VANISH: The evolution of pulmonary lesions on high resolution computed tomography scans in immunocompromised children with a suspected invasive fungal disease.

Invasive fungal disease (IFD) remains an important cause of morbidity and
mortality in children with hemato-oncological malignancies. The incidence of
IFD in pediatric oncology patients varies widely between studies and ranges
between 1.7- 35%, depending on the type of malignancy. In paediatric
immunocompromised patients, the most common IFD is invasive aspergillosis (IA).
Persistent neutropenic fever in the presence of radiological abnormalities on a
HRCT of the lungs suggestive of IFD often leads to antifungal therapy as timely
treatment in those patients who do have a IFD is important for survival. For
patients with IA initial combination therapy with voriconazole/isavuconazole
plus liposomal amphotericin B (L-AmB), or voriconazole/isavuconazole plus an
echinocandin is recommended. Definitive diagnosis of IA however is cumbersome
and even after invasive microbiological investigation most cases of suspected
IA remain possible or probable according to the EORTC/MCG criteria.
Consequently, radiological assessment of the lung is an important component in
the management of IA and continuation, or adaptation of antifungal treatment
relies heavily on sequential analysis of Computed Tomography (CT) scans.
Evolution of CT scan images of patients with IA has been studied poorly. The
volume of Aspergillosis lesions from 30 adult patients with probable or proven
IA increased significantly from day 0 to day 7 and decreased from day 7 to day
14. Moreover, sequential analysis of lesion volumes seems to predict outcome
more precisely than comparison to baseline images. Any increase in CT volume
between day 7 and day 14 was a sensitive marker of a lethal outcome.
In addition, a mixed pattern of a reduction of the initial lesions and the
appearance of new lesions has been described on CT scans, it has been suggested
that this mixed response is the result of a combination of an azole-resistant
and azole-susceptible infection.
More knowledge of the evolution of pulmonary lesions in order to determine
therapeutic response in children with IA could hopefully lead to earlier
de-escalation of combination therapy or prevent unnecessary escalation of
antifungal treatment. Focusing on the reduction of antifungal agents is
important as current treatments have side effects, drug interactions, high
costs and emergence of resistance.
Besides the radiological assessment, microbiological is a pivot component of
the IFD diagnostic workup. Although progress has been made over the last
decades, microbiological confirmation of a pulmonary IFD is hampered by the low
sensitivity of diagnostic test. The SOC microbiological testing consists out of
Galactomannan (GM) antigen testing, culture, and PCR testing on bronchial
alveolar lavage (BAL) fluid or GM testing on serum. Ideally, new diagnostic
test is able to detect IFD from minimally invasive obtained blood with high
sensitivity and specificity. A promising novel method is the sequencing of
cfDNA to detect microbial (e.g. Aspergillus spp.) in plasma. A proof-of-concept
study (submitted) showed a high sensitivity and specificity in the detection of
Aspergillus fumigatus. To confirm the potential of this new diagnostic method,
it needs to be tested in a broader population and compared to the standard of
care diagnostic work-up. This will include clinically relevant fungal
pathogens, Aspergillus and non-Aspergillus species.
Over the last two years (2020-2021) 43 children were treated for a possible
(n=19), probable (n=22) or proven (n=1) IA in the Princess Maxima Center. Three
children died due to underlying disease progression not directly related to IA.
Antifungal treatment was given for prolonged period of time (primary treatment
and secondary prophylaxis) both for children with possible or probable/ proven
IA. The objective of this study is to examine the evolution of pulmonary
lesions on serial HRCT scans in pediatric patients with possible or probable/
proven IA by evaluating volume size of the lesions.

Primary Objective:
1. The first objective of this study is to examine the evolution of pulmonary
lesions on serial HRCT assessments in pediatric patients with possible or
probable/ proven IA. The lesions will be measured three dimensionally and five
scans per patients will be compared (day 0, 7, 14, 28, 42) and the evolution
will be expressed as increase or decrease of volume compared to the baseline
scan (day 0) and compared to the preceding scan. This will be done by measuring
the volume size of (maximally five) pulmonary lesion(s).
2. The second objective of this study is to compare two diagnostic test. The
sensitivity of two tests (SOC vs cfDNA sequencing) in the detection of IFD in
blood will be compared.


Secondary Objective(s):
Secondary exploratory objectives of this study are:
- to identify other qualitative radiological markers that are sensitive in
differentiating in the course of the fungal disease and corresponding clinical
outcome
- The additional value of a scan on day 7 will be compared to the standard of
care and evaluated.
- to collect blood and BAL to improve molecular detection (besides cfDNA)
methods for pulmonary fungal infections
- To describe the proportion of patients in which new lesions appear during the
treatment period and describe the evolution of these new lesions over time
(mixed-effect)

The study is a prospective observational trial and will be executed at the
Princess Máxima Center for pediatric oncology. Patients be included during a 3
years period.

To assess accurate radiological response an extra HRCT scan at day 7 will be
performed compared to standard care. The burden of extra radiation will be
minimal. A HRCT scan of the lungs takes approximately 5-10 minutes. The
additional blood draw and collection of BAL poses a minimal additional burden,
the blood draw will be done, as much as possible, simultaneously with standard
care blood draw and only the residue of the bronchoalveolar washing (BAL) will
be collected and stored. The total amount of blood draw will not exceed 0.8
mL/kg. This poses minimal additional burden for the patient.