Agranulocytosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Daniel A. Gerber, M.D. [2]

Overview

Agranulocytosis is a hematological disorder characterized by the acute-onset of severe neutropenia. Neutrophils - a subset of white blood cell - normally make up 50-70% of circulating white blood cells and serve as the primary defense against infections. Hence, patients with neutropenia are more susceptible to infections, mainly bacterial; without prompt medical attention, the condition is often life-threatening. Similar to severe neutropenia in the setting of infection, cases related to cytotoxic chemotherapy, hematopoietic stem cell transplant, or other causes of bone marrow suppression are considered a medical emergency.

Agranulocytosis is defined as severe neutropenia with an absolute neutrophil count (ANC) <500 cells/microliter.

While agranulocytosis technically refers to a reduction in all cells in the leukocyte lineage (neutrophils, eosinophils, and basophils), the vast majority of cases refer to neutropenia as neutrophils constitute the majority of leukocytes and the primary defense against infection.

Historical Perspective

Agranulocytosis, or severe neutropenia, was first noted around the start of the 20th century on review of blood cell differentials described in patients with lupus, other autoimmune disorders, and with various drug toxicities.[1]

Classification

Agranulocytosis is often used interchangeably with severe neutropenia. Calculated based on complete blood count differential, agranulocytosis is loosely defined as an absolute neutrophil count (ANC) less than 500, 200, or 100 cells per microliter, with mild and moderate neutropenia defined below.[2] The ANC is calculated by multiplying the total white blood cell (WBC) count by the percentage of neutrophils (including both mature neutrophils and band forms).

  • Mild Neutropenia: ANC 1,000-1500 cells/microliter
  • Moderate Neutropenia: ANC 500-1000 cells/microliter
  • Severe Neutropenia or Agranulocytosis: ANC <500 cells/microliter

This distinction is important diagnostically and prognostically. Patients with ANC <500 cells/microliter are at a markedly increased risk for severe infections and those <100 cells/microliter have just over a 3-fold increased risk of mortality[2] Importantly, due to severely limited neutrophil activity an inflammatory response, these patients may present with a fever absent additional localizing signs of infection.

Pathophysiology

Agranulocytosis develops as a result of one of the three following mechanisms:

  1. Impaired granulocyte production
  2. Margination: the process by which free flowing blood cells are signaled to adhere to the endothelial wall and exit circulation.
    • Splenic sequestration and destruction
    • Adherence to the vascular endothelium
  3. Accelerated peripheral destruction[3]

Causes

Agranulocytosis is most commonly attributed to malignancy and idiosyncratic drug reactions.

Malignancy is associated with neutropenia through various mechanisms. These include impaired production from myelodysplastic syndromes, hematological malignancies with bone marrow infiltration, and bone marrow suppression from cytotoxic chemotherapy; hemolysis from cytotoxic chemotherapy; and antibody-mediated destruction.

In addition to chemotherapeutics, more than 125 drugs have been identified as causative agents of agranulocytosis. The following medications account for over 50% of definitive cases: antiepileptics, antithyroid drugs (carbimazole, methimazole, propylthiouracil), antibiotics (penicillin, chloramphenicol, co-trimoxazole, dapsone), cytotoxic chemotherapeutics, arsenic, gold, NSAIDs (indomethacin, naproxen, phenylbutazone, metamizole), antihelminths (mebendazole, albendazole), allopurinol, mirtazapine, and the antipsychotic clozapine.[4][5][6]

Immunodeficiencies are frequently associated with neutropenia (38% in Hyper IgM syndrome, 12% in CVID, and 7% in X-linked agammaglobulinemia) as are autoimmune disorders including up to 50% of patients with systemic lupus erythematosus, yet with lower overall prevalence. While rheumatoid arthritis infrequently presents with neutropenia, agranulocytosis can develop in the setting of large granular lymphocyte (LGL) leukemia or Felty's syndrome.[7]

Causes by Organ System

Cardiovascular No underlying causes
Chemical / poisoning Arsenic trioxide, gold salts, strontium-89
Dermatologic Chediak-Higashi disease, dyskeratosis congenita, x-linked, Elejalde syndrome , reticular dysgenesis, reticular dysplasia
Drug Side Effect 5-azacytidine, acetophenazine, aclarubicin, actinomycin D, acyclovir, aflibercept, albendazole, alemtuzumab, allopurinol, amantadine, amiloride, aminoglutethimide, aminoglutethimide, aminopyrine, amiodarone,amodiaquine, ampicillin, amsacrine, anakinra, anidulafungin, anti-thymocyte globulin, antibiotics, antipyrine, aprepitant, aripiprazole, arsenic trioxide, asenapine, atazanavir, atovaquone, auranofin, azacitidine, azathioprine, aztreonam, barbiturates, belinostat, benazepril, bendamustine, bevacizumab, blinatumomab, boceprevir, bortezomib, bosutinib, brentuximab, busulfan, cabazitaxel, cabozantinib, canakinumab, candesartan, capecitabine, captopril, carbimazole, carboplatin, carfilzomib, carmustine, cefaclor, cefadroxil, cefazolin, cefepime, cefixime, cefoperazone, cefotetan, cefotiam, cefoxitin, ceftaroline, ceftriaxone, cefuroxime, cephalexin, cephapirin, cephradine, cetuximab, chemotherapy, chlorambucil, chloramphenicol, chloroquine, chlorpromazine, chlorthalidone, cidofovir, cilazapril, cimetidine, cisplatin, cladribine, clarithromycin, clindamycin, clofarabine, clopidogrel, clozapine, colchicine, crizotinib, cromolyn, cyclophosphamide, cytarabine, cytosine arabinoside, dabrafenib,dacarbazine, daclatasvir, dactinomycin, dasatinib, daunorubicin, decitabine, deferasirox, deferiprone, delavirdine, desipramine, dexrazoxane, diatrizoate, diazepam, diazoxide, dicloxacillin, Diethylpropiondiflunisal, dipyrone, docetaxel, dolutegravir, doripenem, dothiepin, doxorubicin, doxycycline, efavirenz, eflornithine, elvitegravir, enalapril, enalaprilat, enfuvirtide, enzalutamide, epirubicin, eprosartan, eribulin, etanercept, ethacrynic acid, ethambutol, ethosuximide, ethotoin, etodolac, etoposide, everolimus, felbamate, fentanyl, fidaxomicin, flucytosine, fludarabine, fluorouracil, fluoxetine, fosamprenavir, foscarnet, fosinopril, ganciclovir, gefitinib, gemcitabine, gemifloxacin mesylate, glyburide, golimumab, griseofulvin, guanidinium, haloperidol, hydroxycarbamide, hydroxyurea, ibuprofen lysine, ibritumomab tiuxetan, ibrutinib, ibuprofen, idarubicin, idelalisib, iloperidone, imatinib, imipenem cilastatin, indinavir, indomethacin, infliximab, interferon alfa-2a, interferon alfa-2b, interferon alfacon-1, interferon beta-1b, irinotecan, isoniazid, isotretinoin, itraconazole, ixabepilone, lamivudine, lamotrigine, lansoprazole, lenalidomide, levamisole, levetiracetam, levomepromazine, lincomycin, linezolid, lisinopril, loxapine, lurasidone, maprotiline, maraviroc, meclofenamate, mercaptopurine, meropenem, mesalamine, methazolamide, methimazole, methotrexate, methyldopa, metolazone, mexiletine, mianserin, micafungin, mifamurtide, milnacipran, minocycline, mirtazapine, mitotane, mitoxantrone, moexipril, moxalactam, mycophenolate, mycophenolic acid, nafcillin, naproxen, nefazodone, nelarabine, nelfinavir, nevirapine, nilotinib, nilutamide, norfloxacin, nortriptyline, obinutuzumab, ofatumumab, ofloxacin, olanzapine, olaparib, olsalazine,omacetaxine, omeprazole, oprelvekin, oxacillin, oxaliplatin, paclitaxel, palbociclib, paliperidone, panobinostat, pantoprazole, pazopanib, peginterferon alfa-2a, peginterferon alfa-2b, pemetrexed, penicillamine, penicillin, penicillin G, pentamidine, pentostatin, peramivir, perazine, perindopril, pertuzumab, phenylbutazone, phenytoin, piperacillin, piperaquine, pipothiazine, piroxicam, pixantrone, pomalidomide, ponatinib, posaconazole, pralatrexate, prednisone, probenecid, procainamide, procarbazine, prochlorperazine, proguanil, propylthiouracil, pyrimethamine, quetiapine, quinapril, quinidine, quinine, radium chloride, raltitrexed, ramipril, ramucirumab, ranitidine, rasagiline, rasburicase, regorafenib, remoxipride, ribavirin, rifabutin, rifapentine, rifaximin, rilonacept, riluzole, risperidone, ritodrine, ritonavir, rituximab, romidepsin, ruxolitinib, saquinavir, satraplatin, secukinumab, sirolimus, sodium aurothiomalate, sofosbuvir, sorafenib, stavudine, stiripentol, succimer, Sulfacetamide, Sulfamethoxazole/Trimethoprim (oral),

sulfasalazine, sulfonamide, sulindac, sunitinib, suramin, tacrolimus, tedizolid, teicoplanin, temozolomide, temsirolimus, teniposide, tenofovir, terbinafine, teriflunomide, thalidomide, thiothixene, ticarcillin, ticlopidine, tipranavir, tocilizumab, tofacitinib, tolazamide, tolmetin, topotecan, tositumomab, trabectedin, trametinib, trandolapril, trastuzumab, trimethadione, trimethoprim, trimetrexate, valganciclovir, valproic acid, valrubicin, valsartan, vancomycin, vandetanib, vesnarinone, vincristine, vindesine, vinflunine, vinorelbine, zidovudine, zileuton, ziprasidone, ziv-aflibercept, zoledronic acid

Ear Nose Throat No underlying causes
Endocrine Hyperthyroidism
Environmental No underlying causes
Gastroenterologic Glycogen storage disorder, hypersplenism, Shwachman-Diamond syndrome
Genetic Barth syndrome, cartilage-hair hypoplasia, Chediak-Higashi disease, Cohen syndrome, Dubowitz syndrome, Elejalde syndrome , familial histiocytic reticulosis, Fanconi syndrome, fumarate hydratase deficiency, Griscelli syndrome type 1, methylmalonic aciduria, myelokathexis, propionic acidemia, propionyl-CoA carboxylase deficiency PCCA type, Shwachman-Diamond syndrome, WHIM syndrome
Hematologic Alloimmune neonatal neutropenia, alloimmune neutropenia in infancy, aplastic anemia, autoimmune neutropenia, chronic lymphocytic leukemia, cyclical neutropenia, familial histiocytic reticulosis, Hermansky-Pudlak syndrome, histiocytosis X, hypersplenism, Kostmann disease, myelodysplastic syndrome, myelofibrosis, pancytopenia, paroxysmal nocturnal haemoglobinuria, Shwachman-Diamond syndrome, x-linked agammaglobulinemia
Iatrogenic Hemodialysis, radiation therapy
Infectious Disease Brucellosis, cytomegalovirus, dengue, Epstein-Barr virus, hepatitis A, hepatitis B, hepatitis C, hepatitis, human granulocytic ehrlichiosis, human immunodeficiency virus, human monocytotropic ehrlichiosis, kala azar, Kostmann disease, lassa fever, Lyme disease, malaria, measles, rickettsiae, rickettsial infections, rocky mountain spotted fever, rubella, salmonella infection, sepsis, severe acute respiratory syndrome, shigellosis, tuberculosis, tularemia, varicella, visceral leishmaniasis, WHIM syndrome
Musculoskeletal / Ortho Cartilage-hair hypoplasia, metaphyseal chondrodysplasia, Mckusick type
Neurologic Fumarate hydratase deficiency
Nutritional / Metabolic Copper deficiency, glutathione synthase deficiency, glycogen storage disorder, glycogenosis type 1b, hereditary orotic aciduria, isovaleric acidemia, methylmalonic aciduria, propionic acidemia, propionyl-CoA carboxylase deficiency PCCA type, vitamin deficiencies
Obstetric/Gynecologic No underlying causes
Oncologic Chronic lymphocytic leukemia, hairy cell leukemia, histiocytosis X, leukemia, myelodysplastic syndrome, myelofibrosis
Opthalmologic No underlying causes
Overdose / Toxicity Alcoholism
Psychiatric No underlying causes
Pulmonary Severe acute respiratory syndrome
Renal / Electrolyte Fanconi syndrome
Rheum / Immune / Allergy Alloimmune neonatal neutropenia, alloimmune neutropenia in infancy, autoimmune lymphoproliferative syndrome type 1, autoimmune lymphoproliferative syndrome type 2, autoimmune neutropenia, common variable immune deficiency, Felty's syndrome, histiocytosis X, hyper-immunoglobulin M syndrome, lupus, rheumatoid arthritis, secondary autoimmune neutropenia, WHIM syndrome, x-linked agammaglobulinemia, x-linked hyperimmunoglobulin M syndrome
Sexual No underlying causes
Trauma No underlying causes
Urologic No underlying causes
Dental No underlying causes
Miscellaneous No underlying causes

Differentiating Agranulocytosis from Other Diseases

Agranulocytosis is a laboratory diagnosis based off of the complete blood count differential, however the differential diagnosis for the etiology of neutropenia and agranulocytosis is quite important as patients can deteriorate rapidly without appropriate treatment.

Consider the following differential when evaluating a patient with agranulocytosis:

  • Drug-induced: An idiosyncratic (dose-independent) reaction. Accounts for 65-75% of all cases of agranulocytosis in the United States. More commonly presents with isolated neutropenia in the absence of anemia or thrombocytopenia.[8]
  • Malignant: Typically, a dose-dependent reduction in neutrophils to cytotoxic chemotherapy, malignant infiltration of the bone marrow, or immune-mediated hemolysis. Often seen concurrently with severe anemia, thrombocytopenia, hepatosplenomegaly, and lymphadenopathy.
  • Autoimmune: Antibody-mediated neutrophil destruction.[7]

Epidemiology and Demographics

Neutropenia is typically identified in at-risk patients undergoing cytotoxic chemotherapy or on other myelosuppressive medications. While some ethnicities have an unusually high prevalence of asymptomatic mild neutropenia (ANC 1,000-1500 cells/microliter) known as constitutional or benign ethnic neutropenia (BEN), these do not progress to agranulocytosis, do not increase the risk of infection, and present no additional risk in the setting of cytotoxic chemotherapy as these individuals have normal bone marrow neutrophil reserves.[9][10][11]

Immunodeficiencies are frequently associated with neutropenia (38% in Hyper IgM syndrome, 12% in CVID, and 7% in X-linked agammaglobulinemia) as are autoimmune disorders including up to 50% of patients with systemic lupus erythematosus, yet with lower overall prevalence. While rheumatoid arthritis infrequently presents with neutropenia, severe neutropenia can develop in the setting of large granular lymphocyte (LGL) leukemia or Felty's syndrome.[7]

Risk Factors

Risk factors for agranulocytosis include:

Screening

There are no routine screening recommendations for agranulocytosis. It is typically identified incidentally on routine blood work or while monitoring after cytotoxic therapy.[13]

Natural History, Complications, and Prognosis

Natural History

Neutropenia, and progression to agranulocytosis, occurs in either a dose-dependent or idiosyncratic process dependent upon the etiology. Neutropenia caused by cytotoxic chemotherapy or malignant bone marrow infiltration and failure is typically dose-dependent or related to tumor burden, as opposed to idiosyncratic - unpredictable, dose-independent, and typically immune-mediated - drug reactions.

Complications

Severe neutropenia or agranulocytosis warrant significant attention to any symptoms of infection, malignancy, or potentially contributing medications as infectious complications carry a mortality rate of up to 10%.[14]

Prognosis

While the prognosis for low risk neutropenia is excellent, with >90% probability of complete resolution without complications, high risk patients have >40% risk of serious complications. Risk stratification for patients with neutropenia is defined below.

Low risk: typically patients with solid tumors on chemotherapy plus the following:

  • Anticipated neutropenia (ANC<500 cells/microliter) <7 days
  • No significant hepatic or renal dysfunction
  • No significant comorbidities**
  • MASCC Risk Score >21 (PPV 91%, specificity 68%, sensitivity 71%)

High risk

  • Anticipated neutropenia (ANC<500 cells/microliter) >7 days
  • Significant hepatic or renal dysfunction
  • Significant comorbidities**
  • Disease progression
  • MASCC Risk Score <21 (PPV 91%, specificity 68%, sensitivity 71%)

**Significant comorbidities: Hemodynamic instability, mucositis, GI symptoms, acute neurological changes, intravascular catheters, pulmonary infiltrates, or underlying chronic lung disease

Diagnosis

Diagnostic Criteria

The diagnosis is made on complete blood count differential, a routine blood test, with an ANC <500 cells/microliter. To formally diagnose agranulocytosis, other pathologies with a similar presentation must be excluded, such as aplastic anemia, paroxysmal nocturnal hemoglobinuria, myelodysplasia, and leukemias. This requires a bone marrow examination that shows normocellular (normal amounts and types of cells) marrow with underdeveloped promyelocytes. These underdeveloped promyelocytes are the precursors to these missing granulocytes.

History and Symptoms

History of patients with agranulocytosis should focus on symptoms suggestive of malignancy, infection, or autoimmune disorders, and careful attention to identifying any new or recent medications. Some common infections can take an unexpected course in neutropenic patients; for example, formation of pus can be notably absent, as this requires circulating neutrophil granulocytes.[13] As a result, neutropenia and agranulocytosis may remain undetected until the patient develops secondary, and often severe, infections or sepsis.

Common symptoms include:

Physical Examination

Physical examination should focus on identifying any potential signs of infection and is directed by the patients' presenting symptoms. A rectal examination should not be performed in a patient with neutropenia.[13]

Vital signs

General appearance

Neurological exam

  • Confusion or disorientation
  • Neck stiffness
  • Focal neurological abnormalities

Chest

Abdomen

Extremities

Laboratory Findings

Agranulocytosis is detected on a full blood count. A peripheral blood smear is often useful to evaluate for abnormal morphology of the visible cells, which may help suggest the underlying cause. Additional laboratory studies include evaluation for hemolysis, metabolic abnormalities related to rapid cell turnover or organ involvement, and toxic etiologies. Bone marrow biopsy may be indicated if the etiology is uncertain or if malignancy or marrow infiltration are suspected.[13]

Imaging Findings

Agranulocytosis is not identified on or correlated with any particular imaging. In cases of neutropenic fever, imaging findings are dependent upon the source of the fevers. Initial evaluation for neutropenic fever should include a chest radiograph to evaluate for masses, pulmonary infiltrates or effusions. Further imaging, such as CT or MRI scans, are indicated depending upon presenting symptoms and physical examination findings.[13]

Other Diagnostic Studies

Additional diagnostic work up is determined based upon the patient's specific presentation.

Treatment

Medical Therapy

There is no specific medical therapy for agranulocytosis. Treatment is directed at identifying and removing the offending agents, treating the underlying disease, and monitoring closely for signs of infection and treating quickly and aggressively. Recombinant granulocyte-colony stimulating factor (G-CSF) may be considered to accelerate myeloid reconstitution.[15] These patients often warrant urgent hospitalization for close monitoring and treatment. Furthermore, in cases of drug-induced agranulocytosis, reinitiating the offending agent is contraindicated as this reaction is likely to recur.

In cases of febrile neutropenia, empiric antibiotics should be implemented as early as possible after cultures are drawn and within 60 minutes of presentation, as there is significantly higher mortality when antibiotic administration is delayed.[16][17][18] Initial antibiotic selection should provide broad bactericidal coverage of the most common, virulent, and likely pathogens so as not to rely on assistance from the host's impaired immune system. Central venous catheters and other indwelling devices should be removed when possible if there is suspicion for infection or with positive blood cultures.

Surgery

There are no surgical treatments for agranulocytosis. In patients with neutropenic fever, surgical intervention may be necessary depending on the source of infection.[13]

Prevention

Prevention of agranulocytosis is dependent upon avoiding certain medications or treatment of underlying conditions. Occasionally, when agranulocytosis is anticipated, such as in the setting of cytotoxic chemotherapy, recombinant G-CSF (granulocyte-colony stimulating factor) can be considered to speed myeloid reconstitution.

See also

References

  1. Dameshek W. (1944). "Leukopenia and Agranulocytosis.". Oxford University Press. 1: 841–52.  Text "NLM ID 39120200R" ignored (help)
  2. 2.0 2.1 Andersohn F, Konzen C, Garbe E. (2007). "Systematic review: agranulocytosis induced by nonchemotherapy drugs.". Ann Internal Med. 146(9): 657–65.  Text "PMID 17470834" ignored (help)
  3. Kumar, Vinay (2007). Robbins Basic Pathology (8 ed.). 441: Elsevier. 
  4. Elisa Mari; Franco Ricci; Davide Imberti; Massimo Gallerani (June 2011). "Agranulocytosis: an adverse effect of allopurinol treatment". Italian Journal of Medicine. 5 (2): 120–3. doi:10.1016/j.itjm.2011.02.006. 
  5. Diaz, Jaime (1996). How Drugs Influence Behavior. Englewood Cliffs: Prentice Hall. ISBN 0132815605. 
  6. Andersohn F, Konzen C, Garbe E (May 2007). "Systematic review: agranulocytosis induced by nonchemotherapy drugs". Ann. Intern. Med. 146 (9): 657–65. PMID 17470834. doi:10.7326/0003-4819-146-9-200705010-00009. 
  7. 7.0 7.1 7.2 Bucknall RC, Davis P, Bacon PA, Jones JV (2009). "Neutropenia in rheumatoid arthritis: studies on possible contributing factors". Ann Rheum Dis. 41 (3): 242–7. PMID 6979979. 
  8. Andersohn F, Konzen C, Garbe E (May 2007). "Systematic review: agranulocytosis induced by nonchemotherapy drugs". Ann. Intern. Med. 146 (9): 657–65. PMID 17470834. doi:10.7326/0003-4819-146-9-200705010-00009. 
  9. Shoenfeld Y, Alkan ML, Asaly A, Carmeli Y, Katz M (1988). "Benign familial leukopenia and neutropenia in different ethnic groups". Eur J Haematol. 41 (3): 273–7. PMID 3181399. 
  10. Shoenfeld Y, Ben-Tal O, Berliner S, Pinkhas J (1985). "The outcome of bacterial infection in subjects with benign familial leukopenia (BFL)". Biomed Pharmacother. 39 (1): 23–6. PMID 4027348. 
  11. Hsieh MM, Tisdale JF, Rodgers GP, Young NS, Trimble EL, Little RF (2009). "Neutrophil count in African Americans: lowering the target cutoff to initiate or resume chemotherapy?". J Clin Oncol. 28 (10): 1633–7. PMID 20194862. 
  12. Andrès E, Zimmer J, Affenberger S, Federici L, Alt M, Maloisel F. (2006). "Idiosyncratic drug-induced agranulocytosis: Update of an old disorder.". Eur J Intern Med. 17 (8): 529–35.  Text "pmid 17142169" ignored (help)
  13. 13.0 13.1 13.2 13.3 13.4 13.5 Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, Raad II, Rolston KV, Young JA, Wingard JR; Infectious Diseases Society of America. (2011). "Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america". Clin Infect Dis. 52 (4): e56–95. PMID 21258094. 
  14. Andrès E, Maloisel F. (2008). "Idiosyncratic drug-induced agranulocytosis or acute neutropenia.". Curr Opin Hematol. 15 (1): 15–21. PMID 18043241. 
  15. Aapro MS; et al. (2011). "2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumors". Eur J Cancer. 47 (1): 8–32. PMID 21095116. 
  16. Schimpff S, Satterlee W, Young VM, Serpick A (1971). "Empiric therapy with carbenicillin and gentamicin for febrile patients with cancer and granulocytopenia". N Engl J Med. 284 (19): 1061–5. PMID 4994878. 
  17. Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, Suppes R, Feinstein D, Zanotti S, Taiberg L, Gurka D, Kumar A, Cheang M (2006). "Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock". Crit Care Med. 34 (6): 1589–96. PMID 16625125. 
  18. Rosa RG, Goldani LZ. (2014). "Cohort study of the impact of time to antibiotic administration on mortality in patients with febrile neutropenia". Antimicrob Agents Chemother. 58 (7): 3799–803. PMID 24752269. 

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