Johan Van Eldere

Use of Circulating Galactomannan Screening for Early Diagnosis of Invasive Aspergillosis in Allogeneic Stem Cell Transplant Recipients

Screening for galactomannan (GM) has been adopted by many European centers as part of the management plan for allogeneic stem cell transplant recipients. However, the temporal onset of GM antigenemia remains unknown. A series of allogeneic stem cell transplant recipients were monitored prospectively, and the relationship between antigenemia and other diagnostic triggers for initiation of antifungal therapy was analyzed. GM detection had a sensitivity of 94.4% and a specificity of 98.8%. Positive and negative predictive values were 94.4% and 98.8%, respectively. This statistical profile was better than that of other triggers, including unexplained fever, new pulmonary infiltrates, isolation of Aspergillus species, and abnormalities seen on computed tomography. Antigenemia preceded diagnosis on the basis of radiologic examination or Aspergillus isolation by 8 and 9 days in 80% and 88.8% of patients, respectively. Antigenemia preceded therapy in 83.3% of patients. Detection of GM was especially useful when patients were receiving steroid treatment or when coexisting conditions masked the diagnosis of invasive aspergillosis. Prospective screening for GM allows earlier diagnosis of aspergillosis than do conventional diagnostic criteria.

High doses of vitamin d to reduce exacerbations in chronic obstructive pulmonary disease: a randomized trial

BACKGROUND Low serum 25-hydroxyvitamin D (25-[OH]D) levels have been associated with lower FEV(1), impaired immunologic control, and increased airway inflammation. Because many patients with chronic obstructive pulmonary disease (COPD) have vitamin D deficiency, effects of vitamin D supplementation may extend beyond preventing osteoporosis. OBJECTIVE To explore whether supplementation with high doses of vitamin D could reduce the incidence of COPD exacerbations. DESIGN Randomized, single-center, double-blind, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00666367) SETTING University Hospitals Leuven, Leuven, Belgium. PATIENTS 182 patients with moderate to very severe COPD and a history of recent exacerbations. INTERVENTION 100,000 IU of vitamin D supplementation or placebo every 4 weeks for 1 year. MEASUREMENTS The primary outcome was time to first exacerbation. Secondary outcomes were exacerbation rate, time to first hospitalization, time to second exacerbation, FEV(1), quality of life, and death. RESULTS Mean serum 25-(OH)D levels increased significantly in the vitamin D group compared with the placebo group (mean between-group difference, 30 ng/mL [95% CI, 27 to 33 ng/mL]; P < 0.001). The median time to first exacerbation did not significantly differ between the groups (hazard ratio, 1.1 [CI, 0.82 to 1.56]; P = 0.41), nor did exacerbation rates, FEV(1), hospitalization, quality of life, and death. However, a post hoc analysis in 30 participants with severe vitamin D deficiency (serum 25-[OH]D levels <10 ng/mL) at baseline showed a significant reduction in exacerbations in the vitamin D group (rate ratio, 0.57 [CI, 0.33 to 0.98]; P = 0.042). LIMITATION This was a single-center study with a small sample size. CONCLUSION High-dose vitamin D supplementation in a sample of patients with COPD did not reduce the incidence of exacerbations. In participants with severe vitamin D deficiency at baseline, supplementation may reduce exacerbations. PRIMARY FUNDING SOURCE Applied Biomedical Research Program, Agency for Innovation by Science and Technology (IWT-TBM).

Bronchoalveolar Lavage Fluid Galactomannan for the Diagnosis of Invasive Pulmonary Aspergillosis in Patients with Hematologic Diseases

BACKGROUND Prompt diagnosis of invasive pulmonary aspergillosis (IPA) remains a challenge. Galactomannan (GM) detection in bronchoalveolar lavage (BAL) fluid by the Platelia enzyme immunoassay aims to further improve upon the tests utility by applying it directly to specimens from the target organ. METHODS A retrospective analysis of the Platelia assay was performed on BAL samples from 99 evaluable high-risk hematology patients, including 58 with proven or probable IPA. RESULTS BAL GM demonstrated an improved sensitivity profile (91.3% with an optical density [OD] index cutoff of >or=1.0) in comparison with culture and microscopy (50% and 53.3%, respectively). The diagnostic accuracy as given by the area under the receiver operating characteristic curve was 0.93 (95% confidence interval, 0.88-0.99); further decreasing the OD index cutoff to 0.5 compromised specificity more than it improved sensitivity. Estimates of the positive and negative predictive value of the Platelia assay on BAL samples (OD index, >or=1.0) were 76% and 96%, respectively. The mean BAL GM OD index was not different in neutropenic versus nonneutropenic case patients (3.9 and 4.5, respectively; P = .3); however, a trend toward decreased sensitivity in patients receiving mold-active prophylaxis was noted. CONCLUSION BAL GM is a valuable adjunctive diagnostic tool to other conventional microbiologic and radiologic studies.

Prospective clinical evaluation of lower cut‐offs for galactomannan detection in adult neutropenic cancer patients and haematological stem cell transplant recipients

The recent advent of an improved commercial serum enzyme‐linked immunosorbent assay (ELISA) for the detection of circulating galactomannan (GM), a major constituent of Aspergillus cell walls, has contributed to the diagnosis of invasive aspergillosis (IA) in many haematology and transplant centres. However, the optimal threshold for positivity remains a matter of debate. We prospectively evaluated the impact of lowering the cut‐off in 124 neutropenic episodes with a high pretest probability for IA. Two new cut‐off points, lower than previously accepted, are proposed: (a) a ‘static’ cut‐off at 0·8 and (b) a ‘dynamic’ cut‐off at 0·5. A single assay with an optical density (OD) index ≥0·8 warrants the initiation of anti‐Aspergillus therapy. A further lowering of the ‘static’ threshold seems not clinically feasible given the drop in positive predictive value (PPV). However, the demonstration of at least two sequential sera with an OD ≥0·5 (‘dynamic’ threshold) increased the specificity and the PPV to 98·6% and the efficiency to 98%. Applying both cut‐offs to a subgroup of 21 ‘possible’ fungal infections further identified and upgraded six cases of IA. However, the clinical benefit of lower cut‐offs (particularly for earlier diagnosis) depends upon the kinetics of antigenaemia and the intensity of serum sampling.

Galactomannan serves as a surrogate endpoint for outcome of pulmonary invasive aspergillosis in neutropenic hematology patients

A noninvasive, objective, reproducible, and quantitative Aspergillus‐specific surrogate marker is needed for a more accurate assessment of the outcome of invasive aspergillosis (IA) in patients with a hematologic disorder. The quantitative serum galactomannan index (GMI) assay seems to fulfill the requirements of surrogacy for outcome evaluation.

Candida albicans biofilm formation in a new in vivo rat model.

Device-associated microbial growth, including Candida biofilms, represents more than half of all human microbial infections and, despite a relatively small risk of implant-associated diseases, this type of infection usually leads to high morbidity, increased health-care costs and prolonged antimicrobial therapy. Animal models are needed to elucidate the complex host-pathogen interactions that occur during the development of attached and structured biofilm populations. We describe here a new in vivo model to study Candida biofilm, based on the avascular implantation of small catheters in rats. Polyurethane biomaterials challenged with Candida cells were placed underneath the skin of immunosuppressed animals following only minor surgery. The model allowed the study of up to ten biofilms at once, and the recovery of mature biofilms from 2 days after implantation. The adhering inoculum was adjusted to the standard threshold of positive diagnosis of fungal infection in materials recovered from patients. Wild-type biofilms were mainly formed of hyphal cells, and they were unevenly distributed across the catheter length as observed in infected materials in clinical cases. The hyphal multilayered structure of the biofilms of wild-type strains was observed by confocal microscopy and compared to the monolayer of yeast or hyphal cells of two well-known biofilm-deficient strains, efg1Delta/efg1 Delta cph1Delta/cph1Delta and bcr1Delta /bcr1Delta, respectively. The subcutaneous Candida biofilm model relies on the use of implanted catheters with accessible, fast and minor surgery to the animals. This model can be used to characterize the ability of antimicrobial agents to eliminate biofilms, and to evaluate the prophylactic effect of antifungal drugs and biomaterial coatings.

Expression of Biofilm-Associated Genes in Staphylococcus epidermidis during In Vitro and In Vivo Foreign Body Infections

The expression of the genes icaA, icaC, aap, and atlE--with a putative role in the pathogenesis of Staphylococcus epidermidis foreign body infections--and of mecA and 3 housekeeping genes (gmk, tpi, and hsp60) was examined in vitro and in vivo. In vitro expression levels of ica, atlE, and gmk were higher in sessile than in planktonic bacteria. Exposure to foreign bodies in vitro and in vivo induced a sharp increase in ica expression that was followed by a progressive decrease. The in vivo expression of aap and mecA was high during early but low during late foreign body infections. The in vivo expression of atlE and gmk remained relatively high and stable. In conclusion, biofilm genes encoding for structural elements are mainly expressed during early foreign body infections. The ica genes are associated with initial colonization but not with persistence. The constant expression of atlE and gmk may indicate a role during the entire course of foreign body infections.

Serum (1-3)-β-d-Glucan as a Tool for Diagnosis of Pneumocystis jirovecii Pneumonia in Patients with Human Immunodeficiency Virus Infection or Hematological Malignancy

ABSTRACT (1-3)-β-d-Glucan (BG) reactivity was tested in serum samples from 28 patients with human immunodeficiency virus infection or a hematological malignancy and Pneumocystis jirovecii pneumonia (PCP) and 28 control patients. The sensitivity and specificity of BG detection with the Fungitell assay for PCP were 100 and 96.4%, respectively, using a cutoff value of 100 pg/ml. Serum BG testing looks promising for the noninvasive diagnosis of PCP. Our data suggest that a higher cutoff value for the diagnosis of PCP than for the diagnosis of invasive aspergillosis or candidiasis could be used safely and will improve the specificity of the test.

Individualized decreasing-dose maintenance fluconazole regimen for recurrent vulvovaginal candidiasis (ReCiDiF trial)

OBJECTIVE Although many women with recurrent vulvovaginal candidiasis initially benefit from prophylactic intermittent treatment with antimycotics, most of them experience relapse after cessation of therapy, and often they return to the pretreatment recurrence rate. The purpose of this study was to demonstrate the efficacy and safety of an individualized, degressive, prophylactic regimen in 136 women with recurrent vulvovaginal candidiasis. STUDY DESIGN After an induction dose of 600 mg fluconazole during the first week, 117 women started maintenance therapy: 200 mg fluconazole weekly for 2 months, followed by 200 mg biweekly for 4 months, and 200 mg monthly for 6 months, according to their individual response to therapy. All women were tested for recurrences monthly with wet mount microscopy and vaginal culture during the first 6 months and bimonthly during the next 6 months. Patients were allowed to move on to the next level of maintenance therapy only if they were symptom free and microscopy and culture negative. RESULTS Of the women who were cured successfully after the induction phase, 101 women (90%) were disease-free after 6 months of maintenance therapy with this degressive regimen, and 80 women (77%) were disease-free after 1 year. The weekly incidence of the first clinical relapse was 0.5% during any period of the maintenance phase, and the rate of all new relapses, which included evidence of mycologic or microscopic colonization, was 1% per week. Women who experienced several relapses (poor responders) had experienced more relapses before entering the study compared with the optimal responders (odds ratio, 4.9; 95% CI,1.8-13.7; P = .002), experienced the disease for a longer period of time (6.5 vs 3.7 years; P = .06), and harbored significantly more Candida non-albicans during maintenance therapy (P = .001). No serious side-effects were noted. CONCLUSION Individualized, degressive, prophylactic maintenance therapy with oral fluconazole is an efficient treatment regimen to prevent clinical relapses in women with recurrent vulvovaginal candidiasis.

Difference in time to positivity of hub-blood versus nonhub-blood cultures is not useful for the diagnosis of catheter-related bloodstream infection in critically ill patients.

ObjectiveThe differential time to positivity (DTTP), defined as the difference in time necessary for the blood cultures taken by a peripheral puncture and through the catheter to become positive has been suggested to be useful in differentiating between catheter-related bloodstream infection (CR-BSI) and other sources of bacteremia. A DTTP of >120 mins was found predominantly in CR-BSI. The objective of our study was to investigate whether DTTP is useful for the diagnosis of CR-BSI in a medical-surgical intensive care unit. DesignProspective clinical study. SettingA 60-bed medical-surgical intensive care unit of a university hospital. PatientsOne hundred consecutive adult patients from whom catheter(s) were to be removed for suspected CR-BSI were studied. InterventionA blood culture (using aerobic and anaerobic culture bottles) was first taken from a new puncture site. Next, a blood culture was taken through every intravascular catheter in place. Measurements and Results DTTP was calculated using the automated BacT/Alert blood culture system. Three patients had CR-BSI and nine patients had noncatheter-related bacteremia. Five patients had catheter-related sepsis without proven bacteremia. There was no significant difference in median DTTP between patients with CR-BSI and noncatheter-related bacteremia (2.1 hrs and 3.3 hrs, respectively;p = .6). Moreover, catheter-related sepsis in patients without bacteremia could not be detected using DTTP. ConclusionDTTP seems not to be useful for the diagnosis of CR-BSI in a medical-surgical intensive care unit.