etiologies. Isolated neutropenia (where red blood cell and platelet production is unaffected) is much less common and generally felt to be antibody-mediated. Autoimmune neutropenia, neonatal alloimmune neutropenia, or drug-induced processes should be considered. Anti-neutrophil antibodies may also arise in the setting of rheumatoid arthritis, systemic lupus erythematosus, Felty's syndrome, and myasthenia gravis.1, 3-9 Several medications are associated with drug-induced immune neutropenia and include quinine, quinidine, infliximab, lamotrigine, methimazole, oxacillin, penicillin G, procainamide, propylthiouracil, rituximab, sulfasalazine, trimethoprim-sulfamethoxazole, and vancomycin.10 The systematic review, “Agranulocytosis Induced by NonChemotherapy Drugs,” reviewed 980 reported cases of agranulocytosis, and identified 125 drugs with definite or probable causality.11 To our knowledge, micafungin has not previously been associated with drug-induced immune neutropenia. The mechanism underlying drug-induced immune neutropenia is not well-elucidated, but it is hypothesized that some medications, or their metabolites, are immunogenic and lead to the production of anti-neutrophil antibodies.12 Some drugs, such as flecainide, amodiaquine, and propylthiouracil, bind directly against the neutrophil cell membrane and serve as haptens in the production of anti-neutrophil antibodies.13-15 Other drugs are oxidized to reactive metabolites that provoke an immune response, likely via inflammasome activation.12 Further, some HLA types, such as HLA-B38 and HLA-B27, predispose individuals to agranulocytosis in response to certain medications and it is possible that certain HLA antigens increase the likelihood of developing drug-induced neutropenia as well.16-18 Typically, severe neutropenia will present within the first 3 months of initiating the responsible agent.11 Neutropenia can be lethal: neutrophil counts of less than 0.1 × 109 cells/L are associated with fatal infectious complications.11 Management of drug-induced neutropenia includes withdrawal of the offending agent, treatment of infection, antimicrobial prophylaxis, infectious precautions, and administration of granulocyte colony stimulating factor to increase neutrophil counts, which is associated with a shorter duration of neutropenia and decreased fatality.11, 19 The time until recovery is variable and depends on the etiology of the neutropenia and the offending agent.11 In the setting of multiple co-administered medications, as in this patient, consideration should be given to flow cytometric analysis in order to definitively determine the offending agent and direct the patient's future management appropriately. In conclusion, drug-induced immune neutropenia should be considered in a patient with otherwise unexplained isolated neutropenia. If infectious and other autoimmune workup is unrevealing, flow cytometric analysis for drug-induced immune neutropenia is warranted. Withdrawal of the offending agent should lead to a recovery in neutrophil counts.