Proven Invasive Pulmonary Aspergillosis Research Articles

Clinical utility of Aspergillus galactomannan and PCR in bronchoalveolar lavage fluid for the diagnosis of invasive pulmonary aspergillosis in patients with haematological malignancies

Interpretation of Aspergillus galactomannan (GM) and PCR results in bronchoalveolar lavage (BAL) fluid for the diagnosis of invasive pulmonary aspergillosis (IPA) in patients with haematological malignancies requires clarification. A total of 116 patients underwent BAL for investigation of new lung infiltrates: 40% were neutropenic, 68% and 36% were receiving mould-active antifungal agents and β-lactam antibiotics. The diagnosis of proven IPA (n=3), probable IPA (n=15), and possible invasive fungal disease (IFD, n=50) was made without inclusion of GM results. BAL GM (at cut-off of 0.8) had lower diagnostic sensitivity for IPA than PCR (61% versus 78%) but higher specificity (93% versus 79%). Both tests had excellent negative predictive values (85–90%), supporting their utility in excluding IPA. The use of BAL GM and PCR results increased the certainty of Aspergillus aetiology in 7 probable IPA cases where fungal hyphae were detected in respiratory samples by microscopy, and upgraded 24 patients from possible IFD to probable IPA. Use of BAL GM and PCR improves the diagnosis of IPA.

Clinical findings in 19 cases of invasive pulmonary aspergillosis with liver cirrhosis

Background: Aspergillus infection was mostly reported with high mortality rates and a bad prognosis in immunocompromised patients, but data were lacking on the clinical characteristics of aspergillus infection in liver cirrhosis. The aim of this study was to retrospectively assess the morbidity and mortality rate, clinical manifestation, risk factors, and medication of invasive pulmonary aspergillosis (IPA) in liver cirrhosis in The First Affiliated Hospital, College of Medicine, Zhejiang University.
 Methods: Patients with liver cirrhosis who had been diagnosed with proven or probable IPA by clinical and laboratory parameters from 1st December 2008 to 1st May2012 were retrospectively evaluated for predisposing factors for IPA and clinical outcome. The follow up ended on 30th July2012. IPA was defined according to European Organization for Research and Treatment of Cancer/Mysoses Study group criteria.
 Results: In total, 6,600 patients with liver cirrhosis were enrolled, and 19 out of these developed IPA. Seventeen out of 19 patients died. Imaging findings such as the halo sign and lower respiratory tract infection symptoms contributed to the early diagnosis of IPA. Possible risk factors for IPA included a high Child-Turcotte-Pugh (CTP) score, broad antibiotic usage and steroid exposure. The use of antifungal compounds may prolong a patient’s life.
 Conclusions: The mortality of liver cirrhosis with IPA is high. Liver cirrhosis should be considered a risk factor of IPA. Once patients with high CTP scores and steroid and broad spectrum antibiotics exposure present cough and fever, IPA should be taken into consideration and antifungal agents should be used as soon as possible.

Clinical findings in 19 cases of invasive pulmonary aspergillosis with liver cirrhosis

BackgroundAspergillus infection was mostly reported with high mortality rates and a bad prognosis in immunocompromised patients, but data were lacking on the clinical characteristics of aspergillus infection in liver cirrhosis. The aim of this study was to retrospectively assess the morbidity and mortality rate, clinical manifestation, risk factors, and medication of invasive pulmonary aspergillosis (IPA) in liver cirrhosis in The First Affiliated Hospital, College of Medicine, Zhejiang University.MethodsPatients with liver cirrhosis who had been diagnosed with proven or probable IPA by clinical and laboratory parameters from 1st December 2008 to 1st May2012 were retrospectively evaluated for predisposing factors for IPA and clinical outcome. The follow up ended on 30th July2012. IPA was defined according to European Organization for Research and Treatment of Cancer/Mysoses Study group criteria.ResultsIn total, 6,600 patients with liver cirrhosis were enrolled, and 19 out of these developed IPA. Seventeen out of 19 patients died. Imaging findings such as the halo sign and lower respiratory tract infection symptoms contributed to the early diagnosis of IPA. Possible risk factors for IPA included a high Child-Turcotte-Pugh (CTP) score, broad antibiotic usage and steroid exposure. The use of antifungal compounds may prolong a patient’s life.ConclusionsThe mortality of liver cirrhosis with IPA is high. Liver cirrhosis should be considered a risk factor of IPA. Once patients with high CTP scores and steroid and broad spectrum antibiotics exposure present cough and fever, IPA should be taken into consideration and antifungal agents should be used as soon as possible.

Use of Mycological, nested PCR, and Real-time PCR Methods on BAL Fluids for Detection of Aspergillus fumigatus and A. flavus in Solid Organ Transplant Recipients

Invasive aspergillosis continues to be a significant cause of morbidity and mortality in solid organ transplant (SOT) recipients. A reliable and early diagnostic method is needed to improve survival. In this study, four methods direct microscopy, culture, nested PCR on internal transcribed spacer region, and TaqMan real-time PCR targeted β-tubulin gene were examined for the detection of Aspergillus fumigatus and A. flavus in sixty-four bronchoalveolar lavage (BAL) fluids that were obtained from SOT recipients. Direct examination with 20% KOH (potassium hydroxide) and culture on mycological media were also performed. Of the 64 samples, seven (10.9%) were positive in direct examination (five with septate hyphae and two with aseptate hyphae), and 15 (23%) had positive culture including five A. flavus, four A. niger, two Penicillium spp., two Rhizopus spp., one Fusarium spp. and one mixed A. flavus/A. niger. Twenty five (39%) samples had positive nested PCR with A. flavus and 6 (9.4%) with A. fumigatus-specific primers. Only eight (12.5%) had positive real-time PCR for A. flavus and nine (14%) for A. fumigatus. The incidence of aspergillosis in these patients included proven invasive pulmonary aspergillosis (IPA) in two (3%), probable IPA in 14 (22%), possible IPA in 38 (59%), and not IPA in 10 (16%). A. flavus was the most common cause of pulmonary aspergillosis (PA) in the study. The results suggest that because nested PCR is too sensitive it may increase the number of false-positive results and is not recommended for BAL samples for diagnosis of PA. Although further studies with significant number of proved positive/negative standard BAL samples are necessary for better evaluation, the novel multiplex real-time PCR developed in the study could be promising as a valid diagnostic method for IPA.

Aspergillus sp. isolated in critically ill patients with extracorporeal membrane oxygenation support

This study reports Aspergillus isolation in critically ill patients who underwent extracorporeal membrane oxygenation (ECMO) and highlights the difficulty in establishing a diagnosis of aspergillosis in this population. The diagnosis of Aspergillus infection or colonization was retrospectively performed using the proposed modified criteria of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group (EORTC/MSG) adapted to critically ill patients. Between 2005 and 2011, 11 of 151 patients (7.2%) who underwent ECMO had Aspergillus sp. isolates, 10 in a pulmonary sample and 1 in a mediastinal wound sample. Five patients did not have any classical risk factors for aspergillosis. One patient had a proven invasive pulmonary aspergillosis (IPA), 2 had a putative IPA, and 1 patient had a possible Aspergillus mediastinitis, whilst in 7 patients this was considered colonization. However, the clinical relevance of Aspergillus isolation was based on an algorithm not validated in patients undergoing ECMO. Our data support the need to implement non-invasive diagnostic procedures for aspergillosis in this population.

The initial CT findings in patients suffering from invasive pulmonary aspergillosis

To approach the initial CT findings of invasive pulmonary aspergillosis (IPA) in patients with immunosuppression. All consecutive adult patients who met the diagnostic criteria of the 2008 European Organization for Research and Treatment of Cancer/ Mycoses Study Group (EORTC/MSG) for proven or probable IPA were included as of January 2005 to June 2011. The patients were divided into two groups according to patients with or without hematological malignancy. The initial CT findings in our study were retrospectively reviewed by two thoracic radiologists, while patients' demographics and clinical outcomes were blinded. The pattern and number of abnormalities were recorded. A total of 65 IPA patients were eligible, with 34 hematological malignancy patients and 31 non-hematological patients. Among all IPA patients, the pattern of ground-glass opacity and consolidation or mass formation was most commonly seen (56.9%), followed by macronodules (46.2%); halo sign (32.3%) was relatively uncommon. Ground-glass opacity and consolidation or mass formation were more commonly identified in non-hematological patients than in hematological malignancy patients (54.8%, 45.2% vs. 8.8%, both P<0.05), but macronodules, infarct-shaped macronodules and halo signs were less frequently identified in the non-hematological group (16.1%, 3.2%, 12.9%, respectively) than in the hematological malignancy group (73.5%, 23.5% and 50.0%, respectively, P<0.05 or P<0.01). The airway-invasive form of IPA was more frequently seen in non-hematological patients (67.8%), whereas the angioinvasive form was more common in hematological malignancy patients (64.7%, P<0.01). Our data indicate that CT findings of IPA in non-hematological patients more commonly present as the airway-invasive form, manifesting ground-glass opacity and consolidation or mass formation, whereas in patients with hematological malignancy it more likely shows evidence of the angioinvasive form with macronodules and halo signs.

Invasive pulmonary aspergillosis in non‐neutropenic patients with and without underlying disease: A single‐centre retrospective analysis of 52 subjects

Invasive pulmonary aspergillosis (IPA) remains a life-threatening infection in patients with prolonged neutropenia. Few data are available on IPA in non-neutropenic patients without underlying immunocompromising conditions. All non-neutropenic patients managed at the institution for a proven and probable IPA over the last 10 years were reviewed retrospectively, and the difference between non-neutropenic patients with and without underlying disease was investigated. Among 52 cases of IPA analysed here, 33 were histologically proven; 19 were probable. Forty-two (80.8%) patients had underlying diseases; 10 (19.2%) patients had no any underlying diseases. There is a significant difference in seasonal distribution among patients with underlying conditions (P = 0.026), but no seasonal difference was found in the other group (P = 0.622). The only significant difference in symptoms between the two groups was fever (P = 0.015). Radiological findings were non-specific in the two groups. Despite treatment, the overall crude mortality rate among 52 patients was 39%. The overall mortality rate in patients with underlying disease was 45%, while that in patients without underlying conditions was 11%. A Cox multivariate analysis showed that organ failure (hazard ratios: 8.739, 95% CI: 3.770-20.255; P = 0.000) was independently associated with overall mortality. Clinical features of IPA are not well known in non-neutropenic patients, especially in those without underlying conditions. In this study, organ failure was associated with a lower rate of survival of non-neutropenic patients with IPA.

Invasive pulmonary aspergillosis in the ICU: reply to Wichmann et al.

Dear Editor, We thank Dr. Wichmann and colleagues for their interesting remarks and discussion on our study [1] and we aim to further clarify their concerns. Although the diagnosis of invasive pulmonary aspergillosis (IPA) was made before or on the day of ICU admission in three of the five proven IPA patients, IPA diagnosis was made a median of 2 days after H1N1 diagnosis, as stated in the ‘‘Results’’ section of the paper. In none of the nine IPA patients (5 proven, 4 probable) was the diagnosis of IPA established before the diagnosis of H1N1. Moreover, respiratory symptoms, myalgia and fever were present before formal H1N1 diagnosis based on the respiratory sample taken at hospital or ICU admission, suggesting a delay in H1N1 diagnosis. We do acknowledge that the retrospective character of the study does not allow one to confirm a causal relationship and our findings have to be confirmed in larger prospective studies. On the other hand, the incidence of IPA in solid organ transplant patients is known to be about 0.5 % for kidney and up to 12 % for lung transplants [2–4]. The higher incidence (23 %) found in our study again may suggest that IPA is probably a true H1N1related superinfection on top of the existing risk for fungal infection associated with a solid organ transplant. We appreciate Wichmann et al.’s concern that some of the probable IPA cases were merely colonization. The clinical condition of critically ill patients, however, often does not allow invasive diagnostic procedures. However, even if only taking into account the five proven IPA cases, H1N1-related IPA incidence still was much higher than the 1.6–1.8 % reported so far in current literature [5, 6].

Risk Factors for Invasive Pulmonary Aspergillosis and Hospital Mortality in Acute-On-Chronic Liver Failure Patients: A Retrospective-Cohort Study

Background: Invasive pulmonary aspergillosis (IPA) in acute-on-chronic liver failure (ACLF) patients is associated with a high mortality. But the clinical characteristics of and the risk factors for IPA among patients with ACLF remains unclear. This study was aimed at assessing clinical manifestation, the risk factors and antifungal medications for as well as the mortality due to IPA in ACLF patients at the First Affiliated Hospital, College of Medicine, Zhejiang University.Patients and Methods: Patients with ACLF who were diagnosed with proven or probable IPA by clinical and laboratory parameters from 1 December 2008 to 1 May 2012 were retrospectively evaluated to determine the risk factors for IPA and the clinical outcomes. The follow-up ended on 30 July 2012. Multivariate analysis was performed to identify the risk factors for mortality and the development of IPA.Results: In total, 787 patients with ACLF were enrolled, and 39 of these patients developed IPA. Thirty seven of these 39 patients died in spite of treatment with antifungal drugs. Controls included 48 patients who did not have a pulmonary infection. The survival rate of patients with IPA was significantly lower than that of those without IPA. IPA was found to be independently associated with age (p = 0.021), encephalopathy (p = 0.002), and steroid use (p = 0.000). There was significant difference in the prognosis between the patients treated with either voriconazole or itraconazole and those without antifungal treatment.Conclusions: Patients with ACLF and IPA have a high mortality rate. Patients with ACLF who present with encephalopathy should avoid steroids, as they increase the mortality rate. Azoles may prolong the survival time.

Diagnostic Accuracy of PCR Alone Compared to Galactomannan in Bronchoalveolar Lavage Fluid for Diagnosis of Invasive Pulmonary Aspergillosis: a Systematic Review

PCR in bronchoalveolar lavage (BAL) fluid has not been accepted as a diagnostic criterion for invasive pulmonary aspergillosis (IPA). We conducted a systematic review assessing the diagnostic accuracy of PCR in BAL fluid with a direct comparison versus galactomannan (GM) in BAL fluid. We included prospective and retrospective cohort and case-control studies. Studies were included if they used the EORTC/MSG consensus definition criteria of IPA and assessed ≥80% of patients at risk for IPA. Two reviewers abstracted data independently. Risk of bias was assessed using QUADAS-2. Summary sensitivity and specificity values were estimated using a bivariate model and reported with a 95% confidence interval (CI). Nineteen studies published between 1993 and 2012 were included. The summary sensitivity and specificity values (CIs) for diagnosis of proven or probable IPA were 90.2% (77.2 to 96.1%) and 96.4% (93.3 to 98.1%), respectively. In nine cohort studies strictly adherent to the 2002 or 2008 EORTC/MSG criteria for reference standard definitions, the summary sensitivity and specificity values (CIs) were 77.2% (62 to 87.6%) and 93.5% (90.6 to 95.6%), respectively. Antifungal treatment before bronchoscopy significantly reduced sensitivity. The diagnostic performance of PCR was similar to that of GM in BAL fluid using an optical density index cutoff of 0.5. If either PCR or GM in BAL fluid defined a positive result, the pooled sensitivity was higher than that of GM alone, with similar specificity. We conclude that the diagnostic performance of PCR in BAL fluid is good and comparable to that of GM in BAL fluid. Performing both tests results in optimal sensitivity with no loss of specificity. Results are dependent on the reference standard definitions.

Diagnosis of invasive pulmonary aspergillosis in children with bronchoalveolar lavage galactomannan

Invasive pulmonary aspergillosis (IPA) is a life-threatening complication in immunocompromised patients. Early diagnosis and therapy improves outcome. Assessment of galactomannan (GM) in bronchoalveolar lavage (BAL) fluid is a proposed tool to diagnose IPA. Little is known about the diagnostic value of BAL GM in children. Retrospectively, 72 bronchoscopies were analyzed for GM in patients fulfilling the host factor criteria as defined by the EORTC/MSG. A cut-off index value GM of ≥0.5 was used. Clinical data, results of chest CT-scans and BAL cultures were collected. Sensitivity, specificity, PPV, and NPV of BAL GM for a diagnosis of proven and probable IPA (n = 41) were 82.4%, 87.5%, 82.4%, and 87.5% respectively. A significant relation was found for BAL GM and abnormal chest CT (P = 0.01). No significant relationship was observed between BAL Aspergillus sp. culture and chest CT (n = 47). BAL GM and serum GM correlated significantly. In 9 out of 12 patients classified as possible IPA, antifungal therapy was continued or started, despite a negative BAL GM. BAL GM test had good diagnostic value in children suspected of IPA. However, the decision to continue or start antifungal therapy was mainly determined by the clinical suspicion of IPA based on chest CT-outcome, serum GM index values and failure of antibiotic therapy.

Concurrent lung infections in patients with hematological malignancies and invasive pulmonary aspergillosis: How firm is the Aspergillus diagnosis?

Immunocompromised patients with hematological malignancies and/or recipients of hematopoietic stem cell transplants are constantly exposed to several fungal, bacterial, and viral respiratory pathogens. We retrospectively evaluated all patients with invasive pulmonary aspergillosis (IPA) and underlying hematological malignancies for the presence of concurrent, microbiologically documented pulmonary infections during a 5-year period (2005-2010). We found 126 such patients that frequently had coinfections (49%) with respiratory pathogens other than Aspergillus species, with a higher rate in patients with probable IPA (53%) than in those with proven IPA (29%; P=0.038). As the majority of patients with IPA in daily practice have probable IPA, often according to only the combination of positivity for serological biomarkers and radiological findings, our data may raise skepticism about both the certainty of IPA diagnosis and the evaluation of response to antifungals in a subset of these patients.

Serum antigens assay combined with chest CT scan in diagnosis of invasive pulmonary aspergillosis

To evaluate serum antigens assay combined with chest CT scan in the diagnosis of patients of invasive pulmonary aspergillosis (IPA) without neutropenia. One hundred and thirteen patients with suspected IPA admitted in Department of Respiratory Medicine, Infectious Diseased, Kidney Disease Centre and ICU were included in the study. Serum levels of 1-3-β-D-glucan (G) antigen and galactomannan antigen (GM) were assayed and chest CT scans were performed in all cases. Clinically invasive pulmonary aspergillosis was defined as proven, probable and possible. Treatment effectiveness was recorded. In this series 4 proven IPA, 36 probable IPA, 16 possible IPA, and 57 non-aspergillosis infection were diagnosed. GM test was more sensitive than G test. The specificity of two serum test was 84.2% and 87.7%, respectively. The sensitivity of chest CT was 30.0 %. The specificity of GM assay combined with chest CT was 100.0 %, while the sensitivity was 47.5%. The GM assay combined with chest CT may increase the specificity of diagnosis for IPA patients without neutropenia.

Dectin-1 and DC-SIGN Polymorphisms Associated with Invasive Pulmonary Aspergillosis Infection

The recognition of pathogen-derived structures by C-type lectins and the chemotactic activity mediated by the CCL2/CCR2 axis are critical steps in determining the host immune response to fungi. The present study was designed to investigate whether the presence of single nucleotide polymorphisms (SNPs) within DC-SIGN, Dectin-1, Dectin-2, CCL2 and CCR2 genes influence the risk of developing Invasive Pulmonary Aspergillosis (IPA). Twenty-seven SNPs were selected using a hybrid functional/tagging approach and genotyped in 182 haematological patients, fifty-seven of them diagnosed with proven or probable IPA according to the 2008 EORTC/MSG criteria. Association analysis revealed that carriers of the Dectin-1 rs3901533 T/T and Dectin-1 rs7309123 G/G genotypes and DC-SIGN rs4804800 G, DC-SIGN rs11465384 T, DC-SIGN 7248637 A and DC-SIGN 7252229 C alleles had a significantly increased risk of IPA infection (OR = 5.59 95%CI 1.37–22.77; OR = 4.91 95%CI 1.52–15.89; OR = 2.75 95%CI 1.27–5.95; OR = 2.70 95%CI 1.24–5.90; OR = 2.39 95%CI 1.09–5.22 and OR = 2.05 95%CI 1.00–4.22, respectively). There was also a significantly increased frequency of galactomannan positivity among patients carrying the Dectin-1 rs3901533_T allele and Dectin-1 rs7309123_G/G genotype. In addition, healthy individuals with this latter genotype showed a significantly decreased level of Dectin-1 mRNA expression compared to C-allele carriers, suggesting a role of the Dectin-1 rs7309123 polymorphism in determining the levels of Dectin-1 and, consequently, the level of susceptibility to IPA infection. SNP-SNP interaction (epistasis) analysis revealed significant interactions models including SNPs in Dectin-1, Dectin-2, CCL2 and CCR2 genes, with synergistic genetic effects. Although these results need to be further validated in larger cohorts, they suggest that Dectin-1, DC-SIGN, Dectin-2, CCL2 and CCR2 genetic variants influence the risk of IPA infection and might be useful in developing a risk-adapted prophylaxis.

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.

What should be the optimal cut-off of serum 1,3-β-d-glucan for the detection of invasive pulmonary aspergillosis in patients with haematological malignancies?

The detection of 1,3-β-d-glucan (BDG), a cell wall component of several medically important fungi, is a promising tool for the diagnosis of invasive pulmonary aspergillosis. The aim of this study was to evaluate the diagnostic accuracy of the BDG test in invasive pulmonary aspergillosis (IPA) by focusing on the optimal cut-off value. The records of the Infection Control Committee were reviewed to identify patients with haematological malignancies and stem cell transplantation who had at least 1 BDG (Fungitell kit) measurement during the period January 2008 through April 2011. The European Organization for Research and Treatment of Cancer and the Mycoses Study Group (EORTC/MSG) criteria (independent of BDG results) were used to categorize the patients with IPA. Patients with possible IPA were not included in the study. A total of 128 patients (50 with proven or probable IPA) were included in the study. At the manufacturer's recommended cut-off value of 80 pg/ml, the sensitivity of BDG was 66% (95% CI 51.2-78.7), specificity 75.6% (95% CI 64.6-84.5), positive predictive value (PPV) 63.4%, and negative predictive value (NPV) 77.6%. A receiver operating characteristic (ROC) curve was constructed to define the optimum serum BDG cut-off for the diagnosis of IPA. At a cut-off value of 181 pg/ml, the sensitivity was 52% (95% CI 37.4-66.3), specificity 94.8% (95% CI 87.4-98.6), PPV 86.7%, and NPV 75.5%. Although higher cut-off levels increased the specificity of the BDG test, sensitivity decreased to an unacceptable level; the commercially recommended cut-off value appears to be appropriate for screening purposes.

Computed tomography findings in invasive pulmonary aspergillosis in non-neutropenic transplant recipients and neutropenic patients, and their prognostic value

We evaluated CT findings and their prognostic value in non-neutropenic transplant recipients with invasive pulmonary aspergillosis (IPA) compared with neutropenic patients with IPA. All adult patients during a 27-month who met the criteria for proven or probable IPA according to the 2008 EORTC/MSG criteria were retrospectively enrolled. Initial CT findings were reviewed by two radiologists blinded to the patients' demographics and clinical outcomes. A total of 50 non-neutropenic transplant recipients and 60 neutropenic patients were enrolled. Consolidation-or-mass, halo signs, and angio-invasive form were observed less often in non-neutropenic transplant recipients than in neutropenic patients: (56%, 26%, and 32%) versus (78%, 55%, and 60%, p = 0.01, p = 0.002, and p = 0.003, respectively). Multivariate analysis revealed that macronodules (HR 0.31, p = 0.001), multiple infarct-shaped consolidations (HR 4.26, p < 0.001), renal replacement therapy (HR 5.62, p < 0.001) and persistence of a positive serum galactomannan (HR 7.14, p < 0.001) were independently associated with 90-day mortality. Our data indicate that CT findings in non-neutropenic transplant recipients with IPA are similar to those in neutropenic patients with IPA except that consolidation-or-mass, halo sings, and angio-invasive form are less frequent, and certain CT findings such as macronodules and multiple infarct-shaped consolidations have prognostic implications in IPA.

Galactomannan Testing in Bronchoalveolar Lavage Fluid Facilitates the Diagnosis of Invasive Pulmonary Aspergillosis in Patients with Hematologic Malignancies and Stem Cell Transplant Recipients

Invasive pulmonary aspergillosis (IPA) is a major cause of mortality in patients with stem cell transplants and hematologic malignancies. Timely diagnosis of IPA improves survival but is difficult to make. We evaluated the effectiveness of bronchoalveolar lavage (BAL) galactomannan (GM) in diagnosing IPA in these populations by retrospectively reviewing records of 67 consecutive patients, in whom 89 BAL GM tests were performed. For patients with IPA, only the first BAL sample linked to the IPA episode was analyzed. Eighty samples were associated with proven, 12 with probable, and 32 with possible invasive fungal infections (IFI), and 37 were associated with no IFI. Among patients with IFIs, 4 had proven, 11 probable, and 32 possible IPA. Using BAL GM ≥ 0.5 (cutoff for serum GM) and ≥ 0.85 (optimal cutoff identified by receiver-operating characteristic curve), the sensitivity in diagnosing proven or probable IPA was 73% (11/15) and 67% (10/15), respectively, and specificity was 89% (33/37) and 95% (35/37). At these cutoffs, positive and negative predictive values were 73% (11/15) and 83% (10/12), and 89% (33/37) and 87% (35/40), respectively. BAL GM was more sensitive than cytology (0%, 0/14), BAL culture (27%, 4/15), transbronchial biopsy (40%, 2/5), or serum GM (67%, 10/15) for diagnosing IPA. BAL GM was ≥ 0.85 and ≥ 0.5 in 86% (6/7) and 100% (7/7) of patients with proven or probable IPA who received a mold-active agent for ≤ 3 days. BAL GM added sensitivity to serum GM and other means of diagnosing IPA, and was not impacted by short courses of mold-active agents.

The accuracy of serum galactomannan assay in diagnosing invasive pulmonary aspergillosis.

Galactomannan (GM) antigen is an aspergillus specific antigen that is released during the growth phase of invasive aspergillosis. We aimed to find the optimum cutoff and accuracy of serum Galactomannan assay in immunocompromised patients. Immunocompromised patients diagnosed with invasive pulmonary aspergillosis (IPA) based on the European Organization for Research and Treatment of Cancer/Invasive Mycosis Study Group (EORTC/MSG) with three levels of certainty proven, probable and possible, referred for GM antigen measurement at Immunology, Asthma and Allergy Research Institute (IAARI) from 2006 to 2009 and if they met the criteria were enrolled in this study. Totally 49 patients with IPA were enrolled in our study. According to EORTC/MSG, patients categorized into three levels of certainty: They were diagnosed as 'proven' invasive pulmonary aspergillosis 16(32.7%), 'probable' 18(36.7%) and 'possible' 15(30.6%). The most common host risk factor was solid tumors 17(34.7%). The accuracy of Galactomannan assay increased from 0.5 to 2 cutoffs. The optimum sensitivity and specificity obtained at the index cutoff of ≥1.5 for diagnosis of "proven" IPA; which were respectively, 69.2% and 72.2%. Other cutoffs had high variance between sensitivity and specificity for diagnosis of IPA. The calculated cutoff gained by receiver operating characteristic (ROC) analysis for detecting proven IPA was 1.5. Intermediate accuracy of serum GM test in conjunct with clinical findings would help early IPA detection among immunocompromised patients.

Invasive pulmonary aspergillosis in acute exacerbation of chronic obstructive pulmonary disease and the diagnostic value of combined serological tests

BACKGROUND AND OBJECTIVES:Invasive pulmonary aspergillosis (IPA) among patients with chronic obstructive pulmonary disease (COPD) is increasing in frequency. We conducted this study to find out the approximate incidence of IPA in patients with acute exacerbation of COPD (AECOPD), and to determine whether using a combination of two tests (galactomannan [GM] antigen and 1,3-β-glucan [BG] detection) would result in a more specific diagnosis of IPA.METHODS:The study included 261 patients with AECOPD admitted over two years. The patients were categorized according to the modified definitions for IPA. GM antigen and BG were detected by the Platelia Aspergillus and Glucatell tests.RESULTS:Two patients had proven IPA, three had probable IPA, and two had possible IPA. The rate of proven or probable IPA in patients with AECOPD was 1.91% (5/261). Four patients with proven and probable IPA had been treated with a systemic or inhaled corticosteroid before hospitalization and the typical symptoms and diagnostic signs of IPA were relatively less common in them. Mortality in patients with proven and probable IPA was 80%. The specificity of combined GM and BG detection was 98.8%.CONCLUSION:Combining two serological tests increased the specificity of diagnosis but further trials are needed to prove the value of this approach.