PET/CT Guided Antifungal Stewardship in Invasive Pulmonary Aspergillosis

Invasive pulmonary aspergillosis (IPA) is the 3rd most frequent invasive mycosis in France with a rising incidence and 40% mortality (Bitar, 2014, Lortholary, 2011). Modern antifungals (AF) improved survival of IPA but lead to ecological, toxic and cost issues. In agreement with the " plan national de la bonne maîtrise des anti-infectieux ", optimization of AF duration in IPA appears therefore challenging.

Positron emission tomography using 2-deoxy-2-[fluorine-18] fluoro- D-glucose integrated with computed tomography (18F-FDG PET/CT) was reported to allow shortened AF duration (Hot, 2011, Chamilos, 2008) and is currently evaluated during chronic disseminated candidiasis {CANHPARI trial, PHRC 2012, NCT01916057}. The investigators raise the hypothesis that normalization of the functional imaging 18F-FDG-PET/CT during IPA could occur earlier than that of conventional imaging. However, due to the current lack of data, an intervention trial evaluating an early AF withdrawal based on 18F-FDG-PET/CT appears premature. In order to optimize IPA treatment duration, a two-step evaluation project has been designed. The first step consists in OPTIFIL prospective project. It will evaluate the therapeutic response through a systematic 18F-FDG-PET/CT at week 6 (crucial time point (Segal) used in recent IPA trials (Marr, 2015, Maertens, 2016). The latter response will be correlated with the kinetics of selected biomarkers including antigens (galactomannan, β-D glucans), circulating Aspergillus DNA and anti-Aspergillus host response markers in addition to the conventional imaging tools obtained at weeks 6 and 12. OPTIFIL project results will serve establishing a decision algorithm used during the second step intervention trial evaluating the accuracy of IPA AF interruption.

Pilot prospective multicenter study of therapeutic follow-up of IPA in patients with hematological malignancy.

Patients will have an inclusion visit (D0) and 8 or 9 follow up visits: D3, W1, W2, W4, W6, End of Treatment, W24 and W48.

Each visit will include physical examination.

Lung CT scan, 18F-FDG-PET/CT, samplings of blood will be performed at different visits in respective centers

β-D-Glucan, Aspergillus fumigatus and Aspergillus spp. quantitative PCRs and host biomarkers such as Aspergillus Elispot will be performed and centralized

Response evaluation will be assessed by an independent committee.

CT response will be evaluated by a blinded radiologist. PET/CT response will be evaluated by 2 blinded nuclear medicine physicians.

Inclusion criteria

• Patients ≥18 years-old
• Patient with hematological malignancy
• Proven or probable invasive pulmonary aspergillosis according to EORTC/MSG modified criteria
• Inclusion ≤ 4 days (≤ 5 days in case of week end) after IPA diagnosis
• Possibility to perform 18F-FDG-PET/CT scanner within the 7 subsequent days following diagnosis
• Informed consent form signed
• Affiliation to French social insurance

Exclusion criteria

• Pregnancy or breastfeeding women
• Life expectancy < 3 months
• Fungal or mycobacterial lung co infection at time of IPA diagnosis
• Haematological malignancy with lung location
• Proven or probable mold infection in 6 previous months
• Disseminated aspergillosis (lung and sinus aspergillosis can be included)