Invasive Aspergillosis In Patients Research Articles

Galactomannan antigenemia as a biomarker for therapeutic response of invasive aspergillosis: implications for clinical trial design and patient care

ABSTRACTIntroduction: Clinical trials for invasive pulmonary aspergillosis, a potentially lethal mold infection, are complex investigations that require protracted time and extensive resources, delaying the development of new antifungal agents for this important disease.Areas covered: In this paper, the authors examine a novel approach to study invasive pulmonary aspergillosis in humans, with a focus on the potentials and pitfalls of surrogate end points such as galactomannan antigenemia to evaluate therapeutic response to novel compounds.Expert commentary: The authors believe the use of serum galactomannan as a primary end point in clinical trials may allow for development studies that could be accomplished with fewer resources. It is widely appreciated that serum galactomannan values strongly correlate with outcome of invasive aspergillosis in patients with hematologic cancer and may be applicable to other at-risk patient populations.

Performance of serum (1,3)‐ß‐d‐glucan screening for the diagnosis of invasive aspergillosis in neutropenic patients with haematological malignancies

We report our experience with the use of (1,3)-ß-d-glucan (BDG) screening for the diagnosis of invasive aspergillosis (IA) in neutropenic patients with haematological malignancies. The performance of BDG screening was assessed retrospectively in per patient and per sample analyses. Overall, 20 among 167 patients developed IA (12%). In the per patient analysis, BDG showed 60% sensitivity and 78% specificity when the criterion for positivity was the presence of at least one BDG value ≥80pg/mL. For 2 consecutive positive results, sensitivity decreased to 40%, while specificity increased to 93% and was similar to that of a positive galactomannan (GM; 90%). The highest specificity (97%) was observed for combined positivity of at least one BDG and at least one GM. In the per sample analysis, the specificity of BDG was 100% in the best scenario, 96% in the median scenario and 89% in the worst scenario. BDG became positive before GM in 33% of IA patients with both markers positive (n=12). Despite good specificity for 2 consecutive positive results, the BDG test offered unsatisfactory performance for the diagnosis of IA due to low sensitivity. The combination of BDG and GM showed the potential for increasing specificity.

The burden of Invasive Aspergillosis in patients with haematological malignancy: A meta-analysis and systematic review

Successful treatment of haematological malignancies is frequently complicated by Invasive Aspergillosis (IA), a life-threatening fungal infection that occurs in at least 10% of haemato-oncological patients. Case fatality rates (CFR) may fluctuate over time, depending on host pathogen interactions as well as on treatment and quality of patient care. We conducted a systematic review and metaanalysis of current - i.e. 2008-revised EORTC-MSG criteria era - incidence and case fatality rates (CFR) of IA in patients with haematological malignancy. A systematic search according to PRISMA guidelines was performed to identify all literature reporting populations with a haematological malignancy and the incidence of IA, defined according to the EORTC/MSG 2008 criteria. Pooled cumulative incidences and CFR within 100 days were estimated using a random effects model for predefined patient populations and stratified by use of prophylaxis. The systematic literature search yielded 1285 publications of which n = 49 met the inclusion criteria. Overall, 16.815 patients were involved of which 1056 (6.3%) developed IA. IA risk ranged from 4% (during remission-induction, with prophylaxis) to 11% (during remission-induction, without prophylaxis). Antifungal prophylaxis was associated with a lower rate of IA, especially in the pre-HSCT population. The pooled CFR within 100 days was 29% (95% CI: 20-38%). This study confirms that IA is a relevant threat in the treatment of haematological cancer despite the universal use of antifungal prophylaxis. These outcomes inform scientists and other stakeholders about the current burden of IA and may be used to direct, implement and improve antifungal stewardship programs.

Isavuconazole treatment for rare fungal diseases and for invasive aspergillosis in patients with renal impairment: Challenges and lessons of the VITAL trial.

SummaryInvasive fungal disease (IFD) confers a substantial risk for morbidity and mortality to immunocompromised patients. Invasive aspergillosis (IA) is the most common IFD caused by moulds but the prevalence of other rare mould diseases, such as mucormycosis, hyalohyphomycosis and phaeohyphomycosis, may be increasing. Treatments are available for IA, but evidence to support efficacy and safety of antifungal agents for rare IFDs, or for IFDs in special patient populations, is limited or lacking. The VITAL trial was conducted to assess the efficacy and safety of isavuconazole for the treatment of patients with IA and renal impairment, or with IFDs caused by rare moulds, yeasts or dimorphic fungi. These patients stand to benefit most from a new treatment option but are unlikely to be included in a randomised, controlled trial. In this article, we review the challenges faced in the design and conduct of the VITAL trial. We also review the findings of VITAL, which included evidence of the efficacy and safety of isavuconazole. Finally, we consider the importance of trials such as VITAL to inform therapeutic decision making for clinicians faced with the challenge of treating patients with rare IFDs and as one paradigm of how to determine efficacy and safety of new drugs for rare and resistant infections without a suitable comparator.

Urine Antigen Detection as an Aid to Diagnose Invasive Aspergillosis.

Establishing rapid diagnoses of invasive aspergillosis (IA) is a priority tests that detect galactomannan and β-d-glucan are available, but are technically cumbersome and rely on invasive sampling (blood or bronchoalveolar lavage). We optimized a lateral flow dipstick assay using the galactofuranose-specific monoclonal antibody (mAb476), which recognizes urine antigens after Aspergillus fumigatus pulmonary infection in animals. Urine samples were obtained from a cohort of 78 subjects undergoing evaluation for suspected invasive fungal infections, and stored frozen until testing. Urine was processed by centrifugation through desalting columns and exposed to dipsticks. Reviewers blinded to clinical diagnoses graded results. Western blots were performed on urine samples from 2 subjects to characterize mAb476-reactive antigens. Per-patient sensitivity and specificity for diagnosis of proven or probable IA in the overall cohort was 80% (95% confidence interval [CI], 61.4%-92.3%) and 92% (95% CI, 74%-99%), respectively. In the subgroup with cancer, sensitivity was 89.5% (95% CI, 66.7%-98.7%) and specificity was 90.9% (95% CI, 58.7%-99.8%); among all others, sensitivity and specificity were 63.6% (95% CI, 30.8%-89.1%) and 92.9% (95% CI, 66.1%-99.8%), respectively. Eliminating lung transplant recipients with airway disease increased sensitivity in the noncancer cohort (85.7% [95% CI, 42.1%-99.6%]). Semiquantitative urine assay results correlated with serum galactomannan indices. Western blots demonstrated mAb476-reactive antigens in urine from cases, ranging between 26 kDa and 35 kDa in size. Urine testing using mAb476 may be used as an aid to diagnose IA in high-risk patients.

Spotlight on isavuconazole in the treatment of invasive aspergillosis and mucormycosis: design, development, and place in therapy.

In recent decades, important advances have been made in the diagnosis and treatment of invasive aspergillosis (IA) and mucormycosis. One of these advances has been the introduction of isavuconazole, a second-generation broad spectrum triazole with a favorable pharmacokinetic and safety profile and few drug–drug interactions. Phase III trials in patients with IA and mucormycosis demonstrated that isavuconazole has similar efficacy to voriconazole for the treatment of IA (SECURE trial) and liposomal amphotericin B for the treatment of mucormycosis (VITAL trial with subsequent case–control analysis) and a favorable safety profile with significantly fewer ocular, hepatobiliary, and skin and soft tissue adverse events compared to voriconazole. As a result, recent IA guidelines recommend isavuconazole (together with voriconazole) as gold standard treatment for IA in patients with underlying hematological malignancies. In contrast to liposomal amphotericin B, isavuconazole can be safely administered in patients with reduced renal function and is frequently used for the treatment of mucormycosis in patients with reduced renal function. Updated guidelines on mucormycosis are needed to reflect the current evidence and give guidance on the use of isavuconazole for mucormycosis. Studies are needed to evaluate the role of isavuconazole for 1) anti-mold prophylaxis in high-risk patients, 2) salvage treatment for IA and mucormycosis, and 3) treatment for other mold infections such as Scedosporium apiospermum.

Lung Abscess Due to Aspergillus lentulus and Pseudomonas aeruginosa in a Patient With Granulomatosis With Polyangiitis

Abstract Aspergillus lentulus has been recognized within Aspergillus section Fumigati as a phenotypically similar but genetically distinct species, displaying reduced susceptibility to antifungal agents. It has been described as a cause of invasive aspergillosis in patients who underwent hematopoietic stem cell transplantation, solid organ transplant recipients, those on prolonged corticosteroid therapy, or in patients with structural lung disease including chronic obstructive pulmonary disease. We report a case of successful treatment of probable invasive pulmonary aspergillosis due to A. lentulus and polymicrobial infection with Pseudomonas aeruginosa in a patient with relapsing granulomatosis with polyangiitis and recent high-dose steroid therapy.

Applying host disease status biomarkers to therapeutic response monitoring in invasive aspergillosis patients.

One critical factor impeding successful management of invasive aspergillosis (IA) is the lack of reliable biomarkers to assess therapeutic response. We hypothesized that changes in certain host biomarkers reflect the nature of infection status and disease progression. Upon primary IA diagnosis, these disease status biomarkers can be monitored to track response to antifungal therapy and provide early markers that prognosticate likelihood of response. Herein, we analyzed serum levels of three prominent host disease status biomarkers C-reactive protein (CRP), haptoglobin (Hp), and annexin A1 (ANXA1) in IA patients during antifungal therapy. A total of 81 serial serum samples were collected at five or six different time points relative to IA diagnosis from 15 probable IA patients (10 acute leukemia [AL] and five hematopoietic stem cell transplantation [HSCT]). Of note, different biomarker profiles were observed in AL and HSCT patients, as not only levels of markers were significantly lower in HSCT patients but also more prominent interconnections among markers were observed in AL patients. Using a composite evaluation, patients were categorized as responders, nonresponders, and stable cases at last specimen. For AL responders, typical biomarker profiles were high initially but rapidly decreased for CRP and Hp post antifungal therapy, while low initial ANXA1 values were restored to normal levels after treatment. In contrast, CRP and Hp were persistently elevated whilst ANXA1 remained low throughout therapy in AL non-responders. As a pilot proof-of-concept study, our work demonstrates the great potential of using host biomarkers to monitor early therapeutic response in leukemia patients.

Challenges and Solution of Invasive Aspergillosis in Non-neutropenic Patients: A Review.

Invasive aspergillosis (IA) is a serious opportunistic infection, which has increasingly been recognized as an emerging disease of non-neutropenic patients. In this group of patients, the diagnosis of IA can be challenging owing to the lack of specificity of symptoms, the difficulty in discriminating colonization from infection, and the lower sensitivity of microbiological and radiological tests compared with immunocompromised patients. The aim of this article is to present to clinicians a critical review on the management of IA in non-neutropenic patients.

Circulating Aspergillus fumigatus DNA Is Quantitatively Correlated to Galactomannan in Serum.

The performance of antigen galactomannan (GM) for diagnosing invasive aspergillosis (IA) is hampered by the occurrence of false-positive results. Quantitative PCR has been proposed to improve the diagnosis of IA. Therefore, we analyzed the value of performing a PCR test to the GM-positive serum sample. Using a quantitative PCR assay specific for Aspergillus fumigatus 28S ribosomal DNA, we retrospectively tested 422 GM-positive (Platelia Bio-Rad kit) serum samples collected over 1 year from 147 patients. The cases were classified based on EORTC criteria as “proven,” “probable,” and “no–IA” before availability of the PCR results. After exclusion of 65 samples for non-reproducibility of GM positivity (n = 62) or PCR inhibition (n = 3), 75 (21.0%) of the remaining 357 samples were PCR-positive. GM and fungal DNA showed a significantly positive correlation (p < 0.0001, R2 = 0.27, slope = 0.98 ± 0.19). At least one PCR-positive result was observed in 63.3% (31/49) of IA patients and in 13.2% (13/98) of non-IA patients (p < 0.0001). The PCR positivity was also associated with the presence of other microbiological criteria among the 44 patients with IA and complete mycological workup (p = 0.014), as well as a higher mortality rate at six months among the 135 patients with hematological conditions (p = 0.0198). Overall, we found a quantitative correlation between serum GM and circulating DNA with an increased likelihood of IA when both were positive. A PCR-positive result also supported a higher fungal load when GM was already positive. We advocate adding a PCR test for every confirmed GM-positive serum sample.

VORICONAZOLE-INDUCED HEPATOTOXICITY

Voriconazole, a triazole antifungal, is widely used as the first line treatment of invasive aspergillosis in patients with haematological malignancies and hematopoietic stem cell recipients. Like other triazole antifungals, voriconazole is potentially hepatotoxic. Repeated dose oral studies in rats, mice and dogs have shown the liver to be the main target organ, with a range of adaptive and functional changes such as increasing liver weight,&#x0D; centrilobular hypertrophy, smooth endoplasmic reticulum proliferation and cytochrome P450 induction. Based on the Infectious Diseases society of America (IDSA)’s guidelines for the treatment of invasive aspergillosis,&#x0D; monitoring voriconazole levels and adjusting the dosage are recommended instead of switching to alternative antifungal drugs because of better survival and improved responses on initial therapy with voriconazole. However, if hepatotoxicity occurs, voriconazole will often be discontinued. Considering this, we try to investigatethe voriconazole-induced hepatotoxicity mechanism by reviewing the literature. Based on the similarity of metabolism pathway between ketoconazole and voriconazole, we assume that the mechanism of voriconazole induced hepatotoxicity is mediated probably through N-oxide voriconazole. N-oxide voriconazole is oxidized by flavin-containing monooxygenase (FMO) on the fluoropyrimidine ring. It produces further metabolites showing toxic consequences that produces hepatic injury.&#x0D; &#x0D; Keywords : Voriconazole, hepatotoxic, invasive aspergillosis

Comparing Diagnostic-Driven Approaches to Empiric Therapy in the Treatment of Invasive Aspergillosis in Patients with Hematologic Malignancy

Background Early antifungal therapy of invasive aspergillosis (IA) has been shown to be associated with improved outcome. Given the difficulty to establish the diagnosis of IA based on conventional methods, early initiation of empiric antifungal therapy has been used in patients with clinically suspected IA. Diagnostic-driven approach (DDA) relies on using novel diagnostic methods (e.g., early galactomannan testing). In this current study, we compared the outcomes of hematological malignancy (HM) patients with IA who were treated with Voriconazole using the DDA (DDA-Vori) vs. empiric therapy with a non-Voriconazole containing regimen (EMP-non-Vori) or empiric therapy with Voriconazole (EMP-Vori).Methods We retrospectively reviewed the medical records of 604 HM patients with documented, proven or probable IA (according to EORTC/MSG criteria) diagnosed between July, 1993 and February, 2016 at our center. We included 346 patients with underlying host factors, a suggestive CT findings of IA, and positive biopsy, fungal culture or galactomannan indicative of IA, and who received at least 7 days of DDA-Vori, EMP-Vori, or EMP-non-Vori. Outcome assessment included response to therapy (clinical and radiographic), all causing mortality and IA attributable mortality.ResultsThe patients’ median age was 54 years and 59% were males. By multivariate analysis, factors that were predictive of a favorable response included: localized/sinus IA vs. disseminated/pulmonary IA (P < 0.0001), not receiving WBC transfusion (P < 0.01), and DDA-VORI vs. EMP-non-Vori (P < 0.0001). On the other hand, predictors of mortality within 6 weeks of initiation of IA therapy included disseminated/pulmonary infection vs. localized/sinus IA (P < 0.01), not having stem-cell transplant within 1 year prior of IA (P = 0.01) and EMP-non-Vori vs. DDA-Vori (P < 0.001).Conclusion DDA-Vori is associated with a better outcome (response and survival) when compared with EMP-non-Vori and equivalent outcome to EMP-Vori. The superior to equivalent outcome associated with the DDA approach could also reduce unnecessary costs and adverse events associated with widespread use of empiric therapy.Disclosures I. Raad, Merck: Grant Investigator, Research grant. Allergan: Grant Investigator, Research grant. Infective Technologies, LLC: Co-Inventor of the Nitroglycerin-Citrate-Ethanol catheter lock solution technology which is owned by the University of Texas MD Anderson Cancer Center (UTMDACC) and has been licensed by Novel Anti-Infective Technologies, LLC in which Dr. Raad is a s and Shareholder, Licensing agreement or royalty

Comparative evaluation of galactomannan test with bronchoalveolar lavage and serum for the diagnosis of invasive aspergillosis in patients with hematological malignancies.

INTRODUCTION:Invasive pulmonary aspergillosis (IPA) is a major cause of morbidity and mortality in patients with hematological malignancies. In recent years, testing for values of galactomannan (GM) in serum and bronchoalveolar lavage (BAL) fluid has been investigated as a diagnostic test for IPA for such patients, but global experience and consensus on optical density (OD) cutoffs, especially for BAL galactomannan remains lacking.METHODS:We performed a prospective case–control study to determine an optimal BAL GM OD cutoff for IPA in at-risk patients. Cases were subjects with hematological diagnoses who met established revised definitions for proven or probable IPA established by the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group (EORTC/MSG, 2008), without the use of BAL GM results. Exclusion criteria included the use of piperacillin/tazobactam and use of antifungals that were active against Aspergillus spp. before bronchoscopy. There were two control groups: patients with hematological diagnoses not meeting definitions for proven or probable IPA and patients with nonhematological diagnoses with no evidence of aspergillosis. Following bronchoscopy and BAL, GM testing was performed using the Platelia Aspergillus seroassay in accordance with the manufacturer's instructions.RESULTS:There were 51 cases and 20 controls. Cases had higher BAL fluid GM OD indices (ODIs) (mean: 1.27 and range: 0.4–3.78) compared with controls (mean: 0.26 and range: 0.09–0.35). Receiver operating characteristic analysis demonstrated an optimum ODI cutoff of 1.0, with high specificity (100%) and sensitivity (87.5%) for diagnosing IPA.CONCLUSIONS:Our results support BAL GM testing as a reasonably safe test with higher sensitivity compared to serum GM testing in at-risk patients with hematological diseases. A higher OD cutoff is necessary to avoid overdiagnosis of IPA.

Corticosteroid Use Following the Onset of Invasive Aspergillosis is Associated with Increased Mortality: A Propensity Score-Matched Study

BackgroundThe safety of corticosteroid use (CSU) during active infection is controversial. In the invasive aspergillosis (IA) literature, CSU is typically defined using the time period prior to IA onset. Clinicians caring for patients with IA are unable to control prior CSU. The more clinically relevant question is whether CSU after IA onset is harmful.MethodsPatients hospitalized at our institution from 2004 to 2014 with IA were retrospectively identified. CSU, defined as the average daily prednisone equivalent dose during the 7-day period following IA onset, was calculated for each patient. A CSU cut-off of 7.5mg was used to assign patients to treatment (>7.5mg) or control (<7.5mg, including no CSU) groups. A propensity score (PS) was generated to predict group assignment. Nearest neighbor matching was performed with a caliper width of 0.2. A Cox proportional hazards model was used to assess survival 6 weeks after IA onset.ResultsPS matching generated 61 matched pairs (122 patients). Baseline characteristics did not differ significantly between groups (Table). CSU was associated with increased mortality (PS adjusted hazard ratio [HR] 2.91, 95% CI 1.32–6.40). In the CSU group, a trend towards lower mortality was noted if corticosteroid dose was tapered to 7.5mg/day (HR 0.68, 95% CI 0.46–1.02).ConclusionCSU after IA onset is associated with increased mortality. In IA patients with CSU, efforts to reduce corticosteroid dose may be beneficial. Table: Propensity matched patients at IA OnsetCSU (n = 61)Control (n = 61) P Age, years57.6 (49.2–65.9)53.2 (42.5–63.2).27Male59.0% (36/61)54.1% (33/61).72CSU >7.5mg prior to IA78.7% (48/61)70.5% (43/61).41Leukemia52.5% (32/61)49.2% (30/61).86Allogeneic bone marrow transplant26.2% (16/61)29.5% (18/61).84Graft vs. host disease3.3% (2/61)11.5% (7/61).16Neutropenia48.3% (28/58)42.9% (24/56).58Solid organ transplant11.5% (7/61)6.6% (4/61).53Obstructive lung disease21.3% (13/61)24.6% (15/61).83Diabetes mellitus26.2% (16/61)29.5% (18/61).84Pulmonary IA94.8% (55/58)94.9% (56/59).99Coinfection23.0% (14/61)21.3% (13/61).99Data presented as median (interquartile range) or % (n with feature/n with data available)Figure.Kaplan–Meier curves comparing 6-week survivalDisclosures All authors: No reported disclosures.

Host immune status-specific production of gliotoxin and bis-methyl-gliotoxin during invasive aspergillosis in mice

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.

Azole Resistance in Aspergillus fumigatus in Patients with Cystic Fibrosis: A Matter of Concern?

Aspergillus fumigatus is the most frequent filamentous fungus isolated from respiratory specimens from patients with cystic fibrosis (CF). Triazoles are the most widely used antifungals in the treatment of allergic bronchopulmonary aspergillosis (ABPA) and invasive aspergillosis (IA) in CF patients. Treatment success could be severely compromised by the occurrence of azole-resistant A. fumigatus (ARAf), which is increasingly reported worldwide from both clinical samples and the environment. In previous studies, ARAf has been detected in up to 8% of CF patients. Isolates from CF patients requiring antifungal treatment should therefore be routinely subjected to antifungal susceptibility testing. The optimal treatment of ABPA or IA in CF patients with azole-resistant isolates has not been established; treatment options include liposomal amphotericin B i.v. and/or echinocandins i.v.

The misleading effect of serum galactomannan testing in high-risk haematology patients receiving prophylaxis with micafungin

ObjectivesTo investigate the performance of the routine serum galactomannan (sGM) assay in the diagnosis of invasive aspergillosis (IA) in high-risk haematology patients receiving prophylaxis with micafungin. MethodsRetrospective study including all haematological patients who received prophylaxis with micafungin during high-risk IA episodes (neutropenic patients after chemotherapy for acute myeloid leukaemia/myelodysplastic syndrome; allogeneic haematopoietic stem-cell transplantation during early neutropenic phase or graft-versus-host disease requiring high prednisone doses) and for whom at least one sGM result was available. Episodes were classified as follows: true-positive (positive GM in the context of IA), false-positive (positive GM result in patients who had no evidence of IA), true-negative (negative GM test results and no IA), or false-negative (negative GM test in the context of IA). Non-evaluable patients were excluded. ResultsAmong 146 evaluable episodes, four were true-positive in the context of probable breakthrough IA (incidence of breakthrough IA, 2.7%); 111/146 high-risk episodes (76%) were considered true-negative and 31/146 (21.2%) were considered false-positive. No false-negative episodes were detected. All but one of the false-positive episodes were detected in surveillance GM tests, leading to high-resolution CT scans in eight cases (8/31; 25.8%), all of which were negative. The positive predictive and negative predictive values of sGM for surveillance and diagnostic approaches were 3.2% (1/31) and 100% (110/110) and 75% (3/4) and 100% (1/1), respectively. ConclusionsSurveillance of asymptomatic patients receiving prophylaxis with micafungin using sGM is unnecessary, because the results are either negative or false-positive. However, sGM remains useful in the diagnosis of breakthrough IA in symptomatic patients during prophylaxis.

Effectiveness of environmental control measures to decrease the risk of invasive aspergillosis in acute leukaemia patients during hospital building work

Invasive aspergillosis (IA) is a significant problem in acute leukaemia patients. Construction work near hospital wards caring for immunocompromised patients is one of the main risk factors for developing invasive pulmonary aspergillosis (IPA). To assess the impact of environmental control measures used during hospital construction for the prevention of IA in acute leukaemia patients. A retrospective cohort study was developed to evaluate the IA incidence in acute leukaemia patients with different environmental control measures employed during hospital construction. We used European Organisation for the Research and Treatment of Cancer (EORTC) criterial diagnosis parameters for definition of IA. A total of 175 episodes of inpatient care were evaluated, 62 of which did not have any environmental control measures (when an outbreak occurred), and 113 that were subject to environmental control measures directed to preventing IA. The study showed an IA incidence of 25.8% for the group without environmental control measures vs 12.4% for those who did receive environmental control measures (P=0.024). The relative risk for IA was 0.595 (95% confidence interval: 0.394-0.897) for the group with environmental control measures. The current study suggests that the implementation of environmental control measures during a hospital construction has a positive impact for prevention of IA in patients hospitalized with acute leukaemia.

Invasive aspergillosis in patients with underlying liver cirrhosis: a prospective cohort study.

The aim of this study was to determine the prevalence of invasive aspergillosis (IA) in patients with liver cirrhosis and the performance of serum galactomannan (GM) screening. Patients with decompensated liver cirrhosis and patients with compensated liver cirrhosis presenting with fever and/or respiratory symptoms were prospectively enrolled. All patients were screened by serum GM twice weekly irrespective of clinical signs and symptoms. Positive serum GM triggered work-up consisting of chest computed tomography and in case of pathological findings bronchoscopy. 150 patients were included in the study. Two (1.3%) had probable, one (0.7%) had possible, and 147 (98%) had no evidence of IA. Both patients with probable IA had compensated liver cirrhosis. Sensitivity for serum GM screening for probable versus no IA was 0.5 (95% CI, 0.09-0.91), specificity 0.97 (95% CI: 0.92-0.99), negative predictive value 0.99 (95% CI, 0.96-0.99) and positive predictive value (PPV) 0.17 (95% CI, 0.01-0.64). PPV was 0.5 (95% CI, 0.03-0.98) in patients with clinical suspicion of IA. In conclusion, prevalence of IA in patients with liver cirrhosis seems to be low. Targeted GM testing in case of clinical suspicion of IA may be associated with markedly higher PPVs when compared to universal GM screening in patients with liver cirrhosis.

Evaluation of Serum Galactomannan Enzyme Immunoassay at Two Different Cut-offs for the Diagnosis of Invasive Aspergillosis in Patients with Febrile Neutropenia

Background: Invasive aspergillosis (IA) is an increasingly common and fatal opportunistic fungal infection in patients with haematological diseases. Early diagnosis is difficult as mycological culture techniques have low sensitivity and the radiological tools have low specificity. Galactomannan enzyme immunoassay (GEI) detects galactomannan in the human serum with a reported sensitivity and specificity between 30% and 100%. Aims: The aim of this study was to analyse the role of GEI in diagnosis of IA in patients with febrile neutropenia and to evaluate the role of GEI in the diagnosis of IA as per the revised (2008) European Organization for Research and Treatment of Cancer–Mycoses Study Group (EORTC–MSG) criteria at two different optical density (OD) cut-offs of 0.5 and 1.0. Setting: This prospective study was conducted in Safdarjung Hospital, New Delhi, India. Methods: GEI testing was performed in adult patients of febrile neutropenia with evidence of IA. Results at two different OD indices (ODIs) of 0.5 and 1.0 were analysed. The evaluation of the diagnostic parameter, that is, GEI was measured in terms of sensitivity, specificity and positive and negative predictive value and was validated with the revised (2008) EORTC–MSG diagnostic criteria of IA. Results: One hundred and eleven patients had evidence of IA, of which 79 patients were GEI positive when cut-off ODI was 0.5, whereas with cut-off ODI 1.0, 55 patients were GEI positive. Conclusion: ODI of 1.0 should be considered as positive while in patients with OD between 0.5 and 1.0, repeat sampling from the patient is recommended.