The impact of oral herpes simplex virus infection and candidiasis on chemotherapy-induced oral mucositis among patients with hematological malignancies

The aim of this study was to evaluate the influences of oral candidiasis and herpes simplex virus 1 (HSV-1) infections in chemotherapy-induced oral mucositis (OM). The medical records of 424 consecutive patients with hematological malignancies who had received chemotherapy at a medical center in Taiwan from January 2006 to November 2007 were retrospectively reviewed. The results of swab cultures of fungus and HSV-1 for OM were correlated with associated clinical features. Younger age, myeloid malignancies, and disease status other than complete remission before chemotherapy were significantly correlated with the development of OM. Risks of fever (p <0.001) and bacteremia were higher in patients with OM. Among 467 episodes of OM with both swab cultures available, 221 were non-infection (47.3%) and 246 were related to either fungal infections, HSV-1 infections, or both (52.7%); of the 246 episodes, 102 were associated with fungal infections alone (21.8%), 98 with HSV-1 infections alone (21%), and 46 with both infections (9.9%). Patients who had received antifungal agents prior to OM occurrence tended to have HSV-1 infection (p <0.001). Our results suggest that Candida albicans and HSV-1 play an important role in chemotherapy-induced OM in patients with hematological malignancies.     

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.     

Markers of bacteremia in febrile neutropenic patients with hematological malignancies: procalcitonin and IL-6 are more reliable than C-reactive protein

Since neutropenic patients with hematological malignancies are at high risk of contracting life-threatening infections, specific markers of infection are needed in cases of febrile neutropenia. The study presented here assessed serum concentrations of C-reactive protein (CRP), procalcitonin (PCT) and interleukin-6 (IL-6) in samples obtained from 31 febrile neutropenic patients. A total of 53 episodes were evaluated, and 18 of these were associated with positive blood culture results. Procalcitonin and IL-6 concentrations differed significantly between bacteremic and non-bacteremic episodes. Procalcitonin values were 0.22 ng/ml [interquartile range (IR), 0.15–1.9] for patients with pneumonia without bacteremia, 0.22 ng/ml (IR, 0.16–0.55) for patients with fever of unknown origin, 0.2 ng/ml (IR, 0.13–0.57) for patients with non-microbial fever and 1.8 ng/ml (IR, 0.35–5.3) for patients with bacteremia. The differences between bacteremic and non-bacteremic episodes had a P-value of 0.003 using the Mann–Whitney test. For IL-6 the median values were 301 pg/ml (IR, 152–1,879) for patients with pneumonia without bacteremia, 207 pg/ml (IR, 94–445) for patients with fever of unknown origin, 177 pg/ml (IR, 142–208) for patients with non-microbial fever and 942 pg/ml (IR, 181–2,807) for patients with bacteremia. Using the Mann–Whitney test, the differences between bacteremic and non-bacteremic episodes were P=0.006. No differences were found in CRP concentrations. Cutoff levels to distinguish between bacteremic and non-bacteremic episodes were chosen using receiver operating characteristic curves: 0.62 ng/ml for PCT and 297 pg/ml for IL-6. Negative predictive values were 84% for PCT and 70% for IL-6. The results indicate that PCT and IL-6 are more reliable markers than CRP for predicting bacteremia in patients with febrile neutropenia.     

High-Dose Liposomal Amphotericin B in the Therapy of Systemic Candidiasis in Neonates

High-dose (5–7 mg/kg/day) liposomal amphotericin B was evaluated prospectively during the period 1995–2001 in 41 episodes of systemic candidiasis occurring in 37 neonates (36 of the 37 were premature infants with very low birth weights). Median age at the onset of systemic candidiasis was 17 days. Candida spp. were isolated from blood in all patients and from urine, skin abscesses and peritoneal fluid in 6, 5 and 1 neonates, respectively. Candidiasis was due to Candida parapsilosis in 17 cases, Candida albicans in 15 cases, Candida tropicalis in 5 cases, Candida guilliermondii in 2 cases, Candida glabrata in 2 cases and an unidentified Candida sp. in 1 case. Twenty-eight, five and eight infants received 7, 6–6.5 and 5 mg/kg/day, respectively. Median duration of therapy was 18 days; median cumulative dose was 94 mg/kg. Fungal eradication was achieved in 39 of 41 (95%) episodes; median duration of therapy until fungal eradication was 8.7±4.5 days. Fungal eradication was achieved after 10.9±4.8 days in patients who had received previous antifungal therapy compared to 8.2±4.3 days in those treated with liposomal amphotericin B as first-line therapy. One patient died due to systemic candidiasis on day 12 of therapy. High-dose liposomal amphotericin B was effective and safe in the treatment of neonatal candidiasis. Fungal eradication was more rapid in patients treated early with high doses and in patients who received high-dose liposomal amphotericin B as first-line therapy.     

Iron metabolism and fungal infections in patients with haematological malignancies.

AIM--To determine whether iron metabolism influences the incidence of systemic fungal infection in patients with haematological malignancies. METHODS--The study population comprised 74 patients who had undergone myeloablative chemotherapy. Systemic fungal infections were classified as confirmed (histological confirmation or characteristic septate hyphae) or possible (antibiotic resistant fever which resolved following administration of intravenous amphotericin B, together with either typical radiographic lesions or massive oropharyngeal candidiasis). Parameters of iron metabolism included serum iron concentrations, total iron binding capacity, serum transferrin, and ferritin concentrations and transferrin saturation values. RESULTS--Patients who developed a fungal infection had substantially increased transferrin saturation values and ferritin concentrations at diagnosis together with low serum transferrin and high serum iron concentrations. This profile was present in patients with a fungal infection regardless of the underlying haematological disorder. CONCLUSION--Increased transferrin saturation values and high ferritin concentrations may be additional risk factors for the development of systemic fungal infection in patients with haematological malignancies.     

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.     

Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group

BACKGROUND: In patients with persistent fever and neutropenia, amphotericin B is administered empirically for the early treatment and prevention of clinically occult invasive fungal infections. However, breakthrough fungal infections can develop despite treatment, and amphotericin B has substantial toxicity. METHODS: We conducted a randomized, double-blind, multicenter trial comparing liposomal amphotericin B with conventional amphotericin B as empirical antifungal therapy. RESULTS: The mean duration of therapy was 10.8 days for liposomal amphotericin B (343 patients) and 10.3 days for conventional amphotericin B (344 patients). The composite rates of successful treatment were similar (50 percent for liposomal amphotericin B and 49 percent for conventional amphotericin B) and were independent of the use of antifungal prophylaxis or colony-stimulating factors. The outcomes were similar with liposomal amphotericin B and conventional amphotericin B with respect to survival (93 percent and 90 percent, respectively), resolution of fever (58 percent and 58 percent), and discontinuation of the study drug because of toxic effects or lack of efficacy (14 percent and 19 percent). There were fewer proved breakthrough fungal infections among patients treated with liposomal amphotericin B (11 patients [3.2 percent]) than among those treated with conventional amphotericin B (27 patients [7.8 percent], P=0.009). With the liposomal preparation significantly fewer patients had infusion-related fever (17 percent vs. 44 percent), chills or rigors (18 percent vs. 54 percent), and other reactions, including hypotension, hypertension, and hypoxia. Nephrotoxic effects (defined by a serum creatinine level two times the upper limit of normal) were significantly less frequent among patients treated with liposomal amphotericin B (19 percent) than among those treated with conventional amphotericin B (34 percent, P<0.001). CONCLUSIONS: Liposomal amphotericin B is as effective as conventional amphotericin B for empirical antifungal therapy in patients with fever and neutropenia, and it is associated with fewer breakthrough fungal infections, less infusion-related toxicity, and less nephrotoxicity.     

Review of the Incidence and Prognosis of Pseudomonas aeruginosa Infections in Cancer Patients in the 1990s

 In an attempt to determine the actual relevance of Pseudomonas aeruginosa as a target of empiric antimicrobial first-line therapy in febrile cancer patients, 44 reports of clinical trials on antimicrobial treatment regimens and 53 reports on the epidemiology of microbiologically documented infections in cancer patients were reviewed. The incidence of infections due to Pseudomonas aeruginosa was 1–2.5% among all patients presenting with first fever during neutropenia, and 5–12% among patients with microbiologically documented infections. The proportion of Pseudomonas aeruginosa infections among cases of gram-negative bacteremia has not generally declined during the past 2 decades. There were marked local and regional differences regarding the incidence of documented Pseudomonas aeruginosa infections. No clear differences between neutropenic and non-neutropenic cancer patients, between patients with solid tumors and those with hematologic malignancies, or between inpatients and outpatients presenting with fever and neutropenia were detected with respect to the likelihood of Pseudomonas aeruginosa involvement. The mortality rate in patients with Pseudomonas aeruginosa bacteremia, particularly with polymicrobial bacteremia or bacteremic pneumonia with Pseudomonas aeruginosa involvement, is considerably high. The beneficial impact on mortality of an empiric antimicrobial treatment regimen with high antipseudomonal activity has not yet been demonstrated unequivocally. Additional factors such as the quality of intensive care management, effective second-line antimicrobial regimens, local resistance patterns, and patient-related cofactors are very likely to influence the outcome of Pseudomonas aeruginosa infections in cancer patients.     

Fungal Infections in Patients with Solid Tumors Treated with High-Dose Chemotherapy and Autologous Peripheral Blood Stem Cell Transplantation

The incidence and risk factors for fungal infection were assessed in 291 patients who had solid tumors and were undergoing autologous peripheral blood stem cell transplantation. The first 162 patients received prophylactic itraconazole, and 129 patients received nystatin. Empiric amphotericin B was given at day 7 of febrile neutropenia. Fungal infections developed in 52 patients: 47 (16%) were superficial and 6 (2%) were systemic. Itraconazole prophylaxis and only a few days of febrile neutropenia were independently associated with a decrease in the incidence of superficial infections. Only two patients required empiric amphotericin B. Systemic antifungal prophylaxis does not seem to be justified for patients with solid tumors and autologous peripheral blood stem cell transplantation. Empiric amphotericin B may be safely started at day 7 of febrile neutropenia. Electronic Publication     

Efficacy of fluconazole in the treatment of systemic fungal infections

The efficacy of fluconazole in the treatment of systemic fungal infections was evaluated in an open non-comparative trial. A total of 48 patients with proven or suspected fungal infections were enrolled in 40 of whom efficacy was evaluable.Candida albicans accounted for 90 % of the infections.Candida parapsilosis, Candida glabrata, Histoplasma capsulatum andAspergillus fumigatus caused the infection in one case each. Fluconazole was administered at a dosage of 200–400 mg daily for a mean duration of 15 days. Fluconazole treatment was successful in 53 % of the patients. In patients with proven or probableCandida albicans infections a clinical and mycological response was achieved in 62 % and 65 %, respectively. In 11 patients elevation of liver enzymes was considered to be possibly related to fluconazole treatment; modification of treatment was not necessary in any case. Fluconazole was found to be a well tolerated and effective agent for the treatment of systemicCandida albicans infections.     

An autopsy study of systemic fungal infections in patients with hematologic malignancies

The aim of this study was to determine the incidence of fungal infections detected on autopsy in a group of 40 patients with hematologic malignancies treated with intensive chemotherapy or bone marrow transplantation, and to evaluate the risk factors for fungal infections. A control group included 38 patients with nonhematologic diseases and without granulocytopenia but with at least one of the known risk factors for fungal infections. Standard histopathological and microbiological methods were used. A higher incidence of invasive fungal infections was found in patients with hematologic malignancies as compared to the control group (p<0.01). The predominant causes of fungal infections wereCandida albicans andAspergillus spp. The incidence of fungal infections caused byAspergillus was higher (p<0.05) in patients with hematologic malignancies than in the control group. The independent risk factors for fungal infections were fungal colonization, number of antibiotics and duration of antibiotic therapy, duration of fever and skin rash. A higher proportion of fungal infections was diagnosed on autopsy than during the patients' life (p<0.01).     

Favorable outcome of chronic disseminated candidiasis in four pediatric patients with hematological malignancies

Four children were diagnosed with chronic disseminated candidiasis (CDC) during treatment for hematological malignancies. All presented with persistent fever, not responsive to broad-spectrum antibiotics, abdominal distension and hepatosplenomegaly. Two children needed artificial ventilation because of respiratory insufficiency. The time between onset of neutropenic fever and diagnosis of CDC ranged from 20-49 days. Ultrasound and computed tomography failed to demonstrate CDC during the neutropenic phase. All children needed a liver or spleen biopsy to establish the diagnosis of CDC. Three of four patients continued chemotherapy during treatment for the fungal infection. All patients had a favorable outcome, both in terms of the invasive Candida infections, as well as their underlying malignancies.     

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     

Value of measurement of C-reactive protein in febrile patients with hematological malignancies

The maximum serum levels of C-reactive protein (CRP) in 126 patients with hematological malignancies who had 554 febrile episodes were analyzed retrospectively with regard to documented infections and fever of unknown origin. The CRP levels were significantly higher when the blood culture was positive than when it was negative (p=0.002). The CRP levels were significantly higher when the infection focus was identified than when it was not (p=0.010). In patients with fever of unknown origin the CRP was significantly lower than in patients with microbiologically documented infections (p<0.001). Cytotoxic treatment neither reduced nor enhanced the CRP reaction. The serial measurement of CRP is a reliable and readily available means for differentiating between bacterial infections and other causes of fever in patients with hematological malignancies, also during neutropenia and after cytotoxic treatment.     

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.     

Missed diagnosis in hematological patients—an autopsy study

Autopsy findings of missed diagnoses that would probably have changed management or prognosis occur in up to 29% of cases in general hospitals. Such proportions may be higher in subsets of patients with complex diseases. We reviewed 2908 consecutive autopsies performed over a period of 29 months in a large-volume hospital, analyzing 118 autopsies of patients with hematological malignancies or severe aplastic anemia. A review of macroscopic reports as well as microscopic examination of tissue samples was performed. Medical records were reviewed for clinical diagnoses. Discordances between clinical and autopsy diagnoses were classified using Goldmans criteria. Additionally, we searched for clinical parameters correlated with occurrence of class-I discrepancy using a multivariate method. Median age was 46.5 years, and 25.4% had received a hematopoietic stem-cell transplant. Overall, 11.9% (6.6–19.1%) of patients died before conclusion of the hematological diagnosis and 33% (24.6–42.3%) died with no active hematological disease. We found class-I discrepancy in 31.3% (23.1–40.5 %) of cases. The most common among these diagnoses were hematological disease, pneumonia and gastrointestinal bleeding. In a univariate analysis, being elderly (P=0.04) was positively correlated with the finding of class-I discrepancies; while, having received previous specific hematological treatment (P=0.0005) or hematopoietic stem-cell transplants (P=0.013), or being admitted to a specialized hematology unit (P=0.0006) were negatively correlated to the occurrence of such discrepancies. Multivariate analysis showed that care in a specialized hematology unit (OR 0.34, 0.12–0.93) was independently associated with lower occurrence of discrepancies. We concluded that critical diagnoses are often missed in highly complex hematological patients especially in the absence of admission to specialized hematology units.     

Measurement of the D-Arabinitol/L-Arabinitol Ratio in Urine of Neutropenic Patients Treated Empirically with Amphotericin B

 The aim of the present study was to evaluate the diagnostic significance of the D-arabinitol/L-arabinitol ratio in urine of neutropenic patients with suspected fungal infection. D-arabinitol/L-arabinitol ratios were determined in 373 serial urine samples of 104 patients with haematological malignancies receiving empirical amphotericin B treatment for suspected invasive fungal infection. Twenty-eight (8%) urine samples obtained from 17 (16%) patients were positive (ratio≥4). Eight (47%) patients had positive urine samples at the initiation of empirical amphotericin B treatment and the rest from 7 to 30 days after empirical therapy was started. Several urine samples were positive in six patients. Only one of the five patients with candidemia had elevated D-arabinitol/L-arabinitol ratios (persistent Candida krusei fungaemia). Four patients with transient candidemia and seven patients with invasive mould infections were negative. Patients who died during the study period had significantly higher D-arabinitol/L-arabinitol ratios than patients who survived (P=0.0002). Pneumonia was the most common manifestation of infection (53% of patients with elevated D-arabinitol/L-arabinitol ratios) and was associated with an especially high mortality (67%). The present study shows that elevated urine D-arabinitol/L-arabinitol ratios are common in febrile, neutropenic patients. However, the urine arabinitol test did not detect transient candidemia at elevated levels during the course of infection. Furthermore, D-arabinitol/L-arabinitol ratios were often elevated in the late phase of infection only. This contests the use of this test in guiding the initiation of antifungal therapy. The detection of elevated arabinitol levels in neutropenic patients during empirical amphotericin B treatment is associated with poor prognosis.     

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.     

Laboratory markers of systemic inflammation as predictors of bloodstream infection in acutely ill patients admitted to hospital in medical emergency

The aim of the present study was to determine whether the presence of an infectious focus or of fever alone can predict bloodstream infection and whether levels of C-reactive protein, procalcitonin, interleukin (IL)-6, IL-8, and soluble IL-2 receptor (sIL-2R) improve the diagnosis of community-acquired bloodstream infection. Markers of systemic inflammation were studied in 92 patients with community-acquired infection. On admission to hospital, 54 patients had an infectious focus, 25 had fever without an infectious focus, and 13 had neither. The presence of focus or fever predicted bloodstream infection (n=13 patients) with a sensitivity of 100% (95% confidence interval, 75–100), a specificity of 16% (95%CI, 9–26), a negative predictive value of 100% (95%CI, 75–100), and a positive predictive value of 16% (95%CI, 9–26). Positive predictive values of C-reactive protein, procalcitonin, IL-6, IL-8, and sIL-2R, all measured on admission, were also low (33–44%). Eight febrile patients in whom an infectious focus was found during a 3-day follow-up period had higher on-admission IL-6 (P=0.005) and sIL-2R (P=0.046) levels than did 17 febrile patients without an infectious focus. In conclusion, markers of systemic inflammation do not improve the diagnosis of community-acquired bloodstream infection; however, they may aid in identifying patients with fever due to occult infection.