Clinical trial NCT03004092: Novel Biomarkers for Invasive Aspergillosis
Official title: Novel Biomarkers for Invasive Aspergillosis
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Aspergillosis Invasive
Keywords: bis(methylthio)gliotoxin
lateral flow device
JF5
Galactomannan
Invasive aspergillosis
Lead sponsor: Universitaire Ziekenhuizen KU Leuven
Sponsor class: OTHER
First posted: 2016-12-28
Enrollment: 226
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: DIAGNOSTIC

Brief summary: Diagnosis of invasive aspergillosis remains difficult, and is often based on a combination of patient characteristics, radiological and microbiological findings. To data, galactomannan (GM) is the only well-validated biomarker available. However, GM still has its shortcomings. There is therefore a need for new, complementary biomarkers. In this study, two of those tests, bis(methylthio)gliotoxin (bmGT) and a lateral flow device, will be validated in a hematological population, and compare it to GM.

Detailed description: Diagnosis of invasive aspergillosis is often difficult to achieve with certainty, as this requires direct evidence of invasive growth on histopathological examination. A probable diagnosis can be suspected based on both clinical and mycological evidence of the disease, in presence of a susceptible patient. The EORTC-MSG guidelines offer a widely accepted basis for this diagnosis. Under these guidelines, mycological evidence can consist of a positive culture of aspergillus spp, or of detection of galactomannan (GM) in a relevant body sample. GM is a part of the Aspergillus mould and can be detected using a commercially available immunoenzymatic sandwich microplate assay. However, like most biomarkers, galactomannan is far from a perfect biomarker. Several beta-lactam antibiotics are known to cause false positives, and anti-mould therapy has been reported to significantly lower the sensitivity\[1\]. Additional biomarkers that could circumvent these problems would therefore be beneficial.

A potential new target is gliotoxin (GT), a secondary metabolite of several fungi, the most clinically important of which is Aspergillus\[2\]. GT is released during invasive growth, and can therefore be used as a biomarker of invasive fungal disease by GT-producing fungi. However, GT is quickly removed by red blood cells from circulation, making it an unreliable marker\[3\]. A degradation product of GT, bis(methylthio)gliotoxin (bmGT), appears to be more stable as it is not taken up by red blood cells. Serum bmGT or bmGT in bronchoalveolar lavage (BAL) fluid has already been shown in small studies to be a potential marker of invasive aspergillosis, especially when used in combination with GM\[3-5\].

Recently, another highly specific test has become available, based on detection of an extracellular glycoprotein secreted during the growth of Aspergillus species, using a monoclonal antibody (JF5) in an immunochromatographic lateral-flow device (LFD)\[6,7\]. This test allows fast (\<15 minutes) testing using a commercially available device.

In this study, both the LFD and bmGT will be characterized and validated in a hematological population, and compared to GM.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 16y at start of study
* One of the following diagnoses:
* De novo, refractory or relapsed AML/MDS receiving intensive chemotherapy
* De novo, refractory or relapsed ALL/T-lymphoblastic lymphoma receiving intensive chemotherapy
* Aplastic anemia requiring ATG therapy
* Any patient admitted for either autologous or allogeneic hematopoietic stem cell transplantation
* Written informed consent obtained from the patient

Exclusion Criteria:

* AML or ALL beyond the specified inclusion criteria
* Directed treatment for possible, probable, or proven invasive aspergillosis, at moment of screening, or with end of treatment \< 6 weeks at screening, or no complete response according to EORTC/MSG criteria, or complete response achieved \< 6 weeks at time of screening.

Primary outcomes:
measure: Diagnostic accuracy of serum bmGT
timeFrame: 2 weeks
Secondary outcomes:
measure: Diagnostic accuracy of a combination of serum bmGT and serum GM
timeFrame: 2 weeks
measure: Prognostic value of serum bmGT
timeFrame: 6 weeks
measure: Prognostic value of serum bmGT kinetics
timeFrame: 6 weeks
measure: Renal and hepatic influence on bmGT
timeFrame: 2 weeks
measure: Compare bmGT-HPTLC to bmGT-LC/MS
timeFrame: Same day
measure: Diagnostic accuracy of BAL bmGT
timeFrame: 2 weeks
measure: Diagnostic accuracy of LFD
timeFrame: 2 weeks
Other outcomes:
Locations:
city: Leuven
country: Belgium
facility: University Hospitals Leuven
Study officials:
References:
citation: Pfeiffer CD, Fine JP, Safdar N. Diagnosis of invasive aspergillosis using a galactomannan assay: a meta-analysis. Clin Infect Dis. 2006 May 15;42(10):1417-27. doi: 10.1086/503427. Epub 2006 Apr 14.
citation: Lewis RE, Wiederhold NP, Chi J, Han XY, Komanduri KV, Kontoyiannis DP, Prince RA. Detection of gliotoxin in experimental and human aspergillosis. Infect Immun. 2005 Jan;73(1):635-7. doi: 10.1128/IAI.73.1.635-637.2005.
citation: Domingo MP, Colmenarejo C, Martinez-Lostao L, Mullbacher A, Jarne C, Revillo MJ, Delgado P, Roc L, Meis JF, Rezusta A, Pardo J, Galvez EM. Bis(methyl)gliotoxin proves to be a more stable and reliable marker for invasive aspergillosis than gliotoxin and suitable for use in diagnosis. Diagn Microbiol Infect Dis. 2012 May;73(1):57-64. doi: 10.1016/j.diagmicrobio.2012.01.012. Epub 2012 Apr 4.
citation: Vidal-Garcia M, Domingo MP, De Rueda B, Roc L, Delgado MP, Revillo MJ, Pardo J, Galvez EM, Rezusta A. Clinical validity of bis(methylthio)gliotoxin for the diagnosis of invasive aspergillosis. Appl Microbiol Biotechnol. 2016 Mar;100(5):2327-34. doi: 10.1007/s00253-015-7209-6. Epub 2015 Dec 17.
citation: Thornton CR. Development of an immunochromatographic lateral-flow device for rapid serodiagnosis of invasive aspergillosis. Clin Vaccine Immunol. 2008 Jul;15(7):1095-105. doi: 10.1128/CVI.00068-08. Epub 2008 May 7.
citation: Mercier T, Guldentops E, Lagrou K, Maertens J. Prospective Evaluation of the Turbidimetric beta-D-Glucan Assay and 2 Lateral Flow Assays on Serum in Invasive Aspergillosis. Clin Infect Dis. 2021 May 4;72(9):1577-1584. doi: 10.1093/cid/ciaa295.