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Respiratory InfectionNCT05860387

Early Diagnosis of Invasive Lung Aspergillosis

An observational study of Respiratory Infection and Invasive Pulmonary Aspergillosis, run by University Hospital Ostrava at 7 sites in Czechia.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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Trial summary

The last decade has seen a significant increase in secondary Aspergillus infections, not only due to primary hypersensitivity, and immunodeficiency based on oncological diseases and their therapy, but mainly due to a rise in severe respiratory infections (H1N1, COVID-19, bacterial infections). Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Next generation improvement of early invasive aspergillosis
How many people
150 participants
Where
7 sitesCzechia
Study dates
31 May 2023to 31 Dec 2026
Phase
Observational
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Study population: Critically ill patients (>18 years) with any respiratory symptoms.

Who may be able to join

  • respiratory rate ≥ 30 breaths/min
  • PaO2/FiO2 ratio ≤ 250
  • multilobar infiltrates
  • confusion/disorientation
  • uremia (blood urea nitrogen level ≥ 20mg/dL)
  • leucocytosis (white blood cell count > 12000/mL) or
Show all 13Show fewer
  • leukopenia (white blood cell count < 4 x 109/L)
  • thrombocytopenia (platelet count < 100 x 109/L)
  • hyperthermia (core temperature > 38 °C)
  • hypothermia (core temperature < 36 °C)
  • hypotension requiring aggressive fluid resuscitation
  • invasive mechanical ventilation and septic shock requiring vasopressors
  • Bronchoalveolar Lavage Fluid (BALF) and/or Endotracheal Aspirate (ETA)

Who cannot join

  • patients, in whom PTX3, Aspergillus qPCR, and HPLC-FTICR were not performed or were performed after the start of antifungal treatment

Trial locations and contacts

7 sites in 1 country. Contact the study team or a site near you to ask about taking part.

Jiří Hynčica contact

0042059737 ext. 2587

jiri.hyncica@fno.cz

7 sites in 1 country

Czechia7 sites, 7 recruiting

  • Havířov Hospital

    Havířov, Moravian-Silesian Region, 736 01

    Robert Bocek, MD, 0042059649 ext. 1834, robert.bocek@nemhav.cz

    Robert Bocek, MD

    Recruiting

  • Krnov Hospital

    Krnov, Moravian-Silesian Region, 794 01

    Zbyněk Vrba, MD, 0042055469 ext. 0143, vrba.zbynek@szzkrnov.cz

    Zbyněk Vrba, MD

    Recruiting

  • University Hospital Olomouc

    Olomouc, Olomouc Region, 779 00

    Milan Raška, prof.,MD,PhD, 0042058563 ext. 2751, milan.raska@upol.cz

    Milan Raška, prof.,MD,PhD

    Recruiting

  • Public Health Institute Ostrava

    Ostrava, Moravian-Silesian Region, 702 00

    Radim Dobiáš, Mgr.,PhD, 0042059620 ext. 0239, radim.dobias@zuova.cz

    Radim Dobiáš, Mgr.,PhD

    Recruiting

  • University of Ostrava

    Ostrava, Moravian-Silesian Region, 703 00

    Lenka Kramná, Mgr.,PhD, 0042055346 ext. 1741, lenka.kramna@osu.cz

    Lenka Kramná, Mgr.,PhD

    Recruiting

  • University Hospital Ostrava

    Ostrava, Moravian-Silesian Region, 708 52

    Jiří Hynčica, 0042059737 ext. 2587, jiri.hyncica@fno.cz

    Jozef Škarda, Assoc.Prof.,MD,DVM,PhD

    Recruiting

  • Municipal Hospital Ostrava

    Ostrava, Moravian-Silesian Region, 728 80

    Štefan Kis Pisti, MD, 0042059619 ext. 2656, aro@mnof.cz

    Štefan Kis Pisti, MD

    Recruiting

Other trials in Czechia

About this study

The last decade has seen a significant increase in secondary Aspergillus infections, not only due to primary hypersensitivity, and immunodeficiency based on oncological diseases and their therapy, but mainly due to a rise in severe respiratory infections (H1N1, COVID-19, bacterial infections). This is most evident in critically ill patients whose life is threatened by invasive pulmonary aspergillosis (IPA), with over 90 % of cases being caused by Aspergillus fumigatus. In recent decades, various biomarkers with well-known limits of use (Aspergillus DNA, galactomannan, 1,3-ß-D-glucan) have been used for early diagnosis of IPA. However, the clinical need to clearly distinguish the onset of IPA from colonization is much more significant. The current biomarkers only provide "probable IPA" interpretation, and the diagnosis is rarely confirmed. Based on our preliminary studies, the use of new low molecular weight substances (secondary metabolites) combined with acute-phase proteins (pentraxin 3) allows very reliable immediate confirmation of IPA. In tissue samples, bronchoalveolar lavage fluid, endotracheal aspirate, breath condensate, serum, and urine of critically ill patients, the investigators will be able to recognize and confirm IPA in time using highly sensitive mass spectrometry detecting specific microbial siderophores in correlation with a significantly increased concentration of acute-phase host protein (pentraxin 3) within hours of the beginning of the invasion of lung tissue. Through a prospective multicentre study, the investigators will evaluate the benefit of new biomarkers in non-invasive IPA confirmation, improve the IPA diagnostic algorithm and transfer the detection method to MALDI-TOF spectrometers widely used in Clinical laboratories in the Czech Republic. In MALDI-TOF mass spectrometry, the ion source is matrix-assisted laser desorption/ionization (MALDI), and the mass analyser is a time-of-flight (TOF) analyser.

The study results will contribute to a high clarity of IPA cases, the accurate introduction of antifungal therapy, and a better prognosis of survival of critically ill patients.

Read the detailed description

This is a prospective study of threshold-driven and continuous response variables from independent control and experimental groups of subjects. The intensive care units in the five hospitals include 63 beds and will provide 2292 potentially suitable critically ill subjects annually during a 3-year prospective study.

In patients with suspected IPA, all types of samples will be collected twice a week for analysis from the date of diagnosis until at least 2 consecutive negative results are obtained, or the patient will be discharged from an intensive care unit. If available, stored aliquots of samples taken 14 - 1 days before the day of diagnosis (mainly the serum and BALF/ETA (bronchoalveolar lavage fluid/endotracheal aspirate) used for galactomannan screening) will be used for Pentraxin 3 (PTX3), Aspergillus qPCR, and HPLC-ESI-FTICR analyses. Results will be reported to clinicians in variable time frames depending on the centre.

The control and experimental group sizes are expected to be approximately equal. Based on the previous experimental and published data, the expected AUC value is 0.8 for the power of study limiting laboratory assay. For Ptx3 and qPCR Aspergillus, a sample size of 13 in each group will be sufficient to detect a significant difference, assuming a power of 80%, and a two-sided significance level of 0.05. The second assay used in the study would require only 7 subjects in each group based on a mean difference of 4303 and an estimated standard deviation of 2500 to detect significant differences assuming the power of 80%, a two-sided significance level of 0.05, and the t-test. When an appropriate threshold is applied to the latter assay, the expected AUC value is 0.99, thus rendering the minimum required number of subjects to 3 for each study group. The investigators expect to enrol more subjects (up to a total of 90) to allow for a possible variation of the values in the groups. Statistical analysis for clinical samples will be performed in R 4.0.2 using standard libraries for exploratory data analysis. Descriptive statistics will be reported in the form of mean, median, standard deviation, standard error of the mean, and coefficient of variation. Differences in male proportion and age will be evaluated using the Wilcoxon rank-sum test for equal variance. Sample frequency will be compared with Fisher's exact test. The normal distribution of the data (age and gender) will be tested using the Shapiro-Wilk normality test. If the data do not meet the normality requirement, the nonparametric Kruskal-Wallis test will be followed by the post hoc pairwise Wilcoxon signed-rank test for further data analysis; for all above-mentioned tests, p <0.05 will be considered statistically significant. R library cutpointr estimates the optimal cut-off value, and the ROC characteristics, specificity, and sensitivity will be determined. Maximize spline, gam, and loss estimates for metrics accuracy and a sum of sensitivity and specificity, and Kernel estimate for Youden index methods will be used for cut-off value estimates. False-negative and false-positive rates will be calculated as controls based on probable IPA and non-IPA.

Patients with suspected IPA defined by the presence of host factors, suggestive imaging, and clinical symptoms, according to the 2008 consensus definitions from the European Organization for the Research and Treatment of Cancer / Mycoses Study Group Education and Research Consortium (EORTC/MSGERC) revised in 2019, will be prospectively recruited in five hospital centres in the Czech Republic from 1st June 2023 to 31st December 2025 (Cohort 1). Mycological and clinical investigations will be performed according to the usual procedures in each centre (imaging, mycological culture, identification using microscopy, and histopathological examination). Molecular detection of hyphae recognized in tissue samples, BALF, and/or ETA will be performed using Aspergillus quantitative PCR (qPCR). IPA-specific acute phase biomarker PTX3 elevation will be analysed in BALF and/or ETA and serum commercial PTX3 immunoassays. Mass spectrometry identification of specific Aspergillus siderophores TafC, TafB, Fc, and secondary metabolite Gtx in the tissue biopsies (if available), urine, BC (intubated patient), BALF, and/or ETA will be performed using HPLC/ESI-FTICR (co-PI 1). All other investigations and treatments, including treatment for aspergillosis, will be based on the standards of each co-applicant team in accordance with the procedures defined in each centre. Population characteristics, clinical and biological data, underlying conditions, medical history, biology, imaging, time to diagnosis, and treatment will be collected for each patient after enrolment and recorded in each centre using an online Castor EDC (Castor's Decentralized Clinical Trials Platform, www.castoredc.com). Routine detection of galactomannan antigen, 1,3-β-D-glucan, PTX3, and Aspergillus qPCR assay will be performed in accordance with the procedures defined in co-participant Public Health Institute Ostrava and Faculty of Medicine, University of Ostrava. The HPLC/ESI-FTICR analysis will be performed by the Institute of Microbiology, Academy of Sciences of the Czech Republic in Prague. TafC enrichment by affinity purification column will be performed by co-applicant University Hospital Olomouc, and MS analyses (HPLC/ESI-FTICR, ESI-FTICR, and MALDI-TOF) will be performed by co-applicant Institute of Microbiology, Academy of Sciences, Czech Republic in Prague. The day of sampling of the first histological or positive mycological specimen will be defined as day 0 (D0). Patients will be classified at month 6 as having a possible, probable, or proven IPA according to the 2019 EORTC/MSGERC criteria.

Being tested
Next generation improvement of early invasive aspergillosis
Keywords
biomarkers, qualitative polymerase chain reaction (qPCR), metallomics, mass spectrometry, colonisation, invasive pulmonary aspergillosis, Pentraxin-3
Medical subject headings
Respiratory Tract Infections, Invasive Pulmonary Aspergillosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Next generation improvement of early invasive aspergillosisDiagnostic test

    Next generation improvement of early invasive aspergillosis test is intended to determine the suitability of new potential biomarkers of aspergillosis.

Study groups in NCT05860387
Study groupRoleWhat they receive
Suspicion of IPA at enrolmentStudy subjects with suspicion of IPA at enrolment will be included in this study group.
Receives: Diagnostic Test: Next generation improvement of early invasive aspergillosis
Probable or proven IPA at enrolmentStudy subjects with probable or proven IPA at enrolment will be included in this study group.
Receives: Diagnostic Test: Next generation improvement of early invasive aspergillosis

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Concentration of IPA on mass spectrometry

    IPA in time will be recognized and analysed in tissue samples (bronchoalveolar lavage fluid, endotracheal aspirate, breath condensate, serum, and urine) of critically ill patients using highly sensitive mass spectrometry detecting specific microbial siderophores in correlation with a significantly increased concentration of acute-phase host protein (pentraxin 3) within hours of the beginning of the invasion of lung tissue. The study results will contribute to a high clarity of IPA cases, the accurate introduction of antifungal therapy, and a better prognosis of survival of critically ill patients in a prospective study of threshold driven and a continuous response variable from independent control and experimental groups of subjects.

    Measured: 31 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted16 May 2023
  2. Study start31 May 2023
  3. Primary completion31 Dec 2025 (estimated)
  4. Study completion31 Dec 2026 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Observational
Observational model
Cohort
Time perspective
Prospective
Enrolment
150 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05860387
Sponsor's protocol ID
EDILA
Other IDs
NU23-05-00095
Status last verified
Sep 2023
First submitted
11 Apr 2023
Last updated
7 Sep 2023
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No: There is no plan to make individual participant data available to other researchers.

Publications

  • Latge JP, Chamilos G. Aspergillus fumigatus and Aspergillosis in 2019. Clin Microbiol Rev. 2019 Nov 13;33(1):e00140-18. doi: 10.1128/CMR.00140-18. Print 2019 Dec 18.

    PubMed 31722890

  • Dobias R, Jaworska P, Tomaskova H, Kanova M, Lyskova P, Vrba Z, Holub C, Svobodova L, Hamal P, Raska M. Diagnostic value of serum galactomannan, (1,3)-beta-d-glucan, and Aspergillus fumigatus-specific IgA and IgG assays for invasive pulmonary aspergillosis in non-neutropenic patients. Mycoses. 2018 Aug;61(8):576-586. doi: 10.1111/myc.12765. Epub 2018 Jun 11.

    PubMed 29575150

  • Koehler P, Bassetti M, Chakrabarti A, Chen SCA, Colombo AL, Hoenigl M, Klimko N, Lass-Florl C, Oladele RO, Vinh DC, Zhu LP, Boll B, Bruggemann R, Gangneux JP, Perfect JR, Patterson TF, Persigehl T, Meis JF, Ostrosky-Zeichner L, White PL, Verweij PE, Cornely OA; European Confederation of Medical Mycology; International Society for Human Animal Mycology; Asia Fungal Working Group; INFOCUS LATAM/ISHAM Working Group; ISHAM Pan Africa Mycology Working Group; European Society for Clinical Microbiology; Infectious Diseases Fungal Infection Study Group; ESCMID Study Group for Infections in Critically Ill Patients; Interregional Association of Clinical Microbiology and Antimicrobial Chemotherapy; Medical Mycology Society of Nigeria; Medical Mycology Society of China Medicine Education Association; Infectious Diseases Working Party of the German Society for Haematology and Medical Oncology; Association of Medical Microbiology; Infectious Disease Canada. Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance. Lancet Infect Dis. 2021 Jun;21(6):e149-e162. doi: 10.1016/S1473-3099(20)30847-1. Epub 2020 Dec 14.

    PubMed 33333012

  • Pfister J, Summer D, Petrik M, Khoylou M, Lichius A, Kaeopookum P, Kochinke L, Orasch T, Haas H, Decristoforo C. Hybrid Imaging of Aspergillus fumigatus Pulmonary Infection with Fluorescent, 68Ga-Labelled Siderophores. Biomolecules. 2020 Jan 22;10(2):168. doi: 10.3390/biom10020168.

    PubMed 31979017

  • Alanio A, Delliere S, Fodil S, Bretagne S, Megarbane B. Prevalence of putative invasive pulmonary aspergillosis in critically ill patients with COVID-19. Lancet Respir Med. 2020 Jun;8(6):e48-e49. doi: 10.1016/S2213-2600(20)30237-X. Epub 2020 May 20. No abstract available.

    PubMed 32445626

  • Henneberg S, Hasenberg A, Maurer A, Neumann F, Bornemann L, Gonzalez-Menendez I, Kraus A, Hasenberg M, Thornton CR, Pichler BJ, Gunzer M, Beziere N. Antibody-guided in vivo imaging of Aspergillus fumigatus lung infections during antifungal azole treatment. Nat Commun. 2021 Mar 17;12(1):1707. doi: 10.1038/s41467-021-21965-z.

    PubMed 33731708

  • Meersseman W, Lagrou K, Maertens J, Wilmer A, Hermans G, Vanderschueren S, Spriet I, Verbeken E, Van Wijngaerden E. Galactomannan in bronchoalveolar lavage fluid: a tool for diagnosing aspergillosis in intensive care unit patients. Am J Respir Crit Care Med. 2008 Jan 1;177(1):27-34. doi: 10.1164/rccm.200704-606OC. Epub 2007 Sep 20.

    PubMed 17885264

  • Cao XJ, Li YP, Xie LM, Zhang HL, Qin YS, Guo XG. Diagnostic Accuracy of Bronchoalveolar Lavage Fluid Galactomannan for Invasive Aspergillosis. Biomed Res Int. 2020 Nov 30;2020:5434589. doi: 10.1155/2020/5434589. eCollection 2020.

    PubMed 33335924

  • Khan A, Singh P, Srivastava A. Synthesis, nature and utility of universal iron chelator - Siderophore: A review. Microbiol Res. 2018 Jul-Aug;212-213:103-111. doi: 10.1016/j.micres.2017.10.012. Epub 2017 Nov 2.

    PubMed 29103733

  • Schrettl M, Bignell E, Kragl C, Sabiha Y, Loss O, Eisendle M, Wallner A, Arst HN Jr, Haynes K, Haas H. Distinct roles for intra- and extracellular siderophores during Aspergillus fumigatus infection. PLoS Pathog. 2007 Sep 28;3(9):1195-207. doi: 10.1371/journal.ppat.0030128.

    PubMed 17845073

  • Skriba A, Pluhacek T, Palyzova A, Novy Z, Lemr K, Hajduch M, Petrik M, Havlicek V. Early and Non-invasive Diagnosis of Aspergillosis Revealed by Infection Kinetics Monitored in a Rat Model. Front Microbiol. 2018 Oct 8;9:2356. doi: 10.3389/fmicb.2018.02356. eCollection 2018.

    PubMed 30349512

  • Luptakova D, Pluhacek T, Petrik M, Novak J, Palyzova A, Sokolova L, Skriba A, Sediva B, Lemr K, Havlicek V. Non-invasive and invasive diagnoses of aspergillosis in a rat model by mass spectrometry. Sci Rep. 2017 Nov 28;7(1):16523. doi: 10.1038/s41598-017-16648-z.

    PubMed 29184111

  • Pluhacek T, Lemr K, Ghosh D, Milde D, Novak J, Havlicek V. Characterization of microbial siderophores by mass spectrometry. Mass Spectrom Rev. 2016 Jan-Feb;35(1):35-47. doi: 10.1002/mas.21461. Epub 2015 May 15.

    PubMed 25980644

  • Kamei K, Watanabe A. Aspergillus mycotoxins and their effect on the host. Med Mycol. 2005 May;43 Suppl 1:S95-9. doi: 10.1080/13693780500051547.

    PubMed 16110799

  • Raffa N, Keller NP. A call to arms: Mustering secondary metabolites for success and survival of an opportunistic pathogen. PLoS Pathog. 2019 Apr 4;15(4):e1007606. doi: 10.1371/journal.ppat.1007606. eCollection 2019 Apr. No abstract available.

    PubMed 30947302

Questions about this trial

What is this clinical trial studying?

An observational study of Respiratory Infection and Invasive Pulmonary Aspergillosis, run by University Hospital Ostrava at 7 sites in Czechia.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 7 Sep 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 7 sites in Czechia. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Jiří Hynčica (0042059737 ext. 2587, jiri.hyncica@fno.cz), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Concentration of IPA on mass spectrometry (time frame: 31 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05860387, which also lists 38 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Sep 2023.

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