Kullberg, B.J.

Early Serum Galactomannan Trend as a Predictor of Outcome of Invasive Aspergillosis (Article)

2012-07-01T00:00:00Z

The monitoring and prediction of treatment responses to invasive aspergillosis (IA) are difficult. We determined whether serum galactomannan index (GMI) trends early in the course of disease may be useful in predicting eventual clinical outcomes. For the subjects recruited into the multicenter Global Aspergillosis Study, serial GMIs were measured at baseline and at weeks 1, 2, and 4 following antifungal treatment. Clinical response and survival at 12 weeks were the outcome measures. GMI trends were analyzed by using the generalized estimation equation approach. GMI cutoffs were evaluated by using receiver-operating curve analyses incorporating pre- and posttest probabilities. Of the 202 study patients diagnosed with IA, 71 (35.1%) had a baseline GMI of >/=0.5. Week 1 GMI was significantly lower for the eventual responders to treatment at week 12 than for the nonresponders (GMIs of 0.62 +/- 0.12 and 1.15 +/- 0.22, respectively; P = 0.035). A GMI reduction of >35% between baseline and week 1 predicted a probability of a satisfactory clinical response. For IA patients with pretreatment GMIs of <0.5 (n = 131; 64.9%), GMI ought to remain low during treatment, and a rising absolute GMI to >0.5 at week 2 despite antifungal treatment heralded a poor clinical outcome. Here, every 0.1-unit increase in the GMI between baseline and week 2 increased the likelihood of an unsatisfactory clinical response by 21.6% (P = 0.018). In summary, clinical outcomes may be anticipated by charting early GMI trends during the first 2 weeks of antifungal therapy. These findings have significant implications for the management of IA.

The Y238X stop codon polymorphism in the human b-glucan receptor dectin-1 and susceptibility to invasive aspergillosis (Article)

2011-03-01T00:00:00Z

Background. Dectin-1 is the major receptor for fungal b-glucans on myeloid cells. We investigated whether defective Dectin-1 receptor function, because of the early stop codon polymorphism Y238X, enhances susceptibility to invasive aspergillosis (IA) in at-risk patients. Methods. Association of Dectin-1 Y238X polymorphism with occurrence and clinical course of IA was evaluated in 71 patients who developed IA post hematopoietic stem cell transplantation (HSCT) and in another 21 non-HSCT patients with IA. The control group consisted of 108 patients who underwent HSCT. Functional studies were performed to investigate consequences of the Y238X Dectin-1 polymorphism. Results. The Y238X allele frequency was higher in non-HSCT patients with IA (19.0% vs 6.9%-7.7%; P < .05). Heterozygosity for Y238X polymorphism in HSCT recipients showed a trend toward IA susceptibility (odds ratio, 1.79; 95% CI, .77-4.19; P = .17) but did not influence clinical course of IA. Functional assays revealed that although peripheral blood mononuclear cells with defective Dectin-1 function due to Y238X responded less efficiently to Aspergillus, corresponding macrophages showed adequate response to Aspergillus. Conclusions. Dectin-1 Y238X heterozygosity has a limited influence on susceptibility to IA and may be important in susceptible non-HSCT patients. This is partly attributable to redundancy inherent in the innate immune system. Larger studies are needed to confirm these findings.

Aspergillus fumigatus cell wall components differentially modulate host TLR2 and TLR4 responses (Article)

2011-02-01T00:00:00Z

Aspergillus fumigatus conidia attenuates host proinflammatory responses through modulation of Toll-like receptor (TLR)2 and TLR4 signaling, but the precise mechanisms that mediate this effect are not known. In the present study, the role of the Aspergillus cell wall polysaccharide constituents responsible for the modulation of host capability to mount a proinflammatory response was studied. Aspergillus cell wall fractions and its major components showed differential capabilities in modulating host TLR-mediated interleukin (IL)-6 production. Beta-glucan specifically suppressed TLR4-induced response, while alpha-glucan inhibited IL-6 induced through TLR2- and TLR4-stimulation. Galactomannan diminished TLR4-mediated response, while its inhibitory effects on TLR2-signaling were limited. Chitin, on the other hand, did not have significant immunomodulatory capability. The ability of the fungal cell wall to alter the immune signature of the pathogen may contribute to its virulence and the pathogenesis of co-infection.

Immune response to Aspergillus fumigatus in compromised hosts: From bedside to bench (Article)

2011-01-01T00:00:00Z

The relevance of studies aimed at understanding host immune response against Aspergillus fumigatus takes on much significance given that all patients with invasive aspergillosis are invariably immunocompromised. This article attempts to correlate relevant findings from recent experimental studies to clinical observations made by the physician at the bedside. It is hoped that the increased understanding of host-fungus immune interaction may pave the way for the development of new management strategies against this difficult-to-treat fungal disease.

Early proinflammatory cytokines and C-reactive protein trends as predictors of outcome in invasive aspergillosis (Article)

2010-11-01T00:00:00Z

Background. Monitoring treatment response in invasive aspergillosis is challenging, because an immunocompromised host may not exhibit reliable symptoms and clinical signs. Cytokines play a pivotal role in mediating host immune response to infection; therefore, the profiling of biomarkers may be an appropriate surrogate for disease status. Methods. We studied, in a cohort of 119 patients with invasive aspergillosis who were recruited in a multicenter clinical trial, serum interleukin (IL)-6, IL-8, IL-10, interferon-γ, and C-reactive protein (CRP) trends over the first 4 weeks of therapy and correlated these trends to clinical outcome parameters. Results. Circulating IL-6 and CRP levels were high at initiation of therapy and generally showed a downward trend with antifungal treatment. However, subjects with adverse outcomes exhibited a distinct lack of decline in IL-6 and CRP levels at week 1, compared with responders (P = .02, for both IL-6 and CRP). Nonresponders also had significantly elevated IL-8 levels (P = .001). Conclusions. High initial IL-8 and persistently elevated IL-6, IL-8, and CRP levels after initiation of treatment may be early predictors of adverse outcome in invasive aspergillosis. Cytokine and CRP profiles could be used for early identification of patients with a poor response to antifungal treatment who may benefit from more-aggressive antimicrobial regimens. © 2010 by the Infectious Diseases Society of America. All rights reserved.

Anti-Aspergillus human host defence relies on type 1 T helper (Th1), rather than type 17 T helper (Th17), cellular immunity (Article)

2010-05-01T00:00:00Z

Summary Both interferon-γ-producing type 1 T helper (Th1)- and interleukin-17 (IL-17)-producing Th17 cells have been proposed to be involved in anti-fungal host defence. Although invasive aspergillosis is one of the most severe human fungal infections, little is known regarding the relative importance of the Th1 versus Th17 cellular immune pathways for the human anti-Aspergillus host defence. Using human peripheral blood mononuclear cells and a system consisting of monocyte-derived macrophages with lymphocytes, we found that Aspergillus fumigatus is a weak inducer of human IL-17 but induces a strong Th1 response. These data were validated by the very low IL-17 levels in bronchoalveolar lavage fluid and serum of patients with invasive aspergillosis. Surprisingly, live A. fumigatus reduced IL-17 production induced by mitogenic stimuli. This effect was mediated through the propensity of A. fumigatus to metabolize tryptophan and release kynurenine, which modulates the inflammatory response through inhibition of IL-17 production. In conclusion, A. fumigatus does not stimulate production of IL-17 and human host defence against aspergillosis may not rely on potent Th17 responses.

Fungal strategies for overcoming host innate immune response (Article)

2009-08-17T00:00:00Z

A successful pathogen is one that is able to effectively survive and evade detection by the host innate immune defense. Fungal pathogens have adopted strategies which evade host defense and eventually cause disease in at-risk patients. Shielding of stimulatory surface recognition molecules, shedding of decoy components, induction of anti-inflammatory signals, complement evasion and resilient survival capacity are successful evasion mechanisms employed by fungal pathogens. Understanding these complex pathways of immune evasion can potentially contribute to development of novel therapeutic strategies against fungal infections.

Modulation of toll-like receptor 2 (TLR2) and TLR4 responses by Aspergillus fumigatus (Article)

2009-05-01T00:00:00Z

Toll-like receptor (TLR)-based signaling pathways in the host may be modulated by pathogens during the course of infection. We describe a novel immunomodulatory mechanism in which Aspergillus fumigatus conidia induce attenuation of TLR2- and TLR4-mediated interleukin (IL)-6 and IL-1β proinflammatory responses in human mononuclear cells with suppression of IL-1β mRNA transcription. Background TLR2 and TLR4 mRNA transcription was not influenced. A. fumigatus conidia induced TLR2 internalization and uptake into the phagosome with a resultant decrease in surface receptor expression. A. fumigatus hyphae, on the other hand, selectively downregulated the TLR4-mediated response. These novel immunosuppressive effects may facilitate the invasiveness of A. fumigatus.

Antibiotic prophylaxis and the risk of surgical site infections following total hip arthroplasty: Timely administration is the most important factor (Article)

2007-04-01T00:00:00Z

Background. Surgical site infections (SSIs) following total hip arthroplasty can lead to prolonged hospitalization, increased morbidity and mortality, and high costs. This article analyzes the effect of various parameters of surgical antibiotic prophylaxis on the risk of SSI following total hip arthroplasty. Methods. Data about SSI and potential prophylaxis-, patient-, and procedure-related risk factors were prospectively collected for 1922 patients who underwent elective total hip arthroplasty in 11 hospitals that participated in the Dutch intervention project, Surgical Prophylaxis and Surveillance. Multivariate logistic regression analysis was performed to correct for random variation among hospitals. Results. SSIs (superficial and deep) occurred in 50 patients (2.6%). The highest odds ratios for SSI were found in patients who received prophylaxis after incision (2.8, 95% confidence interval [CI], 0.9-8.6; P = .07), had an American Society of Anesthesiology score that was >2 (2.8, 95% CI, 0.8-9.2; P = .09), and experienced a duration of surgery that was >75th percentile (2.5; 95% CI, 1.1-5.8; P = .04). Prolonged prophylaxis after the end of surgery and the use of antibiotic-impregnated cement did not contribute to fewer SSIs in this study. Conclusions. This study suggests that intervention programs in search of amendable factors to prevent SSI should focus on timely administration of antibiotic prophylaxis.

Effect of recombinant murine granulocyte colony-stimulating factor with or without fluoroquinolone therapy on mixed-infection abscesses in mice. (Article)

2005-09-01T00:00:00Z

The aim of the study was to determine if immunomodulation of host defense with recombinant murine granulocyte colony-stimulating factor (G-CSF) improves the efficacy of trovafloxacin or moxifloxacin in abscesses containing Bacillus fragilis ATCC 23745 and different Escherichia coli strains varying in virulence. Treatment of mice inoculated with 10(7) CFU B. fragilis and 10(5) CFU low-virulence E. coli with either trovafloxacin (150 mg/kg/day every 24 hours, days 3 to 7) or moxifloxacin (96 mg/kg/day every 12 hours, days 3 to 7), significantly reduced the number of B. fragilis to 6.9 +/- 0.35 and 5.8 +/- 0.10 and that of E. coli to 4.9 +/- 0.09 and 4.2 +/- 0.07 log CFU/abscess for trovafloxacin and moxifloxacin, respectively, compared to controls (B. fragilis 8.7 and E. coli 7.4 log CFU/abscess) on day 8. Also, moxifloxacin was more potent than trovafloxacin. Addition of G-CSF prophylaxis (1 mug once on day -1) or therapy (1 mug/day on days 3 to 7) to fluoroquinolone treatment did not improve the efficacy of fluoroquinolone therapy alone. The effect of moxifloxacin with or without G-CSF prophylaxis on abscesses with a virulent hemolytic E. coli strain was also studied. In moxifloxacin-treated mice, 75% survived infection compared to 10% of controls. Combining moxifloxacin with G-CSF prophylaxis significantly decreased survival (30%) compared to moxifloxacin alone. In addition, G-CSF prophylaxis resulted in a threefold (E. coli) to 100-fold (B. fragilis) increased outgrowth in the abscesses of surviving mice. In conclusion, the addition of G-CSF to a fluoroquinolone is not advisable since, depending on the virulence of the E. coli strains, this might detrimentally influence the outcome of therapy.