Diagnosis of disseminated candidiasis by measurement of urine D-arabinitol/L-arabinitol ratio.

Relative amounts of D-arabinitol (fungal origin) and L-arabinitol (part of normal human metabolism) in urine were determined by gas chromatography and mass spectrometry from 61 hospitalized patients with hematological malignancies. Seventeen neutropenic patients with acute leukemia (with 53 samples) had disseminated yeast infections and received empiric antifungal therapy before confirmation of the diagnosis. Control groups consisted of 22 hematologic patients (76 samples) with either mucosal (n = 10) or urinary (n = 12) Candida colonization and 22 neutropenic patients (34 samples) with no clinical or laboratory signs of invasive yeast infection. Reference values were also obtained from 50 healthy adults (50 samples). The mean urine D-arabinitol/L-arabinitol ratio +/- standard deviation (range) was 16.91 +/- 41.79 (1.41 to 254.75) in patients with disseminated infection, 2.73 +/- 2.48 (1.11 to 19.00) in colonized hematologic patients, 2.12 +/- 0.84 (1.16 to 5.84) in neutropenic controls, and 1.95 +/- 0.34 (0.97 to 3.44) in healthy adults (P < 0.001 between patients with disseminated infection and all control groups). The sensitivity and specificity of the assay for detecting disseminated yeast infection were, respectively, 88 and 91% per patient (upper limit of normal, 4.00). Seventy-one percent of patients already expressed elevated values at the onset of empiric antifungal therapy. The diagnosis of disseminated infection was confirmed on average 21.7 days after the first elevation of the D-arabinitol/L-arabinitol ratio. The method contributes to diagnosis of disseminated yeast infection and helps in monitoring patients at risk, to support the initiation of antifungal therapy at an early stage of the disease.     

Gas chromatographic determination of D-arabinitol/L-arabinitol ratios in urine: a potential method for diagnosis of disseminated candidiasis.

A gas chromatographic procedure was developed to determine the relative amounts of D- and L-arabinitol in urine. Samples were filtered, diluted, purified through extractions, evaporated, and treated with trifluoroacetic anhydride; the arabinitol derivatives thus obtained were separated on a chiral stationary phase and registered by using an electron-capture detector. Urine samples from a patient with disseminated candidiasis had higher D-arabinitol/L-arabinitol ratios (referred to as D/L-arabinitol ratios)--up to 19.0--than samples from 96 study individuals with no signs of deep Candida infections (range, 1.1 to 4.5). D/L-Arabinitol ratios in urine samples from hospitalized patients without Candida infections were slightly higher than those in samples from healthy individuals; ratios in urine from children were slightly higher than those in adult urine samples. The D/L-arabinitol ratios in several urine samples culture positive for Candida albicans, but from patients without symptoms of disseminated candidiasis, did not differ from those in the urine of healthy individuals. The described gas chromatographic method is straightforward and can be implemented clinically to determine urine D/L-arabinitol ratios as a means of diagnosing disseminated candidiasis.     

Enantioselective measurement of fungal D-arabinitol in the sera of normal adults and patients with candidiasis.

A new method was used to measure D-arabinitol enantioselectively in the sera of 27 healthy adults and four patients with candidiasis. Arabinitol was measured by gas chromatography in serum that was treated with and without the Klebsiella pneumoniae enzyme D-arabinitol dehydrogenase, lactic dehydrogenase, NAD, and sodium pyruvate. Since enzyme treatment removed 98% of 0 to 20 micrograms of D-arabinitol per ml and none of 0 to 20 micrograms of L-arabinitol per ml from spiked sera, D-arabinitol could be determined from the difference in the treated and untreated samples. The concentrations of D- and L-arabinitol in serum from normal subjects were 0.22 +/- 0.052 and 0.16 +/- 0.055 micrograms/ml, respectively, and their D-arabinitol/creatinine and L-arabinitol/creatinine ratios were 0.024 +/- 0.0089 and 0.017 +/- 0.0053 (all means +/- standard deviations). The infected patients all had markedly elevated serum D-arabinitol levels, but their L-arabinitol levels were either normal or proportionately much lower. The excess arabinitol in the sera of individuals with candidiasis is D-arabinitol, and use of enantioselective analytical methods should result in improved ability to diagnose and estimate the severity of candidiasis.     

Candida tropicalis Vertebral Osteomyelitis Complicating Epidural Catheterisation with Disease Paralleled by Elevated D-Arabinitol/L-Arabinitol Ratios

 Deep-seated Candida infections are challenging to diagnose by noninvasive means, and new modalities are needed to improve the yield of such investigations. Reported here is a case of Candida tropicalis vertebral osteomyelitis complicating epidural catheterisation in a diabetic patient with complicated abdominal sepsis. The diagnosis was supported by detection of increased D-arabinitol/L-arabinitol ratios in urine samples, and failure of medical management was indicated by elevated D-arabinitol/L-arabinitol ratios, which later decreased to baseline with successful surgical debridement and prolonged antifungal therapy.     

Levels of the Candida metabolite D-arabinitol in sera of steroid-treated and untreated patients with sarcoidosis.

We measured the Candida metabolite D-arabinitol and its enantiomer L-arabinitol in 42 serum samples from 33 patients with sarcoidosis and compared the results with those from 27 healthy adults and 4 patients with candidiasis. The D- and L-arabinitol concentrations and the D- and L-arabinitol/creatinine ratios did not differ significantly in the sarcoidosis patients and the controls; the D-arabinitol concentrations and the D-arabinitol/creatinine ratios were much higher in the patients with candidiasis. Among the patients with sarcoidosis, the D- and L-arabinitol levels in the steroid recipients did not differ significantly from those in patients not receiving steroids. Higher D-arabinitol/creatinine ratios were associated with roentgenographic evidence of pulmonary fibrosis and low forced vital capacities, but not with disease activity as determined by the proportion of lymphocytes to total nucleated cells in bronchoalveolar lavage fluid or the CD4/CD8 ratio in bronchoalveolar lymphocytes. We conclude that neither sarcoidosis nor corticosteroid treatment is associated with high levels of D-arabinitol in serum.     

Urine D-arabinitol/L-arabinitol ratio in diagnosis of invasive candidiasis in newborn infants

Infants treated in neonatal intensive care units suffer an increased risk for invasive candidiasis, but the diagnosis is sometimes difficult. D-arabinitol is a metabolite of most pathogenic Candida species. An elevated urine D-arabinitol/L-arabinitol (DA/LA) ratio is a sensitive sign of invasive candidiasis in children with cancer, but the method has not been previously evaluated for newborn infants. We therefore enrolled 117 infants in a neonatal intensive care unit, and 411 urine samples were obtained on filter paper. The DA/LA ratio was measured by gas chromatography-mass spectrometry. For 81 infants with no suspicion of superficial or invasive candidiasis, the urine DA/LA ratio was 2.7 +/- 0.7 (mean +/- standard deviation [SD]). The upper cutoff level was set at 4.8 (mean plus 3 SD). Of 22 infants with mucocutaneous candidiasis and not given systemic antifungal treatment, two had elevated DA/LA ratios, which normalized after removal of intravascular catheters. Eight other infants were given empiric antifungal treatment but had negative cultures; five of these had repeatedly elevated DA/LA ratios. Six infants with culture-positive invasive candidiasis all had one or more samples with elevated ratios. For seven infants, three with suspected and four with confirmed invasive candidiasis (for which follow-up samples were available), ratios normalized during antifungal treatment. In conclusion, urine DA/LA ratio determination is a rapid test and can be used for newborns. It is possibly more sensitive than fungal blood cultures in the diagnosis of invasive candidiasis and can also be used for monitoring the effect of antifungal treatment.     

Diagnosis of invasive candidiasis in neutropenic children with cancer by determination of D-arabinitol/L-arabinitol ratios in urine.

Determination of D-arabinitol/L-arabinitol ratios (referred to as D/L-arabinitol ratios) in urine as a tool for the diagnosis of invasive candidiasis was investigated in a prospective study comprising 100 children with cancer. The analyses were made by gas chromatography. Positive D/L-arabinitol ratios were found for 10 of 10 children with confirmed invasive candidiasis, 12 of 23 patients undergoing empiric antifungal chemotherapy, and 4 of 67 children not receiving antifungal treatment. D/L-Arabinitol ratios were positive 3 to 31 days (median, 12 days) before the first culture-positive blood sample was drawn or empiric therapy was initiated. The regular monitoring of D/L-arabinitol ratios in urine holds great promise as a sensitive method for diagnosing invasive candidiasis in immunocompromised children with cancer. Moreover, it may be possible to use an early rise in D/L-arabinitol ratios as a basis for the institution of antifungal chemotherapy and as a means of avoiding unnecessary treatment with potentially toxic antifungal agents.     

D-arabinitol--a marker for invasive candidiasis.

The five-carbon sugar alcohol D-arabinitol (DA) is a metabolite of most pathogenic Candida species, in vitro as well as in vivo, and can be determined by gas chromatography or enzymatic analysis. Endogenous DA and L-arabinitol (LA) are present in human body fluids, and serum DA and LA increase in renal dysfunction. In prospective clinical studies, elevated DA/LA or DA/creatine ratios in serum or urine have been found in immunocompromised, usually neutropenic, patients with invasive candidiasis. In addition, positive DA results have been obtained several days to weeks before positive blood cultures, and the normalization of DA levels has been correlated with therapeutic response in both humans and animals. However, to date, only a few prospective studies have been conducted in which adequate analytical methods were used. Thus, further investigation of various patient groups is needed to establish the applicability of the 'arabinitol method' in the diagnostic battery for invasive Candida infections.     

Use of Voriconazole to Successfully Treat Disseminated <Emphasis Type="Italic">Trichosporon asahii</Emphasis> Infection in a Patient with Acute Myeloid Leukaemia

Trichosporon spp. is an emerging fungal pathogen in immunocompromised hosts, and disseminated infection is often fatal in neutropenic patients. Reported here is a case of disseminated infection in a neutropenic patient with acute leukaemia. After failure of amphotericin B and fluconazole therapy, the course of infection dramatically improved with voriconazole treatment. A literature search revealed 69 additional cases of disseminated Trichosporon spp. infections in neutropenic patients, and these are also reviewed. Clinical symptoms that suggest infection include fever, disseminated papulopustular cutaneous lesions and pulmonary involvement. Despite treatment with antifungal agents (amphotericin B, fluconazole), 78% of patients died. Voriconazole may represent a promising therapy for this life-threatening infection. Electronic Publication     

Guidelines for the management of deep mycosis in neutropenic patients]

Invasive fungal infections (IFIs) are a major cause of morbidity and mortality in neutropenic patients with leukemia and those undergoing hematopoietic stem cell transplant (HSCT). Two major IFIs are systemic candidiasis (including candidemia, chronic disseminated candidiasis and pneumonia) and invasive pulmonary aspergillosis. Recently, the incidence of the latter has been increasing. Three levels of diagnosis are specified in the Japanese guidelines for the diagnosis and treatment of IFIs. Proven fungal infections are diagnosed by histological/microbiological evidence of fungi at the site of infection or positive blood culture (fungemia). Clinically documented fungal infections are diagnosed by typical radiological findings such as halo sign on chest CT plus positive serological/molecular evidence of fungi such as Aspergillus galactomannan, beta-glucan or fungal DNA. Possible fungal infections are diagnosed by typical radiological findings or positive serological/molecular evidence of fungi. For patients with high risk such as those undergoing HSCT, antifungal prophylaxis using oral antifungal agents is recommended. For possible fungal infections, empiric therapy with fluconazole (FLCZ) or amphotericin B (AMPH) is recommended. For patients with proven fungal infections or clinically documented fungal infections, targeted therapy is warranted. In case of candidemia, the best choice is FLCZ (400 mg/day) or AMPH (0.5-0.7 mg/kg/day), and for invasive pulmonary aspergillosis, a higher dose of AMPH (1.0-1.5 mg/kg/day) is indicated. Micafungin (MCFG), recently licensed in Japan, is an active agent for both Candida and Aspergillus. This drug seems useful for empiric and targeted therapy of IFIs.     

Febrile neutropenia in haematological malignancies

Fever is the principle sign of infection in neutropenic patient and frequently may be the only evidence of infection. The pattern of fever in neutropenia is non-specific and not pathognomonic of any type of infections or non-infectious process and can be suppressed by the antipyretic effects of drugs such as corticosteroids. Neutropenia, resulting from cytotoxic chemotherapy is the most common risk factor for severe infections in hematological malignancies. The duration of neutropenia also contributes significantly to the risk of serious infections. This risk is significantly greater a lower neutrophil counts, such that 100% patients with ANC <100 cells/microl lasting 3 weeks or more develop documented infections. The prompt initiation of empirical antibiotics in febrile neutropenia has been the most important advance in the management of the immunocompromised host. The initial empirical antibiotic regimen started at presentation of the febrile episode frequently requires modifications especially in high-risk febrile neutropenia. Neutropenic patients who remain febrile despite 4-7 days of broad spectrum antibacterial therapy are at a high risk of invasive fungal infection. Empirical antifungal therapy with Amphotericin B in persistently febrile neutropenic patients and other high risk patients has shown to reduce the risk of invasive fungal infection by 50-80% and the risk of fungal infection related mortality by 23-45% in 1980's. The IDSA has recommended that amphotericin B at 0.5-0.7 mg/kg/day be administered till marrow recovery. This approach is limited however by the adverse effects caused by drug infusion (fever, chills, myalgias, nausea, hypotension and bronchospasm). Lipid formulations which improve the therapeutic ratio of the traditional formulation are available. The safety and efficacy of these formulations is well established. These formulations have comparable efficacy and are less nephrotoxic than conventional amphotericin B.A lipid formulation of amphotericin B is appropriate as initial empirical therapy or as definitive therapy for proven mycosis in high risk patients receiving concomitant nephrotoxic drugs (cyclosporine), those with pre-existing renal impairment and those with protracted neutropenia during which dose limiting toxicity may occur.     

Determination of serum arabinitol levels by mass spectrometry in patients with postoperative candidiasis

A combined gas chromatography-mass spectrometry (GC-MS) technique was used for serial determination of serum arabinitol levels in patients with postoperative candidiasis. Forty subjects were investigated, 18 patients with candidiasis, 7 patients with superficialCandida colonization and 15 postoperative control patients. The arabinitol levels were highly elevated, slightly elevated and normal in 13, 1 and 4 patients respectively with candidiasis; in 2, 2 and 3 colonized patients and in 1, 1 and 13 control patients (p<0.001,x ², between all the groups). The sensitivity of a single arabinitol determination for detection of postoperative candidiasis was 27.6 % and the specificity 89.2 %. Use of multiple samples improved sensitivity up to 72.2 % per patient (123 samples) with a specificity of 86.4 %. Highly elevated arabinitol concentrations were detected in only one patient before the onset of therapy. Determination of arabinitol levels by GC-MS is a specific test for diagnosing candidiasis, but multiple samples are required for adequate sensitivity, and the initiation of therapy must still be on an empirical basis.     

Breakthrough Hormographiella aspergillata infections arising in neutropenic patients treated empirically with caspofungin

Hormographiella aspergillata, a filamentous basidiomycete, has rarely been involved in human infections. We describe 2 febrile neutropenic patients who developed a severe pulmonary infection due to H. aspergillata while receiving empirical caspofungin therapy for presumed fungal pneumonia. After introduction of liposomal amphotericin B, one patient, who had neutrophil recovery, presented a favorable outcome, while the other, who remained neutropenic throughout the course of infection, died. Resistant fungi, including basidiomycetes, may emerge during empirical treatment with caspofungin in febrile neutropenic patients. A rapid switch to any other potent antifungal should be rapidly considered in case of failure of caspofungin in this setting.     

Effects of gastrointestinal candidiasis, antibiotics, dietary arabinitol, and cortisone acetate on levels of the Candida metabolite D-arabinitol in rat serum and urine.

We studied the effects of gastrointestinal (GI) colonization by Candida albicans, dietary arabinitol, intragastric antibiotics, and cortisone on levels of the Candida metabolite D-arabinitol in rat serum and urine. Rats given conventional laboratory chow, intragastric gentamicin and chloramphenicol, and 6.0 x 10(8) live C. albicans B311 blastoconidia by gavage had minimal invasive GI disease and no more DL-arabinitol in the urine than controls given killed C. albicans. However, colonized and uncolonized rats given intragastric antibiotics had transiently higher urine arabinitol levels than the corresponding controls given saline. Rats given conventional laboratory chow (which contained 50 micrograms of arabinitol per g) had higher serum and urine arabinitol levels than rats given no dietary arabinitol, but the differences were less than expected. Moreover, intragastric antibiotics did not cause increased arabinitol excretion in rats given no dietary arabinitol. Rats given intragastric antibiotics and live C. albicans but no dietary arabinitol had no more arabinitol in their serum or urine than controls given antibiotics and killed C. albicans or saline and live or killed C. albicans. Lastly, cortisone acetate (10 mg/kg of body weight per day intramuscularly for 10 days) did not cause increased serum or urine arabinitol levels. We conclude that neither GI colonization by C. albicans nor cortisone should interfere with the usefulness of arabinitol as a marker for invasive candidiasis; antibiotics appear to increase arabinitol excretion by suppressing GI bacteria capable of consuming dietary arabinitol.     

Urinary D-arabinitol/L-arabinitol levels in infants undergoing long-term antibiotic therapy

Long-term antibiotic therapy is one of the main risk factors for mycosis. The urinary D-arabinitol/L-arabinitol (D-/L-ARA) ratio (a biomarker of several Candida species) was determined by gas chromatography with an electron capture detector in samples from 51 infants undergoing long-term antibiotic therapy. Although 47 of these children had higher D-/L-ARA ratios than healthy controls (P<0.0003), their values nonetheless remained within upper-normal limits (D-/L-ARA ratio of <3.6). Four children with suspected invasive candidiasis had above-normal ratios that normalized with fluconazole treatment.     

Fluconazole versus itraconazole for the prevention of fungal infections in haemato-oncology

AIMS: To compare the efficacy of and tolerance to oral fluconazole and intraconazole in preventing fungal infection in neutropenic patients with haematological malignancies. PATIENTS: 213 consecutive, afebrile adult patients treated with or without autologous stem cell transplantation for haematological malignancies. METHODS: A randomised, double blind, single centre study. Patients were randomly assigned to receive fluconazole 50 mg or itraconazole 100 mg, both twice daily in identical capsules. An intention to treat analysis was performed on 202 patients, 101 in each group. RESULTS: Microbiologically documented systemic fungal infections occurred in four patients in each group. Clinical fungal infection was thought to be present in seven recipients of fluconazole and four of itraconazole. In all 202 patients, 29 proceeded to intravenous amphotericin (amphotericin B), 16 in the fluconazole group and 13 in the itraconazole group. Superficial fungal infection was seen only in three non-compliant patients in the fluconazole group. All these infections were oral. No major differences were noted in the isolates of fungi in mouth washes and fecal samples. Overall mortality was 8.9% (18 deaths; seven in the fluconazole group, 11 in the itraconazole group). Mortality from microbiologically and clinically documented fungal infection was 4.5% (nine deaths; three in the fluconazole group, six in the itraconazole group). Median time to suspected or proven fungal infection was 16 days in both groups. None of these comparisons reached statistical significance (p < 0.05). No major clinical toxicity was noted and compliance was excellent. CONCLUSIONS: In neutropenic patients treated for haematological malignancies with or without autologous stem cell transplantation, fluconazole and itraconazole in low doses result in a similar low frequency of fungal disease. Fluconazole may be the preferable drug because of the smaller number of capsules and lack of need for timing relative to meals.     

Use of liposomal amphotericin B in bone marrow transplant

Increasing number of transplants worldwide has resulted in an increase in the incidence of fungal infections. Prolonged neutropenia, immunosuppression and graft vs. host disease all result in high predisposition to fungal infections. The likelihood of developing a fungal infection increases with the severity and duration of neutropenia, which, in the case of cancer or chemotherapy for the treatment of hematological malignancies, can range from a few days to several weeks. Invasive fungal infections are difficult to diagnose and neutropenic patients with fever often receive empirical antifungal therapy. This provides a rationale for the prophylactic use of antifungal agents. The empirical use of liposomal amphotericin B has overcome some of the difficulties usually found in this setting. The majority of clinical efficacy data related to liposomal amphotericin B are derived from compassionate use studies and case series. The major advantage of these liposomal formulations of amphotericin B is a reduction in amphotercin toxicity. Use of liposomal amphotericin has been shown to be a cost-effective approach abroad and the same has been our experience also. Commercially ambisome and Fungisome are the only products that contain true liposomes. Unlike ambisome, which needs to be used in dose of 3 mg/kg/day Fungisome is effective in the dose of 1-3 mg/kg bodyweight. The Indian liposomal preparation has shown to be safe and effective used in over 150 transplant patients in our experience. We conclude that the liposomal amphotericin is better-tolerated and also gives,better responses in documented fungal infections.     

Multicenter randomized trial of fluconazole versus amphotericin B for treatment of candidemia in non-neutropenic patients

A randomized trial was conducted to compare the efficacy and safety of fluconazole versus that of amphotericin B in the treatment of candidemia in non-neutropenic adults. Enrollment was stratified by disease severity (APACHE II score). Patients were randomized (1:1) to receive amphotericin B 0.6 mg/kg/day (cumulative dose 8 mg/kg) or fluconazole 800 mg intravenous loading dose, then 400 mg daily for four weeks (intravenous for at least 10 days). Patients were monitored for six months. A total of 106 patients were enrolled. A protocol amendment implemented midway through the trial required patients to be removed from the study and treated with amphotericin B if species identification indicated candidemia due toCandida glabrata orCandida krusei. Baseline characteristics were similar for the two groups; 103 patients (fluconazole, 50; amphotericin B, 53) met the major enrollment criteria. The intention-to-treat analysis indicated successful therapy in 50% of fluconazole recipients compared to 58% of the amphotericin B group (p=0.39; one-sided 95% Cl, –8 to 24%). The efficacy analysis included 84 patients (fluconazole, 42; amphotericin B, 42); successful outcomes were observed in 57% and 62% of cases in the fluconazole and amphotericin B groups, respectively (p=0.66: one-sided 95% Cl, –12 to 22%). The mortality at day 14 for the fluconazole group was 26% and for the amphotericin B group 21% (p=0.52; chi-square test) and remained similar throughout the course of follow-up. Drug-related adverse events were more frequent with amphotericin B than with fluconazole and prompted switching of therapy for two (4%) and zero cases, respectively. Fluconazole and amphotericin B were associated with similar clinical response rates and survival in the treatment of candidemia among non-neutropenic patients; however, drug-related adverse events were more frequent with amphotericin B.     

Comparison of antibody, antigen, and metabolite assays for hospitalized patients with disseminated or peripheral candidiasis.

Repeat serum samples from 22 patients with proven disseminated candidiasis and 42 with simple peripheral colonization were assayed for Candida antibodies by coelectrosyneresis, immunoprecipitation, and A and B immunofluorescence, for metabolites by D-arabinitol measurement, and for antigens by the mannan immunoassay and Cand-tec latex agglutination (mean number of samples tested, 2.5 per patient). For the antibody and metabolite assays, the results showed no statistical difference between the two groups. By contrast, the results of both antigen assays were positive for a significantly larger number of patients with disseminated candidiasis than of those with simple peripheral colonization. Results were regardless of whether the patients were neutropenic. They were not predictive of death. We calculated that the mannan antigen assay had 29% sensitivity and 97% specificity for the diagnosis of disseminated candidiasis. Likelihood ratios of a positive and a negative result of this test were 9.2 and 0.7, respectively, for this diagnosis. In the latex agglutination test, likelihood ratios were 2.5, 1.5, 1.6, and 0.3 when the test was positive for dilutions of 1/8, 1/4, and 1/2 and was negative, respectively.     

Role of granulocyte-macrophage colony-stimulating factor as adjuvant treatment in neutropenic patients with bacterial and fungal infection

The results are presented of two preliminary studies conducted to assess the role of GM-CSF as adjuvant treatment in neutropenic patients with bacterial or fungal infections. In the first study the effect of GM-CSF on the rate of response to antibiotics was assessed. Febrile neutropenic patients (n=91) were randomized to receive ticarcillin-clavulanate plus netilmicin with or without GM-CSF (60 µg/m²). Response rates were significantly higher in patients who received antibiotics plus GM-CSF (p=0.05). An increase in neutrophil count was seen in 89% of GM-CSF patients with initial low neutrophil counts (<100/µl) compared with 67% of control patients (p=0.04). In the second study the activity of GM-CSF in patients with fungal infections was assessed. Neutropenic patients with documented fungal infections received amphotericin B plus GM-CSF. Of the eight evaluable patients, six responded and four had a complete response to treatment. The neutrophil counts of the two non-responding patients did not increase substantially during GM-CSF treatment and both died of their fungal infection. The prognosis of neutropenic patients with fungal infections is usually poor and the results of this pilot study are therefore very encouraging. The two studies show that GM-CSF is able to stimulate neutrophil recovery in neutropenic patients and may improve the response to antibiotic and antifungal treatment.