Future challenges and chances in the diagnosis and management of invasive mould infections in cancer patients.

Diagnosis, treatment, and management of invasive mould infections (IMI) are challenged by several risk factors, including local epidemiological characteristics, the emergence of fungal resistance and the innate resistance of emerging pathogens, the use of new immunosuppressants, as well as off-target effects of new oncological drugs. The presence of specific host genetic variants and the patient's immune system status may also influence the establishment of an IMI and the outcome of its therapy. Immunological components can thus be expected to play a pivotal role not only in the risk assessment and diagnosis, but also in the treatment of IMI. Cytokines could improve the reliability of an invasive aspergillosis diagnosis by serving as biomarkers as do serological and molecular assays, since they can be easily measured, and the turnaround time is short. The use of immunological markers in the assessment of treatment response could be helpful to reduce overtreatment in high risk patients and allow prompt escalation of antifungal treatment. Mould-active prophylaxis could be better targeted to individual host needs, leading to a targeted prophylaxis in patients with known immunological profiles associated with high susceptibility for IMI, in particular invasive aspergillosis. The alteration of cellular antifungal immune response through oncological drugs and immunosuppressants heavily influences the outcome and may be even more important than the choice of the antifungal treatment. There is a need for the development of new antifungal strategies, including individualized approaches for prevention and treatment of IMI that consider genetic traits of the patients. Anticancer and immunosuppressive drugs may alter the ability of the immune system to fight invasive mould infections and may be more important than the choice of the antifungal treatment. Individualized approaches for prevention and treatment of invasive mold infections are needed

Aspergillus fumigatus and its Allergenic Ribotoxin Asp f I: Old Enemies but New Opportunities for Urine-based Detection of Invasive Pulmonary Aspergillosis using Lateral-Flow Technology

This is the final version. Available on open access from MDPI via the DOI in this recordData Availability Statement: The data presented in this study are available on request from the corresponding author. The data are not publicly available due to commercial confidentialities.Invasive pulmonary aspergillosis (IPA) caused by Aspergillus fumigatus is a life-threatening lung disease of immunocompromised patients. Diagnosis currently relies on non-specific chest CT, culture of the fungus from invasive lung biopsy, and detection of the cell wall carbohydrate galactomannan (GM) in serum or in BAL fluids recovered during invasive bronchoscopy. Urine provides an ideal bodily fluid for the non-invasive detection of pathogen biomarkers, with current urine-based immunodiagnostics for IPA focused on GM. Surrogate protein biomarkers might serve to improve disease detection. Here, we report the development of a monoclonal antibody (mAb), PD7, which is specific to A. fumigatus and related species in the Section Fumigati, and which binds to its 18 kDa ribotoxin Asp f I. Using PD7, we show that the protein is secreted during hyphal development, and so represents an ideal candidate for detecting invasive growth. We have developed a lateral-flow device (Afu-LFD®) incorporating the mAb which has a limit of detection of ~15 ng Asp f I/mL urine. Preliminary evidence of the test’s diagnostic potential is demonstrated with urine from a patient with acute lymphoid leukaemia with probable IPA. The Afu-LFD® therefore provides a potential novel opportunity for non-invasive urine-based detection of IPA caused by A. fumigatus.Innovate U

Multicenter evaluation of a lateral-flow device test for diagnosing invasive pulmonary aspergillosis in ICU patients

Introduction: The incidence of invasive pulmonary aspergillosis (IPA) in intensive care unit (ICU) patients is increasing, and early diagnosis of the disease and treatment with antifungal drugs is critical for patient survival. Serum biomarker tests for IPA typically give false-negative results in non-neutropenic patients, and galactomannan (GM) detection, the preferred diagnostic test for IPA using bronchoalveolar lavage (BAL), is often not readily available. Novel approaches to IPA detection in ICU patients are needed. In this multicenter study, we evaluated the performance of an Aspergillus lateral-flow device (LFD) test for BAL IPA detection in critically ill patients. Methods: A total of 149 BAL samples from 133 ICU patients were included in this semiprospective study. Participating centers were the medical university hospitals of Graz, Vienna and Innsbruck in Austria and the University Hospital of Mannheim, Germany. Fungal infections were classified according to modified European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. Results: Two patients (four BALs) had proven IPA, fourteen patients (sixteen BALs) had probable IPA, twenty patients (twenty-one BALs) had possible IPA and ninety-seven patients (one hundred eight BALs) did not fulfill IPA criteria. Sensitivity, specificity, negative predictive value, positive predictive value and diagnostic odds ratios for diagnosing proven and probable IPA using LFD tests of BAL were 80%, 81%, 96%, 44% and 17.6, respectively. Fungal BAL culture exhibited a sensitivity of 50% and a specificity of 85%. Conclusion: LFD tests of BAL showed promising results for IPA diagnosis in ICU patients. Furthermore, the LFD test can be performed easily and provides rapid results. Therefore, it may be a reliable alternative for IPA diagnosis in ICU patients if GM results are not rapidly available. Trial registration: ClinicalTrials.gov NCT02058316. Registered 20 January 2014

Multicenter evaluation of a lateral-flow device test for diagnosing invasive pulmonary aspergillosis in ICU patients.

Published onlineClinical TrialJournal ArticleMulticenter StudyResearch Support, Non-U.S. Gov'tINTRODUCTION: The incidence of invasive pulmonary aspergillosis (IPA) in intensive care unit (ICU) patients is increasing, and early diagnosis of the disease and treatment with antifungal drugs is critical for patient survival. Serum biomarker tests for IPA typically give false-negative results in non-neutropenic patients, and galactomannan (GM) detection, the preferred diagnostic test for IPA using bronchoalveolar lavage (BAL), is often not readily available. Novel approaches to IPA detection in ICU patients are needed. In this multicenter study, we evaluated the performance of an Aspergillus lateral-flow device (LFD) test for BAL IPA detection in critically ill patients. METHODS: A total of 149 BAL samples from 133 ICU patients were included in this semiprospective study. Participating centers were the medical university hospitals of Graz, Vienna and Innsbruck in Austria and the University Hospital of Mannheim, Germany. Fungal infections were classified according to modified European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. RESULTS: Two patients (four BALs) had proven IPA, fourteen patients (sixteen BALs) had probable IPA, twenty patients (twenty-one BALs) had possible IPA and ninety-seven patients (one hundred eight BALs) did not fulfill IPA criteria. Sensitivity, specificity, negative predictive value, positive predictive value and diagnostic odds ratios for diagnosing proven and probable IPA using LFD tests of BAL were 80%, 81%, 96%, 44% and 17.6, respectively. Fungal BAL culture exhibited a sensitivity of 50% and a specificity of 85%. CONCLUSION: LFD tests of BAL showed promising results for IPA diagnosis in ICU patients. Furthermore, the LFD test can be performed easily and provides rapid results. Therefore, it may be a reliable alternative for IPA diagnosis in ICU patients if GM results are not rapidly available. TRIAL REGISTRATION: ClinicalTrials.gov NCT02058316. Registered 20 January 2014.PfizerOesterreichische Nationalbank (Anniversary Fund, project number 15346)

Evaluation of Galactomannan Testing, the Aspergillus-Specific Lateral-Flow Device Test and Levels of Cytokines in Bronchoalveolar Lavage Fluid for Diagnosis of Chronic Pulmonary Aspergillosis

Background: Diagnosis of chronic pulmonary aspergillosis (CPA) is challenging. Symptoms are unspecific or missing, radiological findings are variable and proof of mycological evidence is limited by the accuracy of diagnostic tests. The goal of this study was to investigate diagnostic performance of galactomannan (GM), the newly formatted Aspergillus-specific lateral-flow-device test (LFD), and a number of cytokines in bronchoalveolar lavage fluid (BALF) samples obtained from patients with CPA, patients with respiratory disorders without CPA and healthy individuals.Methods: Patients with CPA (n = 27) and controls (n = 27 with underlying respiratory diseases but without CPA, and n = 27 healthy volunteers) were recruited at the Medical University of Graz, Austria and the Research Center Borstel, Germany between 2010 and 2018. GM, LFD and cytokine testing was performed retrospectively at the Research Center Borstel.Results: Sensitivity and specificity of GM testing from BALF with a cut off level of ≥0.5 optical density index (ODI) was 41 and 100% and 30 and 100% with a cut off level of ≥1.0 ODI. ROC curve analysis showed an AUC 0.718 (95% CI 0.581–0.855) for GM for differentiating CPA patients to patients with other respiratory diseases without CPA. The LFD resulted positive in only three patients with CPA (7%) and was highly specific. CPA patients did not differ significantly in the BALF cytokine profile compared to patients with respiratory disorders without CPA, but showed significant higher values for IFN-γ, IL-1b, IL-6, IL-8, and TNF-α compared to healthy individuals.Conclusion: Both GM and LFD showed insufficient performance for diagnosing CPA, with sensitivities of BALF GM below 50%, and sensitivity of the LFD below 10%. The high specificities may, however, result in a high positive predictive value and thereby help to identify semi-invasive or invasive disease

COVID-19 infection in adult patients with hematological malignancies: a European Hematology Association Survey (EPICOVIDEHA)

Background: Patients with hematological malignancies (HM) are at high risk of mortality from SARS-CoV-2 disease 2019 (COVID-19). A better understanding of risk factors for adverse outcomes may improve clinical management in these patients. We therefore studied baseline characteristics of HM patients developing COVID-19 and analyzed predictors of mortality. Methods: The survey was supported by the Scientific Working Group Infection in Hematology of the European Hematology Association (EHA). Eligible for the analysis were adult patients with HM and laboratory-confirmed COVID-19 observed between March and December 2020. Results: The study sample includes 3801 cases, represented by lymphoproliferative (mainly non-Hodgkin lymphoma n = 1084, myeloma n = 684 and chronic lymphoid leukemia n = 474) and myeloproliferative malignancies (mainly acute myeloid leukemia n = 497 and myelodysplastic syndromes n = 279). Severe/critical COVID-19 was observed in 63.8% of patients (n = 2425). Overall, 2778 (73.1%) of the patients were hospitalized, 689 (18.1%) of whom were admitted to intensive care units (ICUs). Overall, 1185 patients (31.2%) died. The primary cause of death was COVID-19 in 688 patients (58.1%), HM in 173 patients (14.6%), and a combination of both COVID-19 and progressing HM in 155 patients (13.1%). Highest mortality was observed in acute myeloid leukemia (199/497, 40%) and myelodysplastic syndromes (118/279, 42.3%). The mortality rate significantly decreased between the first COVID-19 wave (March–May 2020) and the second wave (October–December 2020) (581/1427, 40.7% vs. 439/1773, 24.8%, p value < 0.0001). In the multivariable analysis, age, active malignancy, chronic cardiac disease, liver disease, renal impairment, smoking history, and ICU stay correlated with mortality. Acute myeloid leukemia was a higher mortality risk than lymphoproliferative diseases. Conclusions: This survey confirms that COVID-19 patients with HM are at high risk of lethal complications. However, improved COVID-19 prevention has reduced mortality despite an increase in the number of reported cases.EPICOVIDEHA has received funds from Optics COMMITTM (COVID-19 Unmet Medical Needs and Associated Research Extension) COVID-19 RFP program by GILEAD Science, United States (Project 2020-8223)