Idiopathic Pulmonary Fibrosis (IPF) is an interstitial lung disease (ILD) characterised by an increase in the quantity of extra-cellular matrix and the destruction of parenchyma structure. The result is a reduction in the lung's ability to undergo gas exchange, ultimately causing systemic hypoxia and cardiac failure. As idiopathic suggests, there is no known cause of the disease and currently, treatment options are very limited. With a mean survival of 3 years after diagnosis, IPF has an extremely high mortality.
Clinical trials investigating IPF treatments are limited by an inability to track progression of disease. However, positron emission tomography / computerised tomography (PET/CT), a functional imaging methodology, may provide a disease progression biomarker making it a very promising technique for use in clinical studies.
PET/CT provides images of the concentration of a radiotracer in the body at a spatial resolution of approximately 4-7mm. While static imaging is the most regularly used imaging method, the parameter derived, the standardised uptake value (SUV) is sensitive to the time of the acquisition and the supply of the radiotracer to the tissue. Dynamic imaging however, makes use of the time variable tracer uptake and radiotracer supply, providing much more robust information on the physiological changes in the tissue. Use of dynamic imaging in diffuse lung diseases is rare and to obtain accurate parameter estimates in this patient group consideration must be given to how the respiratory cycle and the tissue fraction effect (TFE), a result of the time variable lung air and blood components, will impact the PET quantitation.
The Tissue Fraction Effect
As part of this work, a previously published correction method for the TFE was expanded to include correction for the blood component in static imaging and then further developed to allow air and blood corrections (ABC) of the kinetic parameter estimates. Use if the ABC was found to reduce bias due to variations in the quantity and uptake of the air and blood components, ensuring that the measured PET signal originated from the parenchyma. The result is a potential enhancement in the sensitivity of the measured parameter to changes induced by drug interventions .
These techniques were further reviewed using IPF patient data and found that correcting for the air and blood components in the lung inverted the relative SUV and influx rate constant estimates between the fibrotic and normal appearing tissue. This meant that while previously it was thought that there was an increased uptake of FDG in the regions of fibrosis in comparison to the normal appearing lung, after correction, this was no longer the case, changing the possible interpretation of the patient data .
Further work in this area is required to accurately determine and validate the fractional blood volume in the lung, required to apply the ABC. To do this, partial volume effects, both in the aorta and the lung itself need to be accounted for.
PET/CT Mismatch Due to the Respiratory Cycle
Consideration has been given to the effects of PET and CT attenuation map mismatch on PET parameter estimates, static and dynamic, in both the lung and a region representing a lung tumour. Errors associated with the mismatch were found to be predominantly local to the area of the mismatch and dependent on the activity distribution throughout the body in the field of view. The error dependency on activity distribution means that the effects of mismatch between PET and CT are specific to the radiotracer used and the time of acquisition . As a solution to these issues, a combination of CT information from a multi-scan protocol was suggested and, when used as the attenuation map for reconstructing the PET data was found to reduce PET quantitation errors.
Studies undertaken at the INM have allowed characterisation and correction of some of the uncertainties associated when imaging diffuse lung diseases, allowing for more stable and robust parameters to be determined [1,2]. However, more work needs to be done if a useful disease biomarker from dynamic PET data is to be found. The aim of our current research is therefore to investigate and attempt to provide solutions for the issues associated with obtaining quantitative static and kinetic PET parameter estimates in the lung in general and in IPF in particular.
 Holman BF, Cuplov V, Millner L, Hutton BF, Maher TM, Groves AM, and Thielemans K. Improved correction for the tissue fraction effect in lung PET/CT imaging. Phys Med Biol, 60(18):7387-7402, 2015. http://dx.doi.org/10.1088/0031-9155/60/18/7387.
 Holman BF, Cuplov V, Hutton BF, Groves AM, and Thielemans K. The effect of respiratory induced density variations on non-TOF PET quantitation in the lung. Phys Med Biol, 61(8):3148-63, 2016. http://dx.doi.org/10.1088/0031-9155/61/8/3148.