Risk Of Invasive Pulmonary Aspergillosis Research Articles

Influenza-associated invasive aspergillosis in patients admitted to the intensive care unit in Sweden: a prospective multicentre cohort study

Background The purpose of this study was to prospectively investigate the incidence of influenza-associated pulmonary aspergillosis (IAPA) in influenza patients admitted to intensive care units in Sweden. Methods The study included consecutive adult patients with PCR-verified influenza A or B in 12 Swedish intensive care units (ICUs) over four influenza seasons (2019-2023). Patients were screened using serum galactomannan and β-d-glucan tests and fungal culture of a respiratory sample at inclusion and weekly during the ICU stay. Bronchoalveolar lavage was performed if clinically feasible. IAPA was classified according to recently proposed case definitions. Results The cohort included 55 patients; 42% were female, and the median age was 59 (IQR 48-71) years. All patients had at least one galactomannan test, β-d-glucan test and respiratory culture performed. Bronchoalveolar lavage was performed in 24 (44%) of the patients. Five (9%, 95% CI 3.8% − 20.4%) patients were classified as probable IAPA, of which four lacked classical risk factors. The overall ICU mortality was significantly higher among IAPA patients than non-IAPA patients (60% vs 8%, p = 0.01). Conclusions The study represents the first prospective investigation of IAPA incidence. The 9% incidence of IAPA confirms the increased risk of invasive pulmonary aspergillosis among influenza patients admitted to the ICU. Therefore, it appears reasonable to implement a screening protocol for the early diagnosis and treatment of IAPA in influenza patients receiving intensive care. Trial registration ClinicalTrials.gov NCT04172610, registered November 21, 2019

Effect of Aspergillus fumigatus on infection in immunosuppressed rats.

Immunosuppression is believed to increase the risk of invasive pulmonary aspergillosis (IPA), but information on the mechanism is limited. Therefore, we analyze the effect and mechanism of the pathogenesis and disease progression of IPA in a combined immunosuppressed rat model. The immunosuppressed rat model was established by intraperitoneal injection of cyclophosphamide (CTX) and dexamethasone (DXM). IPA was established by nasal inoculation of Aspergillus fumigatus spore suspension. Pathological sections and tissue homogenate culture were used to evaluate the lung tissue. Routine blood and inflammatory indexes were dynamically observed. The expressions of NLRP3/caspase-1/GSDMD protein and gene were determined using western blot and quantitative polymerase chain reaction (q-PCR) respectively. T-test or one-way repeated measures analysis were used to do statistical analysis on the groups. Following intraperitoneal of CTX and DXM injections, the rats showed depression, weight loss, and significant decreases in the numbers of leukocytes and classified cells. Pathological sections revealed more severe lung lesions in the immunosuppressed rats infected with Aspergillus fumigatus. The expression of NLRP3/caspase-1/GSDMD protein increased significantly in both the aspergillosis and immunosuppressed plus aspergillosis groups. The pathological development of IPA in the immunosuppressed rats had the most serious effects, and the findings strongly implicated NLRP3/caspase-1/GSDMD pathway involvement.

293. Risk factors for COVID-19 associated pulmonary aspergillosis (CAPA) in severe COVID-19 and impact of airborne fungal contamination within negative pressure isolation room

Abstract Background COVID-19 increase the risk of invasive pulmonary aspergillosis. However, the risk factors and fungal origin of COVID-19 associated pulmonary aspergillosis (CAPA) is not fully defined yet. We aim to identify the risk factors for CAPA in severe COVID-19 and evaluate association between fungal contamination within the air of negative pressure rooms and diagnosis of CAPAs. Methods We performed a retrospective case-control study to identify risk factors for CAPA with 420 severe COVID-19 patients from March 2020 to January 2022 who admitted to a tertiary care hospital in South Korea. CAPA was defined with modified AspICU criteria. Control, matched by admission date and severity of COVID-19 at admission, was selected for each case. Air sampling and fungal culture was done on Jan 2022 with a microbial air sampler (MAS-100NT) at 11 spaces in the COVID-19 designated isolation ward including 9 negative pressure isolation rooms (IRs). A cross-sectional comparison between rooms with and without airborne fungal contamination was performed. Results A total of 420 COVID-19 patients were hospitalized during the study period, and 51 patients were diagnosed with CAPA (prevalence 12.14%, incidence 6.26 per 1000 patient•day). Multivariate analysis showed that older age (odds ratio [OR] 1.051, 95% confidence intervals [CI] 1.006-1.009, p=0.025), mechanical ventilator use (OR 2.692, 95% CI 1.049-6.911, p=0.04), and lymphopenia (OR 4.353, 95% CI 1.727-10.975, p=0.02) were independent risk factors for CAPA. (Table 1, 2) Aspergillus spp. was identified within the air from 7 out of 11 spaces including 6 IRs and 1 doctors’ room. (Figure 1). All 6 IRs with positive aspergillus culture were being occupied by patients at least 8 days. Among 6 patients, 3 had already been diagnosed with CAPA whereas the other 3 were not diagnosed with CAPA through the observation period. Among 4 patients in isolation rooms without airborne aspergillus contamination, one patient had been diagnosed as CAPA before air sampling. (Table 3). Conclusion Association between CAPA and airborne aspergillus contamination within the negative pressure room could not be demonstrated in this study. Rather than environmental factors, patient factors such as older age, ventilator care, and lymphopenia were found to be associated with CAPA diagnosis. Disclosures All Authors: No reported disclosures.

Genetic determinants of fungi-induced ROS production are associated with the risk of invasive pulmonary aspergillosis

Reactive oxygen species (ROS) are an essential component of the host defense against fungal infections. However, little is known about how common genetic variation affects ROS-mediated antifungal host defense. In the present study, we investigated the genetic factors that regulate ROS production capacity in response to the two human fungal pathogens: Candida albicans and Aspergillus fumigatus. We investigated fungal-stimulated ROS production by immune cells isolated from a population-based cohort of approximately 200 healthy individuals (200FG cohort), and mapped ROS-quantitative trait loci (QTLs). We identified several genetic loci that regulate ROS levels (P < 9.99 × 10−6), with some of these loci being pathogen-specific, and others shared between the two fungi. These ROS-QTLs were investigated for their influence on the risk of invasive pulmonary aspergillosis (IPA) in a disease relevant context. We stratified hematopoietic stem-cell transplant (HSCT) recipients based on the donor's SNP genotype and tested their impact on the risk of IPA. We identified rs4685368 as a ROS-QTL locus that was significantly associated with an increased risk of IPA after controlling for patient age and sex, hematological malignancy, type of transplantation, conditioning regimen, acute graft-versus-host-disease grades III-IV, and antifungal prophylaxis. Collectively, this data provides evidence that common genetic variation can influence ROS production capacity, and, importantly, the risk of developing IPA among HSCT recipients. This evidence warrants further research for patient stratification based on the genetic profiling that would allow the identifications of patients at high-risk for an invasive fungal infection, and who would benefit the most from a preventive strategy.

COVID-19 COMPLICATED BY THE INVASION OF ASPERGILLUS TERREUS

TOPIC: Chest Infections TYPE: Medical Student/Resident Case Reports INTRODUCTION: Coronavirus associated pulmonary aspergillosis (CAPA) appears to be emerging on a global scale. Studies have consistently indicated that CAPA is associated with significantly higher mortality rates, when compared to patients with COVID-19 alone [1]. Unfortunately, definitive guidelines regarding the surveillance, diagnosis, & treatment of CAPA are currently lacking. CASE PRESENTATION: A 59 year old male with hypertension & diabetes presented with dyspnea & cough. On arrival, he was initially afebrile, though hypoxic & tachycardic. He tested positive for COVID-19 & influenza B on admission. Dexamethasone & remdesivir were initiated, along with oseltamivir & empiric antibiotics. CT of the chest was notable for bilateral ground glass opacities. On hospital day 11, he developed respiratory failure on BiPAP therapy, prompting intubation & ICU transfer. He subsequently succumbed to septic shock requiring hemodynamic support. Given concern for bacterial superinfection, antibiotic therapies were escalated. Despite the initial defervescence, he continued to have persistent febrile recrudescence. Blood & sputum cultures remained negative. He ultimately required tracheostomy and PEG tube placement. On day 38, his lower respiratory culture revealed growth of Aspergillus terreus. Voriconazole was initiated. On day 43, his fever returned again. Repeat CT of the chest revealed progressive fibrosis, with a cavitation in the right lower lung. He remained ventilator dependent, given his persistently high FiO2 requirements. On day 52, he became markedly hypoxemic with copious mucoid secretions, prompting emergent bronchoscopy. Despite clearance, he eventually became bradycardic & developed PEA arrest. The patient ultimately expired. DISCUSSION: CAPA remains a diagnostic challenge, fraught by logistical burdens & a variety of crudely defined criteria. Cases may currently be underreported, undertreated, or clinically overlooked. Obscure species such as A. terreus are of particular concern, given the proposed lethality of this strain & it's widely reported resistance to amphotericin B [3]. Unfortunately, guidelines for the surveillance of superinfections are currently insufficient. This is troublesome, considering the well documented risk of invasive pulmonary aspergillosis with the use of immunosuppressive agents, such as tocilizumab & corticosteroids [2]. Co-infection with influenza may augment this risk further. CONCLUSIONS: CAPA presents clinicians with a multitude of clinical uncertainties, which necessitate further analysis & investigation. Given the heightened risk of mortality, we propose a lower threshold for the suspicion, diagnosis & treatment of CAPA in patients with refractory respiratory distress, and/or febrile recrudescence despite the appropriate therapies. Surveillance should be particularly stringent, in those treated with immunosuppressive agents, or concomitantly diagnosed with influenza. REFERENCE #1: Apostolopoulou A, Esquer Garrigos Z, et al. Invasive Pulmonary Aspergillosis in Patients with SARS-CoV-2 Infection: A Systematic Review of the Literature. Diagnostics. 2020;10(10):807. REFERENCE #2: Koehler, P., Bassetti, M, et al. Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance. The Lancet. Infectious diseases. 2020, Dec 20 REFERENCE #3: Steinbach, W, Benjamin, D, et al. Infections Due to Aspergillus terreus: A Multicenter Retrospective Analysis of 83 Cases, Clinical Infectious Diseases, Volume 39, Issue 2, 15 July 2004, Pages 192–198 DISCLOSURES: No relevant relationships by Huda Asif, source=Web Response No relevant relationships by Sunil Bali, source=Web Response No relevant relationships by Christopher Siriphand, source=Web Response No relevant relationships by Christopher Wood, source=Web Response

Diagnosis values of IL-6 and IL-8 levels in serum and bronchoalveolar lavage fluid for invasive pulmonary aspergillosis in chronic obstructive pulmonary disease

Among immunologically normal hosts, patients with chronic obstructive pulmonary disease (COPD) are considered to be at high risk of invasive pulmonary aspergillosis (IPA), and early diagnosis and treatment are the...

Preliminary Attempt to Predict Risk of Invasive Pulmonary Aspergillosis in Patients with Influenza: Decision Trees May Help?

Invasive pulmonary aspergillosis (IPA) is typically considered a disease of immunocompromised patients, but, recently, many cases have been reported in patients without typical risk factors. The aim of our study is to develop a risk predictive model for IPA through machine learning techniques (decision trees) in patients with influenza. We conducted a retrospective observational study analyzing data regarding patients diagnosed with influenza hospitalized at the University Hospital “Umberto I” of Rome during the 2018-2019 season. We collected five IPA cases out of 77 influenza patients. Although the small sample size is a limit, the most vulnerable patients among the influenza-infected population seem to be those with evidence of lymphocytopenia and those that received corticosteroid therapy.

Evaluation of targeted versus universal prophylaxis for the prevention of invasive fungal infections following lung transplantation.

Antifungal prophylaxis to prevent invasive fungal infections (IFI) is widely used following lung transplantation, but the optimal strategy remains unclear. We compared universal with targeted antifungal prophylaxis for effectiveness in preventing IFI. Adult patients who underwent lung transplantation at the University of Michigan from /1 July 2014-31 December 2017 were studied for 18months post-transplant. Universal prophylaxis consisted of itraconazole with or without inhaled liposomal amphotericin B. Using specific criteria, targeted prophylaxis was given with voriconazole for patients at risk for invasive pulmonary aspergillosis (IPA) and with fluconazole or micafungin for patients at risk for invasive candidiasis. Risk factors, occurrence of proven/probable IFI, and mortality were analyzed for the two prophylaxis cohorts. Of 105 lung transplant recipients, 84 (80%) received a double lung transplant, and 38 (36%) of patients underwent transplant for pulmonary fibrosis. Fifty-nine (56%) patients received universal antifungal prophylaxis, and 46 (44%), targeted antifungal prophylaxis. Among 20 proven/probable IFI, there were 14 IPA, 4 invasive candidiasis, 1 cryptococcosis, and 1 deep sternal mold infection. Six (10%) IFI occurred in the universal prophylaxis cohort and 14 (30%) in the targeted prophylaxis cohort. Five of 6 (83%) IFI in the universal prophylaxis cohort, compared with 9/14 (64%) in the targeted prophylaxis cohort, were IPA Candida infections occurred only in the targeted prophylaxis cohort. The development of IFI was more likely in the targeted prophylaxis cohort than the universal prophylaxis cohort, HR=4.32 (1.51-12.38), P=.0064. Universal antifungal prophylaxis appears to be more effective than targeted antifungal prophylaxis for prevention of IFI after lung transplant.

Pentraxin-3 Polymorphisms are Associated with Invasive Pulmonary Aspergillosis after Lung Transplantation

Purpose Pentraxin-3 (PTX3) polymorphisms influence the risk of invasive pulmonary aspergillosis (IPA) in chronic obstructive pulmonary disease patients, hematopoietic stem cell recipients and solid organs recipients. Therefore, we aimed to investigate this association in a large lung transplant population. Methods Patients who underwent lung transplantation (LTx) between 01/01/2011 and 31/12/2015 in the University Hospitals Leuven were included (n=292). Recipient DNA was successfully extracted from peripheral blood (n=268, 91.8%) or explanted lung tissue (n=24, 8.2%) and successfully genotyped for rs2120243 (n=229, 85.4%), rs2305619 (n=244, 91.0%) and rs3816527 (n=255, 95.1%) polymorphisms using TaqMan® OpenArray® genotyping plates. Cumulative IPA frequency, diagnosed according to ISHLT and EORTC/MSG guidelines, and CLAD-free survival were assessed for each polymorphism. Results Median time of follow-up was 3.3 (1.9-4.5) years; 23% of patients (n=68) developed chronic lung allograft dysfunction (CLAD) after a median time of 2.3 (1.0-3.6) years. Cumulative IPA frequency was significantly higher in rs2120243 AC and AA haplotypes compared to the CC haplotype (15.5% vs 4.5% after 1 year and 28.0% vs 14.9% after 5 years, p=0.024). Cumulative IPA frequency was significantly higher in rs2305619 AG and AA haplotypes compared to the GG haplotype (15.3% vs 4.8% after 1 year and 28.3% vs 12.0% after 5 years, p= 0.032). Cumulative IPA frequency was significantly higher in rs3816527 AC and CC haplotypes compared to the AA haplotype (16.3% vs 3.6% after 1 year and 30.9% vs 10.3% after 5 years, p=0.0028) (figure). There was no difference in CLAD-free survival (p=0.53, p=0.50, p=0.50) between different PTX3 genotypes. Conclusion PTX3 polymorphisms are associated with an increased risk for IPA after LTx.

Invasive fungal infections associated with prior respiratory viral infections in immunocompromised hosts.

Increased risk of invasive pulmonary aspergillosis after influenza infection has been reported; however data are limited. To describe Invasive fungal infections (IFI) associated with preceding respiratory viral infection at a large referral center. We reviewed all IFI cases among patients with positive influenza and/or RSV nasopharyngeal/lower respiratory tract PCR from October 2015 to December 2016. Cases of pulmonary IFI were classified as possible, probable, and definite based on EORTC-MSG definitions. We identified 8 cases (4 influenza, 4 RSV); 3 with probable Aspergillosis, 1 possible Aspergillosis, 1 probable Histoplasmosis, 1 probable Mucormycosis, and 2 possible IFI (consistent clinical and imaging findings). Half of our patients were men with a mean age of 64 years (SD 8) and median Charlson Comorbidity Score of 3.5 (IQR 3-7). Most common risk factors were stem cell transplant (75%) and neutropenia (62.5%). Four patients were on antifungal prophylaxis at presentation. All patients received anti-viral therapy with oseltamivir/ribavirin and 50% received empiric antibiotics. Median duration from onset of viral infection to diagnosis of IFI was 8.5 days (IQR 2.5-14) and 75% were diagnosed during the same admission. All received antifungal therapy; 62.5% required ICU care, and 37.5% died during index hospitalization. Our study supports earlier observations describing IFI following respiratory viral infection in immunocompromised hosts. Secondary IFI occurred in 1.4% of our cohort and most occurred during the index admission. IFI following viral illness is associated with high mortality and early detection and therapy may improve outcomes.

Pathogenesis of Invasive Pulmonary Aspergillosis in Transplant Recipients

Transplant patients are at high risk for invasive pulmonary aspergillosis, and the associated mortality is high. The purpose of this study is to review the pathogenesis of invasive pulmonary aspergillosis (IPA) in transplant patients. The pathogenesis of aspergillosis is multifactorial and results from a complex interplay between the pathogen and host. It is well recognized that Aspergillus causes IPA in immunocompromised patients. Recent studies have shown that Aspergillus might also cause diseases likely attributed to an unmodulated immune response in certain transplant recipients such as bronchopulmonary aspergillosis or bronchiolitis obliterans syndrome in lung transplant recipients. This review focuses on two crucial axes of the damage response framework applicable to aspergillosis: (1) Aspergillus virulence attributes that enable it to survive and proliferate in the host (thermotolerance, stress and hypoxic response, secretion of secondary metabolites) and (2) host response with specific focus on innate immunity and angiogenesis.

Evaluation of risk factors for invasive pulmonary aspergillosis and detection of diagnostic values of galactomannan and PCR methods in bronchoalveolar lavage samples from non-neutropenic intensive care unit patients

Non-neutropenic intensive care unit (ICU) patients are at particular risk for invasive pulmonary aspergillosis. In these cases, radiological and microbiological methods (direct microscopy, culture), which can be used for diagnosis, have quite low sensitivity and specificity. The aims of this study were to evaluate the risk factors for invasive pulmonary aspergillosis (IPA) in non-neutropenic ICU patients and to determine the diagnostic values of galactomannan (GM) antigen and Aspergillus nucleic acid detection methods. A total of 44 patients (13 female, 31 male; age range: 36-96 years) who had been followed at pulmonary ICU with invasive mechanical ventilation and undergone bronchoscopy between January to December 2013, were included in the study. Consecutive bronchoalveolar lavage (BAL) and serum samples were obtained from all of the patients. BAL samples were tested for the presence of Aspergillus DNA by polymerase chain reaction (PCR) and both serum and BAL samples were tested for GM antigen by EIA method (Platelia Aspergillus, BioRad, France). EORTC/MSG criteria were used for the case definition of IPA. Patients were classified as high-probable IPA, possible IPA and non-IPA. ROC (receiver operating characteristics) analysis was used to determine the diagnostic values of BAL Aspergillus PCR and BAL GM in the diagnosis of IPA. Five patients were defined as high-probable IPA and six were defined as possible IPA; thus the incidence rate of IPA was estimated as 11.4% (5/44) among non-neutropenic intensive care unit patients. In high-probable IPA patients, BAL GM levels were significantly higher than non-IPA patients (p< 0.05). The prolonged duration in ICU, presence of septic shock and the use of high cumulative doses (> 460 mg) of steroid were found to be risk factors for IPA development. The cut-off value for GM in BAL samples was determined as 0.7, with a sensitivity rate of 100% (95% confidence interval: 47.9-100) and a specificity rate of 87.9% (95% confidence interval: 71.7-96.5), so optimal GM level in BAL was considered as ≥ 0.7 for the diagnosis of IPA. The specificity rates of serum GM and BAL Aspergillus PCR methods were high (97.1% and 93.9%, respectively), however their sensitivity rates were found quite low (33.3% and 40%, respectively), in the diagnosis of IPA. In conclusion, development of IPA should be assessed in non-neutropenic patients when the stay in ICU extends and high dose cumulative steroids are used. GM antigen detection in BAL can be used effectively for diagnosis of IPA in these patients compared to other diagnostic methods.

Approach to invasive pulmonary aspergillosis in critically ill patients

Apparently immunocompetent critically ill patients represent an increasing population at risk for invasive pulmonary aspergillosis (IPA). The current review gives an update on the epidemiology, diagnosis, and management of IPA in the ICU. Patients without apparent severe immunosuppression (e.g. chronic obstructive pulmonary disease, decompensated liver disease, etc.) represent the majority of ICU IPA cases. IPA diagnosis is problematic and the true incidence of IPA is difficult to be estimated because of the nonspecific clinical presentation. A user-friendly clinical diagnostic algorithm for IPA is valuable, particularly through a high negative predictive value. IPA carries a poor prognosis and has an important impact on hospital costs. Timely diagnosis and prompt administration of appropriate treatment may improve the outcomes. Intravenous voriconazole is the recommended primary IPA treatment, but liposomal amphotericin B also has clinical utility. Voriconazole presents bioavailability and toxicity issues, and drug level monitoring is advocated. Caspofungin or antifungal combinations are recommended as salvage therapy. A high level of suspicion in critically ill patients presenting with Aspergillus-positive respiratory tract cultures or nonresolving pulmonary infection may lead to earlier IPA diagnosis. Dosage individualization may decrease treatment discontinuation and improve clinical efficacy.

CD8+ T-cell counts: an early predictor of risk and mortality in critically ill immunocompromised patients with invasive pulmonary aspergillosis

IntroductionCritically ill immunocompromised (CIIC) patients with pulmonary infection are a population at high risk for invasive pulmonary aspergillosis (IPA). The host defenses are important factors to consider in determining the risk and outcome of infection. Quantification of changes in the status of host immunity could be valuable for clinical diagnosis and outcome prediction.MethodsWe evaluated the quantitative changes in key humoral and cellular parameters in CIIC patients with pulmonary infection and their potential influence on the risk and prognosis of IPA. We monitored the evolution of these parameters in 150 CIIC patients with pulmonary infection on days 1, 3 and 10 (D1, D3 and D10) following ICU admission. The primary outcome was 28-day mortality. Follow-up included 60- and 90-day mortality.ResultsAmong the 150 CIIC patients included in this study, 62 (41.3%) had microbiological evidence of IPA. Compared with patients without IPA, CD3+, CD8+, CD28+CD4+ and CD28+CD8+ CD28+CD8+ T-cell counts (D1, D3 and D10) and B-cell counts (D1 and D3) were significantly reduced in patients with IPA (P < 0.05). Multivariate regression analysis revealed that CD8+ (D3 and D10) (odds ratio (OR) 0.34, 95% confidence interval (CI) 0.23 to 0.46; OR 0.68, 95% CI 0.56 to 0.80), CD28+CD8+ (D3) (OR 0.73, 95% CI 0.61 to 0.86) and CD3+ (D10) (OR 0.81, 95% CI 0.63 to 0.98) T-cell counts were independent predictors of IPA in CIIC patients. Receiver operating characteristic analysis of immune parameters predicting 28-day mortality revealed area under the curve values of 0.82 (95% CI 0.71 to 0.92), 0.94 (95% CI 0.87 to 0.99), and 0.94 (95% CI 0.85 to 0.99) for CD8+ T-cell counts (D1, D3 and D10, respectively) and 0.84 (95% CI 0.75 to 0.94), 0.92 (95% CI 0.85 to 0.99) and 0.90 (95% CI 0.79 to 0.99) for CD28+CD8+ T-cell counts (D1, D3 and D10, respectively). Kaplan-Meier survival analysis provided evidence that CD8+ and CD28+CD8+ T-cell counts (<149.5 cells/mm3 and <75 cells/mm3, respectively) were associated with early mortality in CIIC patients with IPA (logrank test; P < 0.001).ConclusionsCD8+ and CD28+CD8+ T-cell counts were significantly lower in CIIC patients with IPA than in non-IPA patients. Lower CD8+ and CD28+CD8+ T-cell counts in CIIC patients with pulmonary infection were associated with higher risk and early mortality in IPA and may be valuable for clinical diagnosis and outcome prediction.

A Retrospective Study of the Risk Factors for Invasive Aspergillosis in Iran

Back ground: Invasive aspergillosis is a well-known complication in immunocompromised patients. Among fungal infections, Invasive Pulmonary Aspergillosis (IPA) is the first cause of death after transplantation, and remains a major complication in curses of leukemia treatment. Despite considerable progress in the management of infections, it remains an important cause of morbidity and mortality, mainly after transplantation. This study was conducted in order to determine the risk factors for Aspergillus infections. Patients and methods: During retrospective investigation of 24 patients with aspergillosis, significant risk factors for invasive aspergillosis have been identified. Diagnosis was confirmed by demonstration of fungi by direct examination of the clinical samples, histopathology and cultures. Results: All patients were immunocompromised or had one or more predisposing factors. Patients with solid organ transplantation, renal transplant recipients and patients with hematologic malignancy or chronic granulomatous disease were at the highest risk for Invasive Pulmonary Aspergillosis (IPA). Fever unresponsive to broad-spectrum antibiotics was the earliest and most common clinical sign in this study. Conclusion: The major advances in the management of invasive fungal infections (IFI) have come from the noticing of the risk factors for the development of IFI, from the development of new biological markers of IFI, and also from well-designed therapeutic trails. However, much remains to be done to decrease the rate of mortality due to IFI in high risk patients. A high degree of knowledge and efforts for an early diagnosis may interfere to improve the poor prognosis.

Detection of galactomannan in bronchoalveolar lavage fluid samples of patients at risk for invasive pulmonary aspergillosis: analytical and clinical validity.

Invasive pulmonary aspergillosis (IPA) is frequent and often fatal in immunosuppressed patients. Timely diagnosis of IPA improves survival but is difficult to make. We examined the analytical and clinical validity of galactomannan (GM) testing of bronchoalveolar lavage (BAL) fluid in diagnosing IPA in a mixed population by retrospectively reviewing records of 251 consecutive at-risk patients for whom BAL fluid GM testing was ordered. The performance of the enzyme immunoassay was evaluated by using a range of index cutoffs to define positivity. Three samples were associated with proven IPA, 56 were associated with probable IPA, 63 were associated with possible invasive fungal disease (IFD), and 129 were associated with no IFD. Using a BAL fluid GM index of ≥0.8 (optimal optical density [OD] index cutoff identified by a receiver operating characteristic curve), the sensitivity in diagnosing proven and probable IPA was 86.4%, and the specificity was 90.7%. At this cutoff, positive and negative predictive values were 81% and 93.6%, respectively. However, an OD index value of ≥3.0 corresponded to a 100% specificity, thus ruling the disease in, irrespective of the pretest probability. Conversely, an OD index cutoff of <0.5 corresponded to a high sensitivity, virtually always ruling the disease out. For all values in between, the posttest probability of IPA depends largely on the prevalence of disease in the at-risk population and the likelihood ratio of the OD index value. Detection of GM in BAL fluid samples of patients at risk of IPA has an excellent diagnostic accuracy provided results are interpreted in parallel with clinico-radiological findings and pretest probabilities.

Role of galactomannan determinations in bronchoalveolar lavage fluid samples from critically ill patients with chronic obstructive pulmonary disease for the diagnosis of invasive pulmonary aspergillosis: a prospective study

IntroductionCritically ill chronic obstructive pulmonary disease (COPD) patients are at particular risk of invasive pulmonary aspergillosis (IPA). Our aims were to determine whether bronchoalveolar lavage fluid (BALF) galactomannan (GM) has a higher sensitivity and specificity than serum GM or lower respiratory tract (LRT) sample culture. Furthermore, we aimed to investigate what the optimal cut-off value would be for BALF GM.MethodsIn this prospective single-center study, BALF and serum samples were collected from critically ill COPD patients on the first day of their intensive care unit admission.ResultsOf 50 critically ill COPD patients admitted, BALF and serum samples were collected in 34 patients. According to the receiver operating characteristics (ROC) curve, an optical density (OD) ratio of 0.8 was chosen as the cut-off value for GM in BALF. Compared to serum GM and LRT Aspergillus isolation, BALF GM yield a better sensitivity, specificity, positive and negative predictive values of 88.9%, 100%, 100% and 94.4%, respectively. Areas under the ROC curve were 0.912 (95%CI, 0.733 to 0.985) for BALF GM, and 0.879 (95%CI, 0.691 to 0.972) for serum GM results from the first day of ICU admission. Pairwise comparison of ROC curves showed P = 0.738. The OD ratio of BALF GM in IPA patients were significantly higher than those of non-IPA patients (2.88 ± 2.09 versus 0.49 ± 0.19, P = 0.009), and the OD ratio of BALF GM was significantly higher than serum GM in IPA patients (2.88 ± 2.09 versus 0.87 ± 0.47, P = 0.023). Positive BALF GM was seen earlier than LRT secretion culture (1 day versus 3.8 days).ConclusionsCompared to serum GM and LRT Aspergillus isolation, BALF GM seems to have a better sensitivity in the diagnosis of IPA in critically ill COPD patients. The ROC curve suggests a possible cut-off value of 0.8 for GM from BALF specimens in critically ill COPD patients.

Clinical analysis of 8 cases with acute invasive pulmonary aspergillosis in younger children

To analyze the clinical features of acute invasive pulmonary aspergillosis in younger children, in order to improve the levels of early recognition, diagnosis and management of this disease. Clinical data of 8 patients aged below 15 months who were diagnosed as acute invasive pulmonary aspergillosis from August 2010 to February 2011 in general pediatric wards in our hospital were retrospectively analyzed for the high-risk factors of the hosts, clinical manifestations, laboratory findings and lung CT imaging, the processes of diagnosis and treatment, and the outcomes. Five cases were tested for serum GM test absorbent index (GMI) ranged from 1.92 to 3.27; in 2 cases sputum culture was positive for Aspergillus fumigatus for twice, and 1 infant was serum GMI 2.85 and a sputum culture was positive for Aspergillus fumigatus positive, all these findings were accordant with the clinical diagnosis. Seven cases had a history of receiving intravenously broad-spectrum antibiotics or plus corticosteroids (6 hospitalized, 1 out-patient), and one was only 1 month old, whose parents had severe tinea pedis. 4 patients of high-fever type had sustained high temperature, severe changes of lungs without obvious respiratory symptoms and signs in early phase, and significant increase of the rod granulocyte rate (0.25 - 0.68), which was apparently discordant with the normal WBC count and high sensitivity C-reactive protein (hs-CRP) value. Another 4 cases of non-high-fever type were present with normal WBC count, hs-CRP value and the percentage of rod granulocyte. Among them, 3 infants had low-grade fever, with serious respiratory symptoms and signs and changes of lungs CT. Another 1-month-old case only showed lower vigor and response. Lung CT imaging often showed multiple irregular large nodules, patches and streaks of density (6 cases) and unilateral lobar consolidation (1 case), with some involving the pleura; one appeared severe peri-main bronchus lesions with stenoses of bilateral main bronchi. The first case died of multiple organ failure because of severe sepsis complication. Another 7 cases were treated with voriconazole promptly after clinical or suspected diagnosis, and the state of patients relieved rapidly within 1 - 3 d. The abuse of broad-spectrum antibiotics and corticosteroids may increase the risk of invasive pulmonary aspergillosis in younger children. There may be the risk of nosocomial infection and spread of aspergillus in general pediatric wards. Cases of high-fever type in early period of disease had two inconsistency: few symptoms and signs, while severe changes of lungs CT; apparent increase of peripheral rod granulocyte, while normal WBC count and hs-CRP value. Preemptive voriconazole therapy could obtain significant effect and reduce the mortality rate.

Value of consecutive galactomannan determinations for the diagnosis and prognosis of invasive pulmonary aspergillosis in critically ill chronic obstructive pulmonary disease

Critically ill chronic obstructive pulmonary disease (COPD) patients who are admitted to intensive care units (ICU) are at particular risk for invasive pulmonary aspergillosis (IPA). The objective of this investigation was to assess the value of consecutive galactomannan (GM) tests in determining the diagnosis and prognosis of IPA in this patient population. We studied 90 critically ill COPD patients admitted to our ICU between February 2007 and November 2009. Two consecutive serum GM tests were done on the first and fourth days of their ICU admissions. Patients were classified as proven IPA (n = 1), probable IPA (n = 18), or non-IPA (n = 71). The sensitivities, specificities, and positive and negative predictive values of GM test results for (i) the first test, (ii) the second test, (iii) at least one positive of two consecutive tests and (iv) two positive consecutive GM tests were, respectively, 57.9%/64.7%/70.6%/47.1%; 87.3%/84.6%/80.8%/94.2%; 55.0%/57.9%/54.5%/72.7%; and 88.6%/88.0%/89.4%/84.5%. The mortality values of IPA patients with (i) a positive first GM test, (ii) at least one of two tests positive, and (iii) both tests positive were (a) 81.8% (9/11), (b) 83.3% (10/12), and (c) 72.7% (8/11), respectively. These results indicate that at least one positive result of two consecutive GM tests appears to be useful in the diagnosis of IPA in critically ill COPD patients in an ICU. In addition, positive serum GM results combined with the isolation of Aspergillus from respiratory samples may be a potential marker of high mortality.

NAC is associated with additional alleviation of lung injury induced by invasive pulmonary aspergillosis in a neutropenic model.

Neutropenic individuals are at high risk for invasive pulmonary aspergillosis (IPA), a life-threatening infection. To evaluate the therapeutic potential of antioxidants, IPA was induced in neutropenic mice and the effect of N-acetyl-l-cysteine (NAC) on oxidative stress levels and lung injury was analyzed. Mice were pretreated with three daily intraperitoneal injections of 150 mg/kg cyclophosphamide, followed by intratracheal inoculation with 4.5x10(6) conidia of Aspergillus fumigatus. The infected mice were then randomly assigned to an amphotericin B (AMB) group, an AMB plus NAC group, or an untreated control (C) group. In each group, the duration of treatment was 24, 48, or 72 h, and activities such as appearance, feeding, and dermal temperature were observed throughout the experiment. Sera and lung tissues were collected and analyzed by quantitative enzyme-linked immunosorbent assay (ELISA) for total protein, superoxide dismutase (SOD), malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-alpha), and interleukin-10 (IL-10) levels. The wet/dry weight ratio of the lung was also calculated and lung sections were stained with hematoxylin-eosin for pathological examination and with methenamine silver stain for fungus detection. Compared with the mice untreated with NAC, mice in the AMB plus NAC group had increased SOD and reduced MDA levels both systemically and locally at 24, 48, and 72 h after inoculation with conidia. NAC treatment also decreased the pulmonary protein content at 48 and 72 h and the lung wet/dry weight ratio at 24 and 48 h. Additionally, NAC enhanced pulmonary production of TNF-alpha and IL-10 at 24 h and 48 h. In combination with antifungal therapy, NAC treatment can alleviate oxidative stress and lung injury associated with IPA in neutropenic mice.Acta Pharmacologica Sinica (2009) 30: 980-986; doi: 10.1038/aps.2009.83.