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Advancements in allogeneic haematopoietic stem cell transplant (alloHSCT) procedures have improved patient outcomes over the last two decades, though invasive fungal infections (IFIs) remain a significant risk. The incidence of IFIs in alloHSCT recipients is estimated at 6%, with a mortality rate of 13%, and Aspergillus species are the most common pathogens involved. Posaconazole is effective in preventing IFIs post-transplant and is standard care during neutropenia or when managing graft-versus-host disease (GvHD) with high-dose steroids. However, azole prophylaxis may cause resistant Aspergillus species like A. calidoustus, which are difficult to treat. We report a case from our institution where a patient developed a dual infection with Aspergillus calidoustus and Talaromyces columbinus after alloHSCT and posaconazole prophylaxis. While A. calidoustus is known to cause IFIs in HSCT recipients, T. columbinus represents a previously unreported occurrence in medical literature. This case underscores the importance of a multifaceted diagnostic strategy, integrating BAL diagnosis, mycological cultures, direct microscopy, fungal speciation, susceptibility testing, and biomarkers. These comprehensive approaches are indispensable for accurate pathogen identification and effective management of IFIs with appropriate antifungal agents., (© 2024. The Author(s).)

Purpose: To report a case of infectious necrotizing scleritis secondary to Aspergillus terreus after intravitreal injection therapy., Methods: This is a case report with literature review., Results: A 98-year-old woman receiving intravitreal aflibercept injections for neovascular age-related macular degeneration in the left eye presented with severe pain, redness, and purulent discharge at the injection site. She was initially treated with topical fortified antibiotics, and clinical improvement was achieved, although microbial cultures showed negative results. Two months later, she presented with severe ocular pain and was diagnosed with anterior necrotizing scleritis. Scleral scrapings were collected for cultures, and intensive topical antibiotic therapy was reintroduced. Evaluation for autoimmune etiology and microbiological testing showed negative results. Because of the progression of the scleral necrotic area, empirical therapy with topical voriconazole was initiated, and surgical debridement was performed. Finally, the culture was positive for A. terreus. The modified therapy consisted of topical voriconazole and oral voriconazole for 3 months with an excellent clinical outcome., Conclusions: To our knowledge, this is the first case of fungal necrotizing scleritis secondary to intravitreal injection. Diagnosis was delayed due to its chronic clinical course and the slow fungal growth in culture media, but the combined medical and surgical approach resulted in a satisfactory outcome., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Fluconazole is one of the most commonly used drugs for antifungal prophylaxis in childhood leukaemia. However, its interaction with vincristine may induce neuropathy and the emergence of antifungal drug resistance contributes to substantial mortality caused by invasive fungal infections (IFIs). In a retrospective single-centre study, we compared tolerability and outcome of different antifungal prophylaxis strategies in 198 children with acute leukaemia (median age 5·3 years). Until 2010, antifungal prophylaxis with fluconazole was offered to most of the patients and thereafter was replaced by liposomal amphotericin-B (L-AMB) and restricted to high-risk patients only. Vincristine-induced neurotoxicity was significantly reduced under L-AMB, as the percentage of patients with severe constipation decreased (15·4% vs. 3·7%, before vs. after 31 December·2010, P = 0·01) and stool frequency increased by up to 38% in polyene-treated patients (P = 0·005). Before 2011, 10 patients developed confirmed IFIs, most of them were infected with Aspergillus species. After risk adaption in 2011, IFIs were completely prevented (P = 0·007). L-AMB prophylaxis is beneficial in childhood leukaemia patients, as it offers effective antifungal activity with improved tolerability as compared to fluconazole. The potential impact of our risk-adapted antifungal treatment should be included in current prophylaxis guidelines for childhood leukaemia., (© 2020 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

In cystic fibrosis (CF) patients, fungal colonization of the respiratory tract is frequently found. Aspergillus fumigatus is the most frequently recorded and is associated with loss of pulmonary function and allergic disease (ABPA). The knowledge on prevalence rates of filamentous fungi in CF patients in Latin America is scarce. One hundred and seventy-six fungal isolates recovered from the upper respiratory tract of CF patients from Argentina were identified to species by morphology and DNA sequencing. In total, 90% of CF patients were colonized by Aspergillus sp., followed by Exophiala sp. (14%) and Scedosporium sp. (10%). Among Aspergillus, six species complexes (Fumigati, Flavi, Terrei, Nigri, Usti, and Nidulante) and different cryptospecies were found. Among Scedosporium, three species were observed (Scedosporium apiospermum, Scedosporium aurantiacum and Scedosporium boydii). All Exophiala isolates were identified as Exophiala dermatitidis. Rare filamentous fungi were also found. All cases of ABPA were associated to the presence of A. fumigatus. Mixed colonization with other mould or rare fungi was observed in half of them. To our knowledge, this is the first prospective study of mould species in CF using molecular methods in Latin America. This study shows that Aspergillus sp., E. dermatitidis and Scedosporium sp. have a high frequency in CF patients from Argentina, and by far, A. fumigatus was the most commonly cultured species. Continuous clinical surveillance is required to detect the emergence of new fungal pathogens and to detect resistant or difficult-to-treat species capable of chronic colonizing the airways and of hematogenous dissemination in case of lung transplantation., (© The Author(s) 2020. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

The molecular epidemiology and antifungal susceptibility of Aspergillus nidulans species complex has not been well studied. To evaluate the genetic diversity and antifungal susceptibility patterns of clinical and environmental isolates of A. nidulans complex. Sixty clinical and environmental isolates of Aspergillus section Nidulantes were collected from five countries (Iran, The Netherlands, Spain, Portugal and Greece). The species were molecularly identified by sequencing of β-tubulin gene. The genetic diversity of A nidulans complex isolates (n = 54) was determined with a microsatellite genotyping assay. Antifungal susceptibility profile was determined using EUCAST method. The isolates were classified as A nidulans (46.7%), A spinulosporus (26.6%), A quadrilineatus (10%), A pachycristatus (3.3%), A rugulosus (3.3%), A unguis (5%), A creber, (1.7%), A olivicola (1.7%) and A sydowii (1.7%). Thirty-four sequence types (STs) were identified among the 54 A nidulans complex isolates. A high level of genetic diversity was found among A nidulans sensu stricto strains but low diversity was found among A spinulosporus strains. Amphotericin B showed high MICs to all species. The most active azole was posaconazole (GM = 0.64 mg/L), while itraconazole showed the highest MICs among azoles (GM = 2.95 mg/L). A spinulosporus showed higher MICs than A nidulans sensu stricto for all antifungals except for micafungin and anidulafungin. Interspecies variations may result in differences in antifungal susceptibility patterns and challenge antifungal therapy in infections caused by A nidulans. Differences in the distribution of STs or persistence of multiple STs might be related to the sources of isolation and niche specialisation., (© 2019 Blackwell Verlag GmbH.)

Background: Liver transplant recipients are at high risk of developing invasive aspergillosis and in particular by Aspergillus fumigatus which is the most commonly encountered species in this population. Other non-fumigatus Aspergillus species with reduced susceptibility to antifungal drugs can also be involved. Accurate identification associated to antifungal susceptibility testing is essential for therapy adjustment. We report a case of invasive pulmonary aspergillosis due to Aspergillus pseudodeflectus in a liver transplant recipient. To our knowledge, this is the first reported case of invasive aspergillosis due to this species with a reduced susceptibility to azoles., Case Presentation: A 64 year-old woman with drug-induced fulminant hepatitis underwent liver transplantation. Prophylactic treatment with caspofungin was introduced due to aspergillosis risk factors consisting in hemodialysis and fulminant hepatitis. Six weeks after transplantation, CT scan showed a right pulmonary opacity associated with an increase of galactomannan (index 5.4). Culture of BAL grew with several colonies of Aspergillus sp. The diagnosis of invasive aspergillosis was probable according to the EORTC criteria. The antifungal susceptibility tests (Etest®) revealed low MICs to echinocandins and amphotericin B) but high MICs to azoles. After these results, voriconazole was switched to liposomal amphotericin B. The patient died one month after diagnosis from a refractory septic shock with multiple organ failure. A molecular identification of isolate, based on partial β-tubulin and calmodulin genes, was performed and identified A. pseudodeflectus., Conclusions: Our case raises the question of pathogenicity of this species, which belongs to Aspergillus section Usti and is genetically and morphologically very close to Aspergillus calidoustus that was previously reported in human transplant recipients.

Aspergillus calidoustus, previously classified as Aspergillus ustus, is an emerging pathogen in immunocompromised persons. We describe four recent cases of A. calidoustus and review 37 additional cases of A. calidoustus (n = 8) or A. ustus (n = 29) published through June 2016. Twenty (49%) cases occurred in patients with hematologic malignancy and/or receipt of hematopoietic cell transplantation, and 13 (32%) occurred in solid organ transplant recipients. Antifungal susceptibility was reported in 49% of cases and in 42% treatment failed. Overall mortality was 66% and, where reported, attributable mortality was 30%. A. calidoustus infection is associated with a high mortality rate and frequently displays in vitro antifungal resistance., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Delayed diagnosis in invasive aspergillosis (IA) contributes to its high mortality. Gliotoxin (GT) and bis-methyl-gliotoxin (bmGT) are secondary metabolites produced by Aspergillus during invasive, hyphal growth and may prove diagnostically useful. Because IA pathophysiology and GT's role in virulence vary depending on the underlying host immune status, we hypothesized that GT and bmGT production in vivo may differ in three mouse models of IA that mimic human disease. We defined temporal kinetics of GT and bmGT in serum, bronchoalveolar lavage fluid (BALF) and lungs of A. fumigatus-infected chronic granulomatous disease (CGD), hydrocortisone-treated, and neutropenic mice. We harvested lungs for assessment of fungal burden, histology and GT/bmGT biosynthetic genes' mRNA induction. GT levels were higher in neutropenic versus CGD or steroid-treated lungs. bmGT was persistently detected only in CGD lungs. GT, but not bmGT, was detected in 71% of sera and 50% of BALF of neutropenic mice; neither was detected in serum/BALF of CGD or steroid-treated mice. Enrichment of GT in Aspergillus-infected neutropenic lung correlated with fungal burden and hyphal length but not induction of GT biosynthetic genes. In summary, GT is detectable in mouse lungs, serum and BALF during neutropenic IA, suggesting that GT may be useful to diagnose IA in neutropenic patients.

Patients with prior invasive fungal infection (IFI) increasingly proceed to allogeneic hematopoietic cell transplantation (HSCT). However, little is known about the impact of prior IFI on survival. Patients with pre-transplant IFI (cases; n=825) were compared with controls (n=10247). A subset analysis assessed outcomes in leukemia patients pre- and post 2001. Cases were older with lower performance status (KPS), more advanced disease, higher likelihood of AML and having received cord blood, reduced intensity conditioning, mold-active fungal prophylaxis and more recently transplanted. Aspergillus spp. and Candida spp. were the most commonly identified pathogens. 68% of patients had primarily pulmonary involvement. Univariate and multivariable analysis demonstrated inferior PFS and overall survival (OS) for cases. At 2 years, cases had higher mortality and shorter PFS with significant increases in non-relapse mortality (NRM) but no difference in relapse. One year probability of post-HSCT IFI was 24% (cases) and 17% (control, P<0.001). The predominant cause of death was underlying malignancy; infectious death was higher in cases (13% vs 9%). In the subset analysis, patients transplanted before 2001 had increased NRM with inferior OS and PFS compared with later cases. Pre-transplant IFI is associated with lower PFS and OS after allogeneic HSCT but significant survivorship was observed. Consequently, pre-transplant IFI should not be a contraindication to allogeneic HSCT in otherwise suitable candidates. Documented pre-transplant IFI is associated with lower PFS and OS after allogeneic HSCT. However, mortality post transplant is more influenced by advanced disease status than previous IFI. Pre-transplant IFI does not appear to be a contraindication to allogeneic HSCT.

Background: Colonization by Aspergillus fumigatus in patients with cystic fibrosis (CF) can cause A fumigatus sensitization and/or allergic bronchopulmonary aspergillosis (ABPA), which affects pulmonary function and clinical outcomes. Recent studies show that specific allergens upregulate the surface-expressed basophil marker CD203c in sensitized subjects, a response that can be readily measured by using flow cytometry., Objective: We sought to identify A fumigatus sensitization in patients with CF by using the basophil activation test (BAT)., Methods: Patients with CF attending Beaumont Hospital were screened for study inclusion. BAT was used to identify A fumigatus sensitization. Serologic (total and A fumigatus-specific IgE), pulmonary function, and body mass index measurements were performed., Results: The BAT discriminates A fumigatus-sensitized from nonsensitized patients with CF. Persistent isolation of A fumigatus in sputum is a significant risk factor for A fumigatus sensitization. Levels of the A fumigatus-stimulated basophil activation marker CD203c inversely correlated with pulmonary function and body mass index in A fumigatus-sensitized but not nonsensitized patients with CF. Total and A fumigatus-specific IgE, but not IgG, levels are increased in A fumigatus-sensitized patients with CF and ABPA when compared with those in A fumigatus-sensitized and nonsensitized patients with CF without ABPA. Itraconazole treatment did not affect A fumigatus sensitization., Conclusion: Combining the BAT with routine serologic testing allows classification of patients with CF into 3 groups: nonsensitized, A fumigatus-sensitized, and ABPA. Accurate and prompt identification of A fumigatus-associated clinical status might allow early and targeted therapeutic intervention, potentially improving clinical outcomes., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Aspergillus thyroiditis (AT) has historically been considered a postmortem diagnosis in immunocompromised patients; most have disseminated disease. This report summarizes the clinical challenge of diagnosing AT. It also highlights the value of the early use of thyroid fine-needle aspiration culture and the need for a high index of suspicion to reach the final diagnosis before disease dissemination., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: After hematopoietic stem cell transplantation, invasive aspergillosis remains one of the most lethal infections. Susceptibility may be due to prophylaxis and treatment of graft-vs.-host disease in T-cell-replete transplants, and delayed immune rebuilding due to T-cell depletion in haploidentical transplantation., Methods: We monitored CD4(+) T-cell recovery and anti-Aspergillus immune competence in pediatric recipients of T-cell-replete matched transplants and of prevalently adult recipients of T-cell-depleted matched or haploidentical transplants for hematological malignancies., Results: Although CD4(+) T-cell counts were higher in T-cell-replete transplant recipients at all post-transplant time points, Aspergillus-specific T cells were first detected 15-18 months after T-cell-replete matched, 7-9 months after T-cell-depleted matched, and 9-12 months after haploidentical transplantation, respectively. Incidence of invasive aspergillosis was 22% with 10% mortality after T-cell-replete transplants, 0% after T-cell-depleted matched, and 7% with 4% mortality after haploidentical transplants., Conclusions: Although T-cell counts were significantly higher after T-cell-replete transplants, post-transplant immune suppression/GvHD appeared to impair their function. Specific Aspergillus immune competence recovered faster after T-cell-depleted transplants, whether matched or haploidentical. T-cell-replete transplants were associated with a higher incidence of invasive aspergillosis and Aspergillus-related deaths. These results showed that T-cell depletion without post-transplant immunosuppression is associated to a faster immune recovery than T-cell-replete transplantation., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: With the increasing use of cardiac implantable electronic devices (CIED), there has been an associated increase in rate of complications. Infection accounts for about 1% of these, of which only a handful were reported secondary to Aspergillus fumigatus. All of these were seen in chronically-ill patients with several co-morbid conditions within a few years of implantation. None have been reported in an otherwise immunocompetent patient at 7 years after CIED implantation., Case Report: A 67-year-old woman with symptomatic sick sinus syndrome required a pacemaker 15 years ago with subsequent revision 7 years prior due to battery depletion. She now presented with a left pectoral non-tender mass that developed over several weeks. She denied history of recent fever, trauma, or infection. An elective pacemaker revision and pocket exploration led to the drainage of 150 cc of serosanguineous discharge from the pocket. She received peri-procedural prophylaxis with Vancomycin, but later, wound cultures grew Aspergillus fumigatus. She underwent complete removal of the pacemaker system along with a 6-week course of voriconazole and is doing well., Conclusions: Even though Staphylococcus aureus causes most CIED infections, there should be a suspicion for fungal organisms, especially in culture-negative infections, in immunocompromised states like diabetes mellitus or with minimal improvement on antibiotics. If not treated appropriately, aspergillosis may have catastrophic outcomes, including endocarditis, often leading to death. Appropriate treatment should include immediate initiation of antifungals and removal of the CIED. It is still unclear why an immunocompetent patient developed aspergillosis, but appropriate management helped avoid a grave outcome.

Introduction: Toll-like receptors (TLRs) detect invading pathogens through several pattern-recognition mechanisms and play a central role in the regulation of the immune system. In allogeneic hematopoietic stem cell transplantation (HSCT), the frequent opportunistic fungal infections remain an important cause of mortality and morbidity in these highly immunocompromised patients., Methods: We analyzed 154 patients after allogeneic HSCT for acute leukemia for TLR4 gene variants 1063A/G (D299G) and 1363C/T (T399I) with their respective donors, and correlated the results with the incidence of invasive aspergillosis (IA) infection after transplant., Results: Probable and proven IA in recipients was significantly increased if either recipients or donors exhibited one of the two TLR4 gene variants. In addition, recipients with TLR gene variants and IA showed a delayed T cell and NKT cell immune reconstitution after transplant. Increased susceptibility for IA was not associated with an increased rate of death-in-remission or decreased estimate for overall survival., Conclusion: These findings reinforce the importance of genetic variants in innate immunity and IA among the recipients of allogeneic HSCT., (© 2013 John Wiley & Sons A/S.)

Background: The clinical characteristics of patients with Aspergillus isolation while supported on extracorporeal membrane oxygenator (ECMO) remain unclear., Objectives: We present a case report of angioinvasive Aspergillus infection on an infant supported on ECMO and also investigate outcomes among patients with Aspergillus infection reported to the Extracorporeal Life Support Organization (ELSO) registry., Design: Case report and retrospective analysis of ELSO registry data set from 1985 to 2009., Setting: One hundred and seventy ECMO centers contributing data to the ELSO registry., Patients: Single case report and patients 0 to 90 years of age with Aspergillus infection requiring ECMO support as reported to the ELSO registry., Methods: Besides presenting details of our institutional case, we compared clinical characteristics and outcomes between pediatric and adult patients with Aspergillus isolation. Risk factors for in-hospital mortality were investigated. Kaplan-Meier estimates for freedom from death on ECMO for pediatric and adult patients were investigated., Measurements and Main Results: (a) we report a case with Aspergillus supported on ECMO, (b) the ELSO registry yielded 46 patients with 59% (n = 27) in the pediatric data set (≤20 years of age) and 41% (n = 19) in the adult data set (>20 years of age) with Aspergillus infection requiring ECMO support. Overall survival to hospital discharge was 30% (14/46) with 22% (6/27) in children as compared to 42% (8/18) in adults (P = .19). Table 1 shows a comparison of clinical characteristics between children and adults. The comparison between adults and pediatric groups differed significantly in age (P = .0001), more use of venoarterial ECMO in children (P = .028). The median age of pediatric group was 1.95 years (range 0-17.3 years) versus 30.2 years (range 22-60 years) among adults., Conclusions: Aspergillus infection/colonization is associated with a 70% overall mortality among patients supported on ECMO. The ELSO registry data confirms that Aspergillus infection among ECMO supported patients occurs often in hosts who do not have known immunodeficiencies. The case stresses the need for a high level of suspicion for Aspergillus infection in nonimproving lung disease in patients on ECMO support.

Invasive aspergillosis (IA) is a leading complication of intensive treatment for haematological malignancies. Earlier diagnosis should facilitate effective antifungal therapy and prevent progression to invasive disease, which is often lethal. Polymerase chain reaction (PCR) assays, targeting the 28S and ITS ribosomal gene regions respectively, were evaluated for early detection of Aspergillus DNA and for diagnostic utility in patients receiving treatment in two busy haematopoietic stem cell transplant centres. Patients undergoing intensive chemotherapy, autologous or allogeneic transplant were eligible for inclusion in the study. EDTA blood and serum samples for circulating Aspergillus biomarkers, including galactomannan (GM), were collected twice-weekly on a prospective basis from all study patients who were categorized according to international consensus criteria for defining invasive fungal disease (IFD). Of 278 patients recruited there were 44 probable IA cases and only one proven case. Moderate sensitivity and specificity, poor positive predictive value (50-80%), but good negative predictive value (>80-90%) were common to both PCR assays. Overall biomarker performance could be improved by combining positive results of either PCR assay with GM taken within a 12-d period. The addition of PCR to GM monitoring in high-risk patients with haematological malignancies provides greater diagnostic accuracy in invasive aspergillosis., (© 2013 John Wiley & Sons Ltd.)

We report a case of two consecutive episodes of invasive aspergillosis caused by cryptic Aspergillus species in a patient with leukaemia. A first episode of pulmonary infection was caused by Aspergillus calidoustus and Aspergillus novofumigatus, and the second episode by A. novofumigatus and Aspergillus viridinutans. Fungal isolates were identified to species level using traditional and sequencing-based molecular methods.

An Aspergillus fungal ball is a rare cause of ureteral obstruction attributed to indwelling catheters, stents, antibiotics, anastomotic leaks, obstruction, and immunosuppressive therapy and other immunocompromised states. We describe a case of unilateral ureteral obstruction caused by Aspergillus terreus following ureteroscopic lithotripsy and ureteral stenting in a 45-year-old diabetic man. The patient was successfully treated with endoscopic removal of the fungal mass and oral voriconazole. We also review briefly the clinical features, treatment, and outcome in 9 previously reported diabetic patients with ureteral obstruction due to aspergillosis. Obstructive uropathy related to Aspergillus mass may be suspected in diabetic patients with a history of manipulation, impaired kidney function, and persistent passage of a soft mass in urine. Direct microscopy and culture of multiple urine and ureteral washing are necessary for early diagnosis. Antifungal therapy and endoscopic removal of the mass are needed to reduce morbidity.

Ceramic workers are at a high risk of developing respiratory problems as they are exposed to high levels of respirable dust containing silica and high microbial counts, including high Aspergillus counts. The aim of the study was to study the percentage of ceramic workers with positive Aspergillus (A.) through polymerase chain reaction (PCR) and specific IgE (sIgE) for the different Aspergillus species. PCR and specific IgE (sIgE) for the different Aspergillus species (A. flavus, A. fumigatus and A. niger) were estimated in 40 ceramic workers and 56 control subjects. Results revealed that 32.5% of the workers' sputum was PCR positive for Aspergillus. About 69.2% of them were A. flavus positive, 15.4% A. niger positive, 7.7% A. fumigatus positive and 7.7% A. flavus and A. fumigatus positive. The percentage change in sIgE for A. fumigatus between the workers and their controls was over 100%, while less than 50% for the other two species. The sIgE levels for the three Aspergillus species were not significantly correlated with the duration of exposure. Fungal exposure could be considered potential hazardous problem in ceramic industry. There were no significant correlations between the duration of exposure and the sIgE for the different Aspergillus species.

Background: Voriconazole treatment increases early survival of allogeneic hematopoietic stem cell transplant recipients with invasive aspergillosis. We investigated whether this survival advantage translates into an increased long-term survival., Design and Methods: This retrospective study involved all patients with an invasive aspergillosis diagnosis transplanted between September 1997 and December 2008, at the Saint-Louis Hospital, Paris, France. The primary end point was survival up to 36 months. Survival analysis before and after 12 weeks, as well as cumulative incidence analysis in a competing risk framework, were used to assess the effect of voriconazole treatment and other factors on mortality., Results: Among 87 patients, 42 received first-line voriconazole and 45 received another antifungal agent. Median survival time was 2.6 months and survival rate at 36 months was 18%. Overall, there was a significant difference in the survival rates of the two groups. Specifically, there was a dramatic difference in survival rates up to ten months post-aspergillosis diagnosis but no significant difference after this time. Over the first 36 months as a whole, no significant difference in survival rate was observed between the two groups. First-line voriconazole significantly reduced aspergillosis-attributable mortality. However, first-line voriconazole patients experienced a significantly higher probability of death from a non-aspergillosis-attributable cause., Conclusions: Although the prognosis for invasive aspergillosis after stem cell transplantation has dramatically improved with the use of voriconazole, this major advance in care does not translate into increased long-term survival for these severely immunocompromised patients.

Background: Outbreaks of invasive aspergillosis (IA) are believed to be caused by airborne Aspergillus conidia. Few studies have established a correlation between high levels of Aspergillus fumigatus conidia and the appearance of new cases of IA or have demonstrated matching genotypes between clinical isolates and those from the environment., Methods: We detected an outbreak of IA (December 2006 through April 2008) in the major heart surgery intensive care unit (MHS-ICU) of our institution. Our local surveillance program consists of monthly environmental air sampling in operating rooms and ICUs for quantitative and qualitative identification of filamentous fungi. During the study period, we obtained 508 environmental samples from 3 different periods: 6 months before the outbreak, during it, and 6 months after it. Available environmental and clinical strains were genotyped according to the short tandem repeats assay., Results: Seven patients developed proven or probable IA (5 with lung infection, 1 with mediastinitis, and 1 with lung infection and mediastinitis). A. fumigatus was involved in 6 cases. The underlying conditions of the patients were heart transplantation (n = 3), corticosteroid-dependent conditions (n = 2), and diabetes mellitus (n = 2). The mortality rate was 85.7%. Before and after the outbreak (±6 months), the median airborne A. fumigatus conidia levels were 0 colony-forming units (CFUs) per cubic meter, and no cases of IA occurred during these periods. However, during the outbreak period, the occurrence of the 6 cases of IA caused by A. fumigatus was linked to peaks of abnormally high A. fumigatus airborne conidia levels (175, 50, 25, 20, 160, and 400 CFUs/m(3)) in the MHS-ICU, whereas counts in the air of both operating rooms remained negative. Matches between A. fumigatus genotypes collected from the air of the MHS-ICU and from representative clinical samples were found in 3 of the 6 patients. The outbreak abated when high-efficiency particulate air filters were installed in the affected areas., Conclusions: Our study revealed that abnormally high levels of airborne A. fumigatus conidia correlated with new cases of IA, even in patients who were not severely immunocompromised. The demonstration of matches between air and clinical genotypes reinforces the role of environmental air in the acquisition of IA during the period following MHS. Environmental monitoring of Aspergillus spores in the air of postoperative units is mandatory, even when these units receive nonimmunocompromised patients undergoing major surgery.

Primary laryngeal aspergillosis is extremely rare, especially in an immunocompetent host. It is commonly found as part of a systemic infection involving the respiratory system in immunocompromised people. Two cases of laryngeal aspergillosis with no systemic extension and no generalized immune deficiency are presented here. We report what is to the best of our knowledge only the second case of Aspergillus infection in a vocal cord cyst. Aspergillus species were identified in tissue sections and confirmed by PCR studies. We present a literature review of laryngeal aspergillosis cases and discuss predisposing factors, clinical presentation, histopathology, PCR, diagnosis and treatment of Aspergillus laryngitis. The known aetiological causes of the disease are increasing and include iatrogenic factors, vocal abuse, vocal-fold cysts and occupational factors, and immunocompetent patients are susceptible to these predisposing factors.

Objectives: Invasive fungal infection (IFI) is a major cause of morbidity and mortality in severely immunocompromised patients and is difficult to diagnose. The significance of molecular methods for diagnosis of IFI is still controversial. In a subset of patients treated within the AmBiLoad Trial, samples were investigated prospectively by a nested Aspergillus PCR assay to re-evaluate the significance of PCR in this setting., Patients and Methods: In the randomized, prospective multicenter AmBiLoad trial, patients with proven or probable IFI were randomized to receive liposomal amphotericin B (L-AMB) 3 or 10 mg/kg QD for 14 d followed by L-AMB 3 mg/kg QD. From 91 patients, 459 serial samples (98% blood samples) were investigated by a nested PCR assay for Aspergillus DNA. All samples were investigated in our laboratory with a previously described nested and a quantitative PCR assay. As required by the study protocol, serial Aspergillus antigen galactomannan was performed. IFI was defined according to modified EORTC/MSG 2002 criteria as applied in the AmBiLoad trial., Results: Seven and 52 patients had proven and probable IFI according to modified EORTC/MSG criteria, respectively. The median number of samples investigated per patient was 4. Seventy percent of samples were obtained during treatment with antifungal study medication. Forty-three samples gave positive PCR results. Patients with an unfavorable outcome had a significantly higher rate of positive PCR results (48% versus 21%)., Conclusions: The sensitivity of Aspergillus PCR testing is limited during antifungal therapy. The tendency for persistently positive PCR results to indicate a poor prognosis has to be confirmed in further studies.

Objectives: To analyse the predominant radiological pattern of pulmonary lesions in adult hematologic patients at risk for invasive aspergillosis (IA) together with the results of serial serum Aspergillus galactomannan antigen testing (GM)., Material and Methods: In a prospective study for patients at high risk of aspergillus pulmonary infection, serum GM were performed 2-3 times per week during the periods of high risk for IA and high-resolution CT (HRCT) was performed in case of abnormal chest X-ray (CXR) and/or persistent fever after 5 days of antibiotic treatment. Changes on HRCT scan were classified as airway IA and angioinvasive IA. IA was classified as proven or probable in accordance with the definitions stated by the European Organization for Research and Treatment of Cancer/Mycosis Study Group (EORTC-MS). Positive GM testing was not considered as microbiological criterion., Results: 38 hematological patients were diagnosed of probable (n=28) or proven (n=10) IA. 55% patients had a neutrophil count less than 500 mm(-3) (n=21), and 37% patients > or =2 risk factors for IA. All probable IA were diagnosed by bronchoalveolar lavage (BAL). Proven IA was reached by positive histopathologic and culture results of samples obtained by autopsy (n=4), percutaneous (n=3) or transbronchial biopsy (n=3). 18 patients had airway IA, and 60% had a GM level > or =1.5. 20 patients were diagnosed of angioinvasive IA from which 80% had a GM level > or =1.5., Conclusion: Serum GM levels may be lower in patients with airway IA than in those with an angioinvasive form. HRCT and serum GM are complementary tests in the diagnosis of IA.

Background: Aspergillus galactomannan (GM) antigenemia is an early marker of invasive aspergillosis (IA), but may yield false-positive results. A prospective study, testing GM periodically in serum samples of liver transplant recipients, was performed., Methods: An index more than or equal to 0.5 were considered positive. Positive GM in samples from patients without any other criteria of proven or probable IA was considered as false-positive. The test was performed weekly during the first month after transplantation., Results: Three patients developed IA. In total, 414 serum samples from 85 liver transplant recipients were analyzed. Mean number of samples per patient (out of those who could be assessed) was 4.8. The number of false-positive GM samples was 40 (9.6%), corresponding to 28 patients. The frequency of false-positive results in samples obtained during the first week posttransplantation was 36% (27 of 75), significantly higher than the number of false-positive samples obtained after the first week (3.8%; 13 of 339; P<0.001). Multivariate analysis showed that antibacterial prophylaxis with ampicillin was the only independent factor associated with a false-positive result. Different vials of beta-lactam antibiotics were tested for GM. We obtained a positive GM value (>0.5) in four of the six vials of ampicillin, in three of the six vials of piperacillin-tazobactam, in none of the six vials of cefotaxime, and in none of the six controls., Conclusions: The present study suggests that the administration of ampicillin as antibacterial prophylaxis during the first days after transplantation could be a possible cause of false-positive GM results.

Aspergillus lentulus was first described in the year 2005, and since it cannot be phenotypically distinguished from Aspergillus fumigatus, it is conceivable that earlier descriptions (before 2005) could be attributed to this new species. Currently invasive infections caused by A. lentulus are rare and very few cases have been previously published in neutropenic patients, all of them with fatal outcome. Here we report a critically ill non neutropenic patient with chronic obstructive pulmonary disease (COPD) who was admitted to the medical intensive care unit with an exacerbation of COPD and who had been treated with long term corticosteroids. A. fumigatus was cultured from two bronchial aspirates and in a third bronchial aspirate both A. lentulus and A. fumigatus were isolated. On two consecutive days detection of galactomannan in serum was negative whilst detection of (1-3) beta-D glucan was positive (> 518 pg/ml). Minimal inhibitory concentrations (MIC) for itraconazole, voriconazole, caspofungin and amphotericin B were high for this strain of A. lentulus. Given the high MIC values of A. lentulus to available antifungals, the accurate identification of this new species is warranted. To our knowledge, this is the first report of the isolation of A. lentulus in a non-neutropenic critically ill patient, although we note that since it was isolated only once from respiratory specimens, its implication as an etiologic agent of infection for this patient remains to be established.

Invasive aspergillosis (IA) is a life-threatening complication of liver transplantation. Detection of circulating galactomannan (GM) in serum samples is a method to improve the microbiological diagnosis in patients at risk for IA. However, the assay is hampered by false-positive results. The search for circulating Aspergillus DNA in the first GM-positive sample could improve the specificity of the test. Among 484 liver transplant recipients followed in a single center over 4 years, 25 patients had at least 1 GM-positive serum sample. The threshold of GM positivity was a ratio >or=1. These 25 patients were classified by the clinicians as probable IA (n=11), possible IA (n=2), and no IA (n=12) using the EORTC/MSG criteria with blinding to the polymerase chain reaction (PCR) results. After 1 mL aliquots of the first GM-positive serum sample were thawed, 2 independent DNA extractions were performed using the MagNA Pure Compact apparatus. Real-time amplification targeted at Aspergillus fumigatus mitochondrial DNA was performed on 10 microL of the final eluate in duplicate in the 2 independent DNA extractions using a LightCycler instrument. A sample was considered positive when the crossing point was

Objectives: Although Aspergillus galactomannan (GM) antigen detection is widely applied in the diagnosis of invasive aspergillosis (IA), false-positive reactions with fungus-derived antibiotics, other fungal genera or the passage of dietary GM through injured mucosa are a matter of concern. The aim of this study was to investigate the cumulative incidence and risk factors for false-positive GM antigenaemia., Patients and Methods: The records of 157 adult allogeneic haematopoietic stem cell transplantation (HSCT) recipients were retrospectively analysed. Episodes of positive GM antigenaemia, defined as two consecutive GM results with an optical density index above 0.6, were classified into true, false and inconclusive GM antigenaemia by reviewing the clinical course., Results: Twenty-five patients developed proven or probable IA with a 1 year cumulative incidence of 12.9%, whereas 50 experienced positive GM antigenaemia with an incidence of 32.2%. Among the total 58 positive episodes of the 50 patients, 29 were considered false-positive. The positive predictive value (PPV) was lower during the first 100 days than beyond 100 days after HSCT (37.5% versus 58.8%). Gastrointestinal chronic graft-versus-host disease (GVHD) was identified as the only independent significant factor for the increased incidence of false-positive GM antigenaemia (PPV 0% versus 66.7%, P = 0.02)., Conclusions: GM antigen results must be considered cautiously in conjunction with other diagnostic procedures including computed tomography scans, especially during the first 100 days after HSCT and in patients with gastrointestinal chronic GVHD.

Returning to work after transplantation is a much-discussed topic today, especially as a measure to avoid permanent work disability. Many transplant patients regain their ability to work 2-6 months after transplantation. However, returning to work should not endanger their health. This means that occupational risks such as occupational exposure to Aspergillus spores must be evaluated. We evaluated the community-acquired aspergillosis risk and in particularly the occupational aspergillosis risk, using the example of a 39-year-old construction worker immunosuppressed after renal transplantation. On one hand the risk is linked to the exposure to microorganisms that the individual is likely to be subjected to, and on the other hand to the factors that modify his state of susceptibility or resistance to these infectious agents. The necessity of immunosuppressive therapy after transplantation elevates the aspergillosis risk, especially 1-6 months after transplantation. There are many professions in which exposure to Aspergillus spores can occur. The risk of acquiring aspergillosis at work exists, but is not quantifiable today. Nevertheless, the risk should be minimized during the period of vulnerability by preventive measures such as restriction of certain activities, changing work methods and reorganizing the work day to adapt to the risk, and wearing personal protective equipment, as well as attention to information about aspergillosis risk and about the likelihood of exposure in the patient's professional and leisure activities.

Background: Here we describe the characterization of a protracted Aspergillus versicolor endophthalmitis caused by a corneal microperforation., History and Signs: A 58-year-old patient noticed blurred vision two weeks after he was hit in the eye by an old cable in a dilapidated house. A traumatic cataract and an intraocular inflammation were diagnosed and treated elsewhere with phacoemulsification and anti-inflammatory drugs. Vitreous samples were sterile. Despite topical steroids visual acuity continued to decrease and the patient presented in Lausanne 6 months later with a visual acuity of counting fingers, major inflammation of the anterior segment and a small corneal scar. Fundus examination revealed massive vitreous inflammation with a voluminous whitish chorioretinal infiltrate temporally., Therapy and Outcome: Vitrectomy with dissection of a protuberant epiretinal filamentous tissue in the temporal fundus was performed, and Amikacine, Vancomycine and Amphothericine were injected intravitreally. Bacteriological work-up revealed Aspergillus versicolor. Visual acuity improved to 0.2 with topical steroids and oral antifungal drugs., Conclusions: Corneal microperforations may cause a protracted endophthalmitis due to Aspergillus versicolor, a rare fungus, which is commonly found in insulation materials and cables in dilapidated houses.

The characteristics of cases diagnosed as aspergillosis and Aspergillus spp. strains isolated from the respiratory tract samples in Mycology Laboratory of Trakya University Hospital between January 2002 and May 2006 were investigated. In this period, 137 bronchoalveolar lavages, 95 sputum, nine tracheal aspirates, three lung biopsies and one bronchial biopsy of 85 patients were processed. The samples were incubated in 25 degrees C and 35 degrees C media by culturing on brain heart infusion agar with blood and Sabouraud dextrose agar. Presence of leucocytes and fungal structures were searched in the smear stained by Gram and Giemsa. The patient was defined as probable aspergillosis case, if he/she patient had clinical findings, lung infiltration or fungus ball radiologically, at least one risk factor predisposing to aspergillosis and isolation of Aspergillus spp. in lower respiratory tract samples without finding of other nonmycotic infection. Of 22 patients isolated Aspergillus spp., 13, six, two, one were internalized in chest diseases, haemotology, neurosurgery and oncology clinics, respectively. Seven positive cultures were considered as findings of aspergillosis. Aspergillus fumigatus, Aspergillus flavus and Aspergillus niger were isolated in three, two, and two patients, respectively. Fungal structures were detected in only one sample in the direct microscopical examination. Ages of seven patients, five were males and two were females, were between 15 and 60. Predisposing risk factors were acute leukemia in six patients and lung cancer in one patient. Five patients were neutropenic and one was neutrophylic. Fungus ball was detected in radiological imaging of one patient, had a pulmonary cavitary lesion. Conventional amphotericine B was used in their therapies. Antifungal agents were switched to caspofungin and itraconazole in two and one patients, respectively. Three patients died in four weeks after isolation of Aspergillus spp. Aspergillosis cases were not high in our hospital because of absence of transplantation center for bone marrow or solid organ.

An outbreak of Aspergillus fumigatus meningitis occurred in 5 women following spinal anaesthesia, performed between 21 June and 17 July 2005 for caesarean section, in Colombo, Sri Lanka. The patients' median age was 27 years. Different teams in 2 maternity hospitals gave spinal anaesthesia. Mean incubation period was 11.2 days. Fever, headache and nuchal rigidity were common presentations. Remittent fever continued despite broad-spectrum intravenous antibiotics. Papilloedema, lateral rectus palsy, cerebral infarction and haemorrhage developed later. Three patients died. Cerebrospinal fluid pleocytosis with low glucose yielded negative PCR for fungi. Fungal cultures subsequently grew Aspergillus fumigatus. A post-mortem of the first patient confirmed Aspergillus meningitis, followed by treatment with amphotericin B and voriconazole, that saved the lives of others. Visual and hearing impairment in one and complete recovery in the other were observed a year after treatment. Examination of unused plastic syringes, needles, cannulae, and ampoules of anaesthetic agents confirmed that 43 syringes from three different manufactures were contaminated with Aspergillus fumigatus. The stores for drugs and devices of the Ministry of Health were examined and found to be full of tsunami donations, while regular procurements of the Ministry were kept in a poorly maintained humid warehouse. Inadequate space for tsunami donations was identified as the most plausible explanation for sub-optimal storage. Withdrawal and incineration of all unused syringes controlled the outbreak. The survival of those aggressively treated for Aspergillus meningitis suggests in hindsight that the availability of diagnostic tests and specific treatment, and early recognition of the outbreak could have saved the lives of victims who died. Early life-threatening side-effects and permanent long term sequelae of antifungal medication stress the need to be cautious with empirical treatment in immuno-competent low-risk individuals.

While invasive aspergillosis occurs typically in severely immunocompromised patients, cases of surgical site infection have been reported in immunocompetent individuals. The Medline, LILACS and EMBASE databases were searched for descriptions of cases of post-operative aspergillosis, and references from relevant articles and conference abstracts were reviewed. More than 500 cases of post-operative aspergillosis were found. Cardiac surgery (n = 188), ophthalmological surgery (n > 90) and dental surgery (n > 100) were associated with the majority of cases. Other cases involved wound infections (n = 22), bronchial infections (n = 30), mediastinitis (n = 11), pleural aspergillosis (n = 1), infections following orthopaedic surgery (n = 42), vascular prosthetic surgery (n = 22), breast surgery (n = 5), abdominal surgery (n = 10) and neurosurgery (n = 25). In most patients, the source was presumed to be airborne infection during the surgical procedure. Prevention of these infections requires special care of the ventilation system in the operating room. Successful treatment requires rapid diagnosis, surgical debridement and antifungal therapy, often with voriconazole. In order to improve the outcome, better diagnostic methods are needed, particularly for cases of endocarditis and aortitis.

Purpose: To report a series of patients with early onset Aspergillus endophthalmitis following cataract surgery., Design: Retrospective consecutive case series., Methods: Medical records were reviewed of all cases of endophthalmitis caused by Aspergillus after cataract surgery treated at the authors' practices between 1992 and 2005., Results: Five patients were identified. Two patients were immunocompromised (one on oral corticosteroids and one on chemotherapy for lung cancer). The mean number of days between cataract surgery and diagnosis with endophthalmitis was 29 (range, 10 to 62 days). Three eyes (60%) were enucleated despite a variety of treatments. In addition to vitrectomy and injection of antifungal agents, the other two eyes underwent surgical debridement of a localized necrotic nidus. Final visual acuity was 20/30 in one eye and 20/200 in the remaining eye., Conclusions: Aspergillus should be considered in the differential diagnosis of early onset endophthalmitis following cataract surgery. Visual outcomes are generally poor and enucleation is common in these patients.

We report a case of a 28-year-old recipient of a cadaveric renal transplant who developed Aspergillus infection in the allograft without having disseminated disease. We review the previously reported cases of isolated Aspergillus in kidney transplant recipients and discuss the possible route of transmission in our patient. We also discuss the alternate but successful treatment that our patient received.

Aspergillus ustus is a mold that rarely infects humans; only 15 systemic cases have been reported. We report the first outbreak of invasive infection caused by A. ustus among hematopoietic stem cell transplant (HSCT) recipients. Six patients with infections were identified; 3 infections each occurred in both 2001 and 2003. Molecular typing by using randomly amplified polymorphic DNA (RAPD) and antifungal drug susceptibility testing were performed on clinical and environmental isolates recovered from our hospital from 1999 to 2003. The highest overall attack rate in HSCT patients was 1.6%. The overall death rate was 50%, and death occurred within 8 days after diagnostic culture collection. Clinical isolates exhibited decreased susceptibility to antifungal drugs, especially azoles. RAPD and phylogenetic analysis showed genetic similarity between isolates from different patients. Based on the clustering of cases in space and time and molecular data, common-source acquisition of this unusual drug-resistant species is possible.

Pseudomembranous and obstructive Aspergillus tracheobronchitis (PMATB/OATB) are still considered to be refractory to therapy and to have a fatal outcome. To evaluate the optimal diagnostic strategy and to describe factors affecting the outcome of PMATB and OATB. Retrospective analysis of four new cases of PMATB and OATB combined with 16 previously reported cases over a 10-year period (1995-2004). Among the four new cases reported and the 16 published cases, four patients survived their infection. The mortality rate was significantly higher in the group of ventilated patients [94% (15 of 16 patients)] than in the group of non-ventilated patients [25% (1 of 4 patients), P < 0.05, Fisher's exact test]. In all 20 patients, diagnosis was established by bronchoscopy. Culture examination of mucous plugs was positive in 8 of 10, culture of the tracheobronchial aspirate was positive in 8 of 12, and bronchoalveolar lavage was diagnostic in 7 of 13 patients. All bronchoscopic techniques were complementary in improving the yield of bronchoscopy. However, microscopy of mucous plugs and/or necrotic material was the best diagnostic modality [positive in 94% (17 of 18 patients)]. Prognosis of PMATB and OATB remains poor. Microscopy of respiratory specimens is the most sensitive tool to confirm the diagnosis. The characteristic appearance of the disease makes it possible to start antifungal therapy immediately.

Aspergillus infections are increasing in frequency in those undergoing solid organ and hematopoietic stem cell transplantation. The ongoing impact of Aspergillus infection on morbidity and mortality after transplantation makes this subject an area of intense clinical and research interest. This article discusses the evolving epidemiologic features of the infection and its management and diagnosis.

Study Objectives: As the failure of amphotericin B therapy in patients with invasive aspergillosis often exceeds 50%, we sought to determine the relationship between in vitro amphotericin B resistance and clinical failure of amphotericin B against invasive aspergillosis., Design: Retrospective study., Setting: University cancer center., Patients: One hundred sixteen patients with cancer and invasive aspergillosis., Measurements and Main Results: The correlation between in vitro amphotericin B susceptibility, defined by both the National Committee for Clinical Laboratory Standards and Etest methods, and other prognostic factors with failure of initial amphotericin B therapy was retrospectively evaluated. Data for correlation could be clearly assessed in only 18 (16%) of the 116 patients. Admission to the intensive care unit was the only prognostic factor associated with failure of initial amphotericin B treatment in these 18 patients (p = 0.01)., Conclusions: Several important obstacles underlie the correlation of in vitro susceptibility testing with in vivo efficacy of individual antifungal agents in the treatment of invasive aspergillosis. Such correlations could be determined in only a small subset of patients.