Blood neutrophil increment after a single injection of rhG-CSF or rhGM-CSF correlates with marrow cellularity and may predict the grade of neutropenia after chemotherapy

Summary. The grade of neutropenia after chemotherapy seems to be correlated to the bone marrow cellularity as judged by biopsies. Prolonged blood neutropenia after sequential chemotherapy reduces dose intensity and increases the risk of severe infections. A predictive non-invasive test for marrow cellularity is needed in the attempt to predict chemotherapy-induced blood neutropenia.
Thirty-one patients with haematological disorders were studied with measurements of blood absolute neutrophil counts (ANC) 24 h after a single subcutaneous injection of recombinant human granulocyte colony stimulating factor (rhG-CSF) or granulocyte-macrophage CSF (rhGM-CSF). Before cytokine administration all patients had bone marrow biopsies performed.
The median increase in blood ANC 24 h after cytokine administration was 15·9 × 10⁹/l (range 3·7–34·2) in 18 patients with normo- or hypercellular marrows and only 0·4 × 10⁹/l (range 0·0–11·2) in 13 patients with hypocellular marrows ( P <0·00001). An increase in ANC or more than 5 × 10⁹/l was predictive for normo- or hypercellular bone marrows with a sensitivity and specificity of 94% and 84%, respectively.
A subsequent pilot study in selected patients with prolonged neutropenia was performed. The ANC increment in 12 cases before chemotherapy correlated to the grade of neutropenia and may predict the risk of febrile neutropenia.
It is suggested that blood responsiveness to myeloid growth factors correlates with marrow cellularity and may identify outpatients with risk for severe neutropenia after cyclic chemotherapy.     

Acquired agranulocytosis with granulocyte specific cytotoxic autoantibody.

Multiple infections and severe neutropenia were found in a previously healthy 29 year old man with no history of similar syndromes in the family, drug ingestion or exposure to environmental toxins. There was no evidence at the time of presentation of diseases previously associated with agranulocytosis (e.g., neoplasia, thyrotoxicosis, chronic infection, collagen-vascular disease or leukoagglutinating antibody). His serum contained a nonagglutinating, complement-dependent, cytotoxic antibody, however, reactive with peripheral blood granulocytes from 35 per cent of normal donors. The neutropenia was not affected by steroids but resolved promptly after splenectomy. Microscopic examination of the spleen revealed ingestion of polymorphonuclear leukocytes by splenic macrophages. Family studies indicated that the target antigen was non-HLA and that the antibody was not absorbed by lymphocytes or platelets. We conclude that the agranulocytosis was autoimmune in origin and suggest that similar myeloid-specific immune responses could influence granulocyte tranfusion and bone marrow transplantation by alloimmune "rejection" that would not be avoided by matching only for HLA specificities.     

Leucemia de linfocitos grandes granulares como complicación de artritis reumatoide

Large granular lymphocyte leukemia is a rare entity belonging to same spectrum of diseases than Felty's syndrome, which might occur in patients with long-standing rheumatoid arthritis. It is clinically characterized by persistent neutropenia and recurrent bacterial infections associated with the presence in both peripheral blood and bone marrow of clonal expansion of atypic lymphocytes with a cytotoxic T cell phenotype, or less frequently an NK-cell phenotype, as well as splenomegaly. It is more frequently diagnosed in seropositive rheumatoid arthritis, with significant structural damage, extra-articular manifestations and persistently elevated values of ESR, despite them havubg low inflammatory joint activity. We report the case of a 70 year old male with a long-standing rheumatoid arthritis, who developed septic shock secondary to prosthetic hip infection by Salmonella spp. He showed persistent neutropenia, and an aberrant monoclonal T cell population was detected in both peripheral blood and bone marrow, consistent with large granular lymphocyte leukemia.     

The successful treatment of G-CSF in autoimmune neutropenia with liver cirrhosis complicated by esophageal varices]

A 72 year-old woman was admitted to our hospital for hematoemesis. After admission, endoscopic examination showed esophageal varices with a red color sign which indicated endoscopic injection sclerotherapy (EIS). Concurrently, however, laboratory findings revealed severe neutropenia in peripheral blood, while bone marrow examination showed marked reduction of mature granulocytes with mild myeloid hyperplasia. As a result of those hematological abnormalities, EIS was halted. Concerning the pathogenesis of this neutropenia, immunofluorescence technique using flow cytometry disclosed the presence of anti-neutrophil autoantibody in the serum, giving a clinical diagnosis of autoimmune neutropenia (AIN). Thereafter, a conventional regimen of corticosteroids as an initial therapy and steroid pulse therapy as a succeeding maneuver were instituted, but in vain. As a last resort, 125 micrograms/body of rhG-CSF was given daily subcutaneously. As a consequence, significant increase in granulocyte count, though transient, was attained, which made EIS possible without any episodes of infections. It seems most likely that a high dose of rhG-CSF exerts beneficial effects as a prophylactic and therapeutic regimen against infections in patients with AIN.     

Autoimmune neutropenia: clinical and laboratory studies in 143 patients

Summary Clinical and laboratory data of 143 patients with primary or secondary autoimmune neutropenia (AIN) were evaluated. Primary AIN was found predominantly in children below 3 years, whereas secondary AIN was more frequent in patients 40–60 years of age. Female patients with primary AIN were slightly more prevalent (54%) than male patients (46%). The peripheral blood count showed normal or diminished leukocyte counts with median absolute neutrophil counts of 250 cells/l. In 38% of the patients neutropenia was accompanied by monocytosis. Bone marrow examination revealed in 95% a normo- or hypercellular marrow with a marked reduction of mature neutrophils in 56% of the specimens. Twenty-three percent of the sera showed specificity for the NA1 antigen. Patients were usually affected by benign bacterial infections of the skin and of the upper respiratory tract, as well as by recurrent otitis media. Infections were treated symptomatically, and only six patients required continuous administration of antibiotics. Remission of neutropenia during treatment occurred in three of six patients treated with intravenous immunoglobulin G and in three of four patients who received steroid therapy. Except for one patient neutropenia relapsed after discontinuation of therapy. During a follow-up of 6–36 months, spontaneous remission has been observed in four patients.This work was supported by theDeutsche Forschungsgemeinschaft (Mu 277/9-7)     

The use of itraconazole as prophylaxis against invasive fungal infection in blood and marrow transplant recipients

Invasive fungal infections play a key role in contributing to morbidity and mortality in patients undergoing treatment for haematological malignancies and related diseases. Risk factors for development of invasive fungal infections after blood or bone marrow transplantation include the use of broad‐spectrum antibiotics, steroids, mismatched or unrelated donor transplant, right atrial catheters, and prolonged or profound neutropenia. Previous attempts at use of oral itraconazole as antifungal prophylaxis in the setting of chemotherapy‐induced neutropenia were unsuccessful because of its poor absorption in capsule form. Itraconazole‐cyclodextrin is well absorbed even in the presence of chemotherapy‐induced neutropenia. Plasma levels of 250–500 ng/ml are required for prophylaxis. Studies to date show a favourable outcome in patients receiving itraconazole as prophylaxis against invasive fungal infections, although many studies looked at small numbers of patients and the incidence of invasive fungal infection in the control groups was low, prohibiting meaningful statistical evaluation. Fungi differ in their sensitivity to antifungal agents, and itraconazole is not the agent of choice in all patients. With the widespread use of antifungal prophylaxis, the possibility of resistance to antifungal agents and an increase in the number of invasive fungal infections caused by ubiquitous fungi previously considered nonpathogenic must be considered as potential problems.     

Fluconazole vs low-dose amphotericin B for the prevention of fungal infections in patients undergoing bone marrow transplantation: a study of the North American Marrow Transplant Group

Systemic fungal infections are a major problem in bone marrow transplant recipients who have prolonged neutropenia or who receive high-dose corticosteroids. Prophylaxis with Fluconazole or low-dose amphotericin B reduces, but does not eliminate these infections. To determine which prophylactic agent is better, we performed a prospective randomized study. Patients undergoing allogeneic (related or unrelated) or autologous marrow or peripheral stem cell transplantation were randomized to receive Fluconazole (400 mg/day p. o. or i.v.) or amphotericin B (0.2 mg/kg/day i.v.) beginning 1 day prior to stem cell transplantation and continuing until recovery of neutrophils to >500/microl. Patients were removed from their study drug for drug-associated toxicity, invasive fungal infection or suspected fungal infection (defined as the presence of fever >38 degrees C without positive culture while on broad-spectrum anti-bacterial antibiotics). Proven or suspected fungal infections were treated with high-dose amphotericin B (0.5-0.7 mg/kg/day). Patients were randomized at each institution and stratified for the type of transplant. The primary end-point of the study was prevention of documented fungal infection; secondary endpoints included fungal colonization, drug toxicity, duration of hospitalization, duration of fever, duration of neutropenia, duration and total dose of high-dose amphotericin B and overall survival to hospital discharge. From July 1992 to October 1994, a total of 355 patients entered into the trial with 159 patients randomized to amphotericin B and 196 to Fluconazole. Patient groups were comparable for diagnosis, age, sex, prior antibiotic or antifungal therapy, use of corticosteroids prior to transplantation and total duration of neutropenia. Amphotericin B was significantly more toxic than Fluconazole especially in related allogeneic transplantation where 19% of patients developed toxicity vs 0% of Fluconazole recipients (p < 0.05). Approximately 44% of all patients were removed from prophylaxis for presumed fungal infection. Proven fungal infections occurred in 4.1% and 7.5% of Fluconazole and amphotericin-treated patients, respectively. Proven fungal infections occurred in 9.1% and 14.3% of related allogeneic marrow recipients receiving Fluconazole or amphotericin B, respectively, and 2.1% and 5.6% of autologous marrow recipients receiving Fluconazole or amphotericin B, respectively (P > 0.05). In this prospective trial, low-dose amphotericin B prophylaxis was as effective as Fluconazole prophylaxis, but Fluconazole was significantly better tolerated.     

Dizygotic twin sisters with myelokathexis: mechanism of its neutropenia.

Dizygotic twin sisters were first found to have neutropenia at 1 year of age when evaluated for recurrent pulmonary infections. Since then they have remained neutropenic (0.05 approximately 0.5 x 10(9)/l). Despite of their neutropenia, myeloid hyperplasia was evident on a marrow smear examination, and a number of cells were hypersegmented with fine interlobular bridging with chromatin strands and cytoplasmic vacuolation. Electron microscopy showed apoptotic cells with condensed nuclei and apoptotic bodies in the cytoplasm. Although life span, hydrogen peroxide production, phagocytosis, spreading, and chemotaxis of peripheral neutrophils were normal, the survival of bone marrow neutrophils in both infants was markedly decreased when compared with that of normal bone marrow neutrophils. During the bone marrow culture apoptotic neutrophils were observed at an earlier stage in both patients than in normal controls, biochemically and morphologically. Morphology of bone marrow neutrophils in both patients resembled that of cultured control bone marrow neutrophils. Peripheral neutropenia and appearance of characteristic neutrophils in the bone marrow in myelokathexis are considered to be an expression of apoptosis of bone marrow neutrophils.     

Neutropenia, neutrophil dysfunction, and bacterial infection in patients with human immunodeficiency virus disease: the role of granulocyte colony-stimulating factor.

Neutropenia frequently complicates infection due to human immunodeficiency virus (HIV). The etiology of neutropenia in this setting includes bone marrow infection or infiltration, myelosuppressive therapies, the presence of antibodies to HIV, and accelerated apoptosis. Protection against microbial invaders by neutrophils is further compromised by impaired chemotaxis and phagocytosis, production of toxic oxygen species, and expression of cellular adhesion molecules. Neutropenia is a significant risk factor for bacterial infection in HIV-infected patients. Endogenous cytokines, such as granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor, regulate neutrophil count and function. Treatment with recombinant human methionyl G-CSF (filgrastim) has lessened neutropenia in patients with HIV infection. Clinical trials have shown that the incidence of bacterial infections and the number of consequent days of hospitalization for HIV-infected patients receiving filgrastim therapy are lower. Filgrastim treatment also allows administration of larger doses of myelosuppressive agents.     

Cyclic hematopoiesis: human cyclic neutropenia

Human cyclic neutropenia is a relatively rare disorder of unknown etiology. Study of patients and animals with the disorder has led to important information regarding the differentiation of blood cells and control mechanisms of hematopoietic regulation. It has a world-wide distribution, occurs in both sexes, and, in about one-fourth of the patients, a family history has been obtained. While usually benign, deaths from overwhelming infections occur. In addition to cycling of neutrophils, in the majority of cases the monocytes cycle and in about one-fifth of the cases eosinophils are elevated. In a small number of patients, cycling of platelets and reticulocytes occurs. Cycles of colony stimulating factor are present. Cycles of bone marrow cells are easily demonstrable. The recent transfer of human cyclic neutropenia following allogenic bone marrow grafting confirms the hypothesis that the disorder is of bone marrow origin. The following subjects are covered in this review article: A. Definition, history, and incidence; B. Etiology, geographic distribution, mode of transmission; C. Symptoms, physical signs, diagnosis, clinical course; D. Clinical laboratory studies; E. Experimental studies; F. Prognosis; G. Treatment. It is felt that human cyclic neutropenia represents a heterogeneous group of disorders and that much remains to be learned about its cause(s).     

Severe neutropenia associated with IgG2 subclass deficiency and bone marrow T-lymphocyte infiltration

Patients with selective IgG2 subclass deficiency (IgG2 SD) usually suffer from recurrent respiratory infections. The occurrence of cytopenia is extremely rare in these patients. We report on two patients with isolated IgG2 SD who experienced unexplained severe neutropenia associated with T-lymphocyte proliferation. IgG2 SD clearly preceded the occurrence of neutropenia in one patient. In the other patient, the long-standing history of recurrent respiratory infections prior to diagnosis of agranulocytosis suggests that IgG2 SD also preceded the occurrence of neutropenia. Analysis of bone marrow biopsy in both patients and skin tissue lesions in one patient showed massive infiltration with CD4+ and CD8+ T-lymphocytes. The pathological feature did not suggest any malignant lymphoproliferative disorder. Neutropenia was refractory to i.v. Ig in both patients and to recombinant G-CSF, steroids, and cyclophosphamide in one patient. Severe cellulitis led to death in one patient. In summary, we reported herein a heretofore undescribed syndrome characterized by the association of IgG2 SD with severe neutropenia and tissue T-cell infiltration. It suggests that bone marrow analysis as well as determination of serum IgG subclasses need to be performed in patients with unexplained neutropenia. Am. J. Hematol. 57:241–244, 1998. © 1998 Wiley-Liss, Inc.     

Low incidence of invasive fungal infections after bone marrow transplantation in patients receiving amphotericin B inhalations during neutropenia

Summary The incidence of invasive fungal infections after bone marrow transplantation (BMT) was analyzed in 303 consecutive marrow graft recipients (allogeneicn=271, autologousn=27, syngeneicn=5). All patients received inhalations with amphotericin B (10 mg twice daily) during neutropenia. The overall incidence of invasive fungal infections within the first 120 days after transplant was 3.6% (11/303; aspergillosis: 6; yeast infection: 5). Four of the 11 cases occurred early, and seven cases were observed after neutrophil recovery and discontinuation of amphotericin B inhalation treatment. Late infection was significantly associated with the development of acute graft-versus-host disease. Four of the 11 infections (early 2/4; late: 2/7) were observed in patients with a history of previous fungal infection. Other patient and treatment characteristics were not helpful in defining potential risk factors. In particular, the incidence of invasive fungal infections did not differ between patients with more or less strict reverse isolation measures. Occasional side effects such as initial mild cough and bad taste were rare, usually disappeared during continued administration, and were in no case the reason for discontinuation of treatment. These data suggest that aerosolized amphotericin B may be a useful, convenient, and efficient prophylactic antifungal regimen in BMT.     

晚期肝病患者并发真菌感染的早期预警指标研究

目的探讨晚期肝病患者并发真菌感染的早期预警指标。方法100例合并院内真菌感染的晚期肝病患者被纳入观察组,选择同期入院、肝病基础相当、未合并真菌感染的另80例患者为对照组,采用多因素logistic回归分析,评价与发生真菌感染有关的各种危险因素,达到预警作用。结果多因素分析显示,细菌感染(OR=4.45,95%C I 1.86-13.68;P=0.006)、广谱抗菌素应用疗程(11~15天疗程,发生真菌感染的OR值为2.02,95%C I 1.54-8.50,P=0.005;16~21天疗程,OR=5.36,95%C I 2.68-12.31,P=0.003;22天以上疗程,OR=12.88,95%C I 6.07-22.40,P=0.001)、糖皮质激素使用(OR=3.78,95%C I 1.07-11.23;P=0.007)、中性粒细胞减少(OR=6.62,95%C I 1.68~14.05;P=0.002)、糖尿病(OR=2.23,95%C I 1.36~9.81;P=0.026)是晚期肝病患者发生真菌感染的重要危险因素。结论细菌感染、广谱抗菌素疗程、糖皮质激素应用、中性粒细胞减少、糖尿病是晚期肝病患者并发真菌感染的主要危险因素,可作为早期预警指标。     

Trichosporonosis in patients with neoplastic disease

Trichosporonosis due to Trichosporon beigelii or T. capitatum is an infrequent but potentially fatal invasive fungal infection in cancer patients. We studied epidemiologic, clinical, pathologic, and microbiologic features of this infection during a 7-year period at the University of Maryland Cancer Center. Fifteen patients with involvement by Trichosporon were identified: 5 were infected, 5 were possibly infected, and 5 were colonized but not infected by Trichosporon. Four of the infected patients had trichosporonemia and/or positive skin biopsy cultures as the first evidence of infection. The fifth infected patient had positive marrow and skin biopsy cultures. Serial surveillance cultures of infected patients showed preceding Trichosporon colonization in only 1 of 5 cases. Pulmonary infiltrates in 3 infected patients correlated at postmortem examination with Trichosporon pneumonia. Renal dysfunction marked by proteinuria, hematuria, red blood cell casts and azotemia correlated with widespread glomerular infiltration with the fungus. The five infected patients died of their infection, whereas the 2 possibly infected patients who died succumbed to their underlying illness. Trichosporonemia may have been averted in possibly infected patients because of a shorter median duration of profound (less than 100/microliter) neutropenia (5 days) when compared to that of infected patients (20 days). No environmental source of Trichosporon was found in environmental surveillance cultures of food, air, or inanimate surfaces. In vitro studies of three pathogenic strains showed resistance to 5-fluorocytosine but susceptibility to amphotericin B, ketoconazole, and miconazole. Norfloxacin augmented the in-vitro antifungal activity of amphotericin B. Trichosporon must be considered an opportunistic pathogen that can cause serious infections among patients with cancer.     

Chronic neutropenia of childhood: frequent association with parvovirus infection and correlations with bone marrow culture studies

Summary. Children with neutropenia of more than 3 months duration often have evidence of immune-mediated destruction of mature neutrophils and variable abnormalities of myeloid precursors in their bone marrow. These patients often have anti-neutrophil antibodies which persist for several months. To further investigate the aetiology of neutropenia in such patients, bone marrow cells were evaluated for the presence of common viruses. Fifteen of 19 patients tested had evidence for parvovirus infection by PCR amplification of bone marrow DNA with parvovirus specific primers. Of these 15, six also had serologic evidence of parvovirus infection. Anti-neutrophil antibodies were identified in nine of 12 patients with parvovirus infection. Bone marrow culture studies done on six patients revealed varying degrees of myeloid and erythroid inhibition by patient plasma. These studies indicate that parvovirus may be a common cause of immune-mediated neutropenia in children.     

Chronic idiopathic neutropenia improved by recombinant granulocyte colony stimulating factor]

A 55-year-old man was admitted to our hospital for the evaluation of neutropenia. On physical examination, he had apthae and splenomegaly. CBC showed 1,000/microliter WBC with 5% neutrophils, and microcytic anemia consistent with iron deficiency. Bone marrow examination revealed a marked decrease of mature neutrophils, but normal percentage of immature myeloid cells. There was no morphological abnormality in the hemopoietic cells. He had no drug or family history responsible for the neutropenia. Anti-neutrophil auto-antibody was negative. Hence, a diagnosis of chronic idiopathic neutropenia (CIN) was made. He developed frequent episodes of infection such as balanitis, peri-anal infection, gingivitis, and pharyngitis. He was treated with steroid pulse therapy, anabolic hormone, and high dose gamma-globulin infusion, but no significant improvement occurred. Then, recombinant granulocyte-colony stimulating factor (rG-CSF) was started. The neutrophil count was normalized by the 7th day of 5 micrograms/kg/day rG-CSF administration. The administration of G-CSF was discontinued after a 14-day course. Thereafter, the neutrophil count remained at near normal level (approximately 1,500/microliter) and there have been no episodes of infection in the last 5 months. However this cannot be explained simply by the direct effect of rG-CSF on the myeloid precursors; rather, it suggests some unknown effect of G-CSF on the bone marrow microenvironment regulating myeloid hemopoiesis. We consider this to be a rare case of CIN with frequent episodes of infection, which was successfully treated with G-CSF.     

Acquired cyclic haematopoiesis associated with a radiation-induced chromosomal abnormality with clonal, morphologically normal circulating leucocytes

A 62-year-old male with a history of vesical carcinoma treated with pelvic radiotherapy and cystectomy developed intermittent fevers associated with oral ulcers and neutropenia. Serial blood counts revealed cyclic haematopoiesis, with periodic neutropenia, lymphocytopenia, monocytopenia and thrombocytopenia. Bone marrow examination revealed intermittent hypoplasia without myelodysplasia or leukaemia. Marrow karyotype revealed a clonal chromosomal abnormality which included trisomy 8 and absence of the Y chromosome. We also provide evidence of spontaneous differentiation of the clonal marrow cells to mature leucocytes.     

Infectious complications after autologous peripheral blood progenitor cell transplantation followed by G-CSF

Infectious complications after autologous peripheral blood progenitor cell transplantation (PBPCT) have been reported in a few studies including small patient numbers. The present study was performed to assess the incidence, types, outcome and factors affecting early and late infections in 150 patients aged 18 to 68 years (median 46.5) who underwent high-dose therapy, with G-CSF. Patients were kept in reverse isolation rooms and received antimicrobial chemoprophylaxis with oral quinolone and fluconazole. One hundred and fifteen patients (76.7%) developed fever (median 3 days, range 1-29); 20 patients (55.5%) had Gram-positive and 13 (36. 2%) Gram-negative bacterial infections. There were no fungal infections or infection-related deaths. Mucositis grade II-IV (P = 0. 0001; odds ratio 3.4) and >5 days on ANC <100/microl (P = 0.0001; odds ratio 2.3) correlated with development of infection. Only days with ANC <100/microl affected infection outcome (P = 0.0024) whereas the antibiotic regimen did not. After day +30 there were four cases of bacterial pneumonitis (2.7%), one case of fatal CMV pneumonia (0. 8%) and 20 of localized VZV infection (13.3%). Reduction of neutropenia duration with PBPCT and G-CSF is not enough to prevent early infectious complications since only a few days of severe neutropenia and mucositis are related to development of early infections. However, no infection-related deaths were seen. Although Gram-positive organisms were the major cause of bacteremia, a glycopeptide in the empirical antibiotic regimen did not affect infection outcome. In PBPCT recipients, early and late opportunistic infections were notably absent, which was at variance with what was seen with bone marrow recipients. Efforts should be made to prevent mucositis and neutropenia and identify new strategies of antibacterial prophylaxis.     

Colony-stimulating factor in patients with chronic neutropenia.

Urinary and serum colony-stimulating factor (CSF) levels were measured in 11 patients with chronic idiopathic neutropenia without infections and in 10 normal individuals. Urinary CSF output was determined using mouse marrow target cells, and serum CSF activity was assayed with human marrow target cells by the double agar layer technique. Using these methods, there was no significant difference between CSF levels of neutropenic and normal subjects. These data indicate that CSF levels are not inversely related to the blood neutrophil count in chronic idiopathic neutropenia and suggest that CSF is not a hormone regulating the blood neutrophil count in a manner analogous to the erythropoietin regulation of circulating erythrocyte levels.     

Improving efficacy of antifungal therapy by polymerase chain reaction-based strategy among febrile patients with neutropenia and cancer.

Early detection of fungal infections in and corresponding early treatment of febrile patients with neutropenia and cancer have been important issues and continue to be major challenges for clinicians. The use of nested PCR to make therapeutic decisions was studied. Sequential blood samples obtained from 42 patients with neutropenia and cancer were tested by nested PCR and culture. Instead of the empirical antifungal therapy strategy, amphotericin B treatment was initiated only for patients who had 2 consecutive positive results by nested PCR. A reduced mortality rate was observed for febrile patients with neutropenia and cancer who had fungal infections. Thus, this strategy, combined with the nested PCR for early detection of fungal infection in febrile patients with neutropenia, may be used as a guideline for antifungal therapy.