A study of a non-invasive measurement method for idiopathic pulmonary fibrosis patients. The predictive value of the IOS for the degree of fibrosis compared to the lung function test.

Idiopathic pulmonary fibrosis (IPF) is the most common cause of interstitial
lung disease (ILD) and has a poor prognosis with a five-year survival of only
20-30 percent. Lung function testing in patients with IPF shows a restriction
(total lung capacity (TLC) <80%) and a reduced diffusion capacity of the lung
for CO (DLCO). The volume flow shows a reduced FVC with a normal FEV1 / FVC
ratio; although the FVC is not the parameter to demonstrate a restriction, it
is often used to follow up patients.
Both the DLCO measurement and the volume flow are tests that require effort
from the patient. In ILD patients, these tests are often difficult to perform
and they are a heavy burden for the patient.
In 1956, DuBois et al. described the forced oscillation technique (FOT) as an
instrument that can measure lung function using sinusoidal sound waves, which
are produced by a speaker and are superimposed over the normal breath.
The pressure / flow ratio is measured at the mouth over a range of frequencies
(usually 3 to 35 Hz), resulting in the respiratory impedance (Zrs). The Zrs is
the sum of respiratory resistance (Rrs) and respiratory reactance (Xrs). The
reactance, Xrs, consists of the capacitance and inertia. The capacitance gives
the ability to store energy in the periphery and is influenced by the elastic
properties of the lung. The capacitance is displayed as a negative number and
dominates at low frequencies (X5Hz). Inertia says something about the
resistance of the respiratory system to move (mass inertia) and dominates at
high frequencies. The balance between capacitance and inertia is expressed in
resonant frequency (Fres), which is represented as an intersection on the zero
line. The AX (AUC) is obtained from the Fres and the X5Hz. All these IOS
parameters provide valuable information about the mechanical properties of the
lung parenchyma.
Michaelson et al. developed a variation on the FOT technique in 1975, in which
a computer-controlled speaker generates pulses of square waves, with the
different frequencies being offered simultaneously: the pulse oscillometry
system (IOS). The IOS measures pressure-flow ratios within a range of
frequencies between 4 and 32 Hz. This new technique was improved over the years
by Jaeger and became commercially available in 1998. Both FOT and IOS are used
clinically in paediatrics, but also in lung diseases in research.
The main advantage of FOT / IOS is that it is a non-invasive test that requires
only a rest breathing of the patient, which requires significantly less
strength and cooperation than, for example, spirometry. The difference between
FOT and IOS is subtle, both measuring Rrs and Xrs on different frequencies, but
they are not comparable in terms of outcomes.
Fisher et al showed in 1968 that an increased respiratory resistance was seen
in ILD patients with FOT, however the number of patients was small and the FOT
analysis was brief. Much later, in 2009, Van Noord et al showed that patients
with advanced ILD showed an increased Rrs and decreased Xrs, however these were
the same in patients with moderate-severe COPD on which it was concluded that
FOT can not differentiate between obstruction and restriction. However, both
Mori et al (FOT) and Sugiyama et al (IOS) report that the reactance at 5 Hz
(X5) is inspiratory more negative than expiratory in patients with ILD, which
is the opposite in COPD patients: there are the expiratory X5 values **are more
negative. The mean Δ X5 values **are therefore negative for COPD and positive
for ILD.
In 2003 Wells et al developed the composite physiological index (CPI); this is
obtained from FEV1, FVC and DLCO. The CPI correlates best with the severity of
fibrosis on the HRCT compared with the independent lung function parameters.
Recently, Fuji et al have shown that the inspirational Fres values **measured
by FOT correlate with the CPI and the severity of the fibrosis on the HRCT. It
is striking that Fuji et al find no correlation between the mean ΔX5, which is
discrepant with the earlier findings of Sugiyama et al.
It could be a huge clinical benefit for the patient to be able to use FOT or
IOS to predict the disease course in severe IPF, as many of these patients can
not easily perform current lung function tests such as spirometry and DLCO
measurement. .

This study investigates the correlation between IOS and the severity of
fibrosis on HRCT in patients with IPF. It also investigates which IOS parameter
best relates to the degree of fibrosis on the HRCT. Furthermore, as a secondary
endpoint, it is investigated whether IOS reflects the degree of fibrosis as
well as the CPI. In addition, patiënts will score the degree of effort off
undergoing IOS measurement versus conventional lung function testing,
furthermore they are being asked how they experience undergoing IOS.

This is a diagnostic cross-sectional cohort study.
An interim analysis* follows, in 60 patients, to determine the independence of
the measurement moments.

The goal (target) is to include 110 diagnosed IPF patients.
The patients will perform an IOS measurement twice during the regular
examination and will answer a short questionnaire with a BORG score.

110 IPF patients / measurements:

Measurement 1:
HRCT
Lung function (IOS, spirometry, DLco, IOS)
Questionnaire (BORG)

Possibly after 6 months measurement 2, depending on interim analysis *:
HRCT
Lung function (IOS, spirometry, DLco, IOS)
Questionnaire (BORG)

* Interim analysis:
If the measurements are independent of the patient, then it is possible to use
two measurement moments of the same patient to determine the coherence of
values.

Participation in the research takes 10 minutes extra time in addition to the
regular measurements.
Patients do not experience any adverse effects or inconveniences of
participating in this study.