Novel insights in cough and breathing patterns of patients with idiopathic pulmonary fibrosis performing repeated 24-hour-respiratory polygraphies
Schertel et al. Respiratory Research
Novel insights in cough and breathing patterns of patients with idiopathic pulmonary fibrosis performing repeated 24-hour-respiratory polygraphies
Anke Schertel 0
Manuela Funke-Chambour 0
Thomas Geiser 0
Anne-Kathrin Brill 0
0 Department of Pulmonary Medicine, Inselspital, Bern University Hospital, University of Bern , Freiburgstrasse, 3010 Bern , Switzerland
Background: The main symptoms of patients with idiopathic pulmonary fibrosis (IPF) are cough and dyspnea. IPF leads to a restrictive lung disorder impacting daytime and nocturnal breathing patterns. In this pilot study we assessed the course of day- and nighttime respiration, oxygenation, and cough over a period of 8 months as well as differences between wakefulness and sleep in IPF patients. Methods: Repetitive 24-h respiratory polygraphies (RP) and pulmonary function tests were performed at baseline and after 3, 4, 7 and 8 months. Cough-index, oxygenation parameters (SpO2, time with SpO2 < 90%, desaturation index), respiratory rate and heart rate were assessed for differences between wakefulness and sleep. The first and the last RP were compared to identify changes of these parameters over time. Statistical analyses were performed with Wilcoxon signed rank tests. Results: Nine IPF patients (8 male, median age 67 years (IQR 60, 77) with 37 valid 24-h RPs were included. Eight patients (88.9%) received antifibrotic treatment. Cough was more prevalent during wakefulness with a median cough-index of 14.8/h (IQR 10.9, 16.8) and 1.6/h (IQR 1.3-2.8) during sleep, p = 0.0039. Oxygenation parameters showed no difference, while respiratory- and heart rate were significantly higher during wakefulness. Despite stable pulmonary function tests over 8 months, the initially elevated respiratory rate increased further during wakefulness (baseline RR median 25.7/min (IQR 19.8, 26.6) vs. RR median 32.2/min (IQR 26.5, 40.9) at follow-up, p = 0.0273). The other respiratory parameters remained stable over time. Conclusion: Cough in IPF patients is more prevalent during wakefulness than during sleep. Further studies with a larger sample size and longer a follow-up period are needed to evaluate the role of the respiratory rate during wakefulness as a potential clinical follow up parameter in IPF.
Idiopathic pulmonary fibrosis; Follow up; Cough; Respiratory rate; Breathing pattern; 24-h-respiratory polygraphy
Idiopathic pulmonary fibrosis (IPF) is a rare but
devastating, chronic progressive interstitial lung disease of
unidentified etiology. IPF usually manifests with dyspnea
and/or dry cough and leads to a restrictive lung disorder,
altered gas exchange and subsequent modifications in
the breathing pattern [
Currently, the forced vital capacity (FVC) serves as the
main follow up parameter to assess disease course, with
a decline in FVC of ≥ 10% over 6 months being
associated with worse survival [
]. However, in the era of
available antifibrotic treatments this parameter might not be
sensitive enough anymore to early identify further
disease progression [
24-h-respiratory polygraphies (RP) with audio tracks
provide additional information on cough, and breathing
patterns and might also allow conclusions on disease
progression, even if FVC remains stable. In this
observational pilot study we used repetitive 24-h-RPs to analyze
the course of breathing patterns, oxygenation and cough
in IPF patients over a period of 8 months. Additionally,
we aimed to identify differences in these parameters
between wakefulness and sleep.
Participants and measurements
For this study, data was obtained from consecutive IPF
patients who were seen in the in the Department of
Pulmonary Medicine of the University Hospital Bern,
Switzerland, and included in a clinical study between
May 2014 and November 2016. The study was approved
by the Cantonal ethics committee Bern (REC-No: KEK
002/14). All participants provided written informed
consent. Inclusion criteria were an age of >18 years, the
diagnosis of IPF with histological or radiological
confirmed UIP pattern based on the current ATS/ERS
], and a subjectively disabling cough.
Patients suffering from combined emphysema and fibrosis
were excluded. As part of the study protocol each
participant underwent repetitive ambulatory 24-h RPs
(NOX T3, Nox Medical, Höfðatorg, Reykjavík, Iceland),
standard pulmonary function tests (PFT),
six-minutewalk-test (6MWT) and St. George Respiratory
Questionnaire (SGRQ) at baseline and 3, 4, 7 and 8 months.
For the 24-h RPs patients were instructed to continue
their normal daily routine during the recording period
and to keep an activity log. Established long-term
oxygen therapies were not interrupted for the study. Scoring
of the RPs was carried out by a blinded investigator
according to the AASM criteria [
] and the following
definitions: lacking EEG-conduction in RP, the RP was
manually divided into periods of assumed wakefulness
and sleep with sleep being defined as periods without an
upright position, no or minimal activity, audible snoring,
no other sounds on the audio track and no other activity
on the patients log. Cough was scored analogous to
Kelsall et al. [
]. Additionally, single cough events were
defined as one, or more cough sounds within less than 4
seconds and no more than 2 seconds between the single
coughs, cough attacks were defined identically, but with
a duration of more than 4 seconds. Furthermore, we
scored sounds of throat clearing. Each of the different
sounds was verified acoustically. Cough-index was
calculated from the sum of all the cough sounds mentioned
above. Sleep disordered breathing was defined according
to the current AASM guidelines. An apnea-hypopnea
index (AHI) <5/h was considered as no SDB, an AHI
between ≥5/h and <15/h was classified as mild, an AHI
between ≥15/h and <30/h as moderate and an AHI ≥30/h
as severe OSA, respectively. Mean SpO2 (%), minimal
SpO2 (%), time in hypoxia [time with SpO2 < 90%
(min)], oxygen desaturation index (ODI), BNP,
respiratory and heart rate were measured over 24 h and then
calculated for the defined periods of wakefulness and
Based on our findings concerning the respiratory rate
(RR) a post-hoc analyses was done to compare the
median overall RR awake of all RPs and FVC values
between the patients that were alive and those, that were
deceased on March 15th, 2017.
Statistical analyses and graphs were performed using
GraphPad Prism 7.0 (GraphPad Software Inc., La Jolla, CA,
USA). Distribution of data was tested with
KolmogorovSmirnov-test. Comparisons of the parameters between
sleep and wakefulness were performed with paired
Wilcoxon signed rank tests from the means of the repetitive
measurements of each participant. Over time, parameters
were compared with paired Wilcoxon tests between first
and last available RP. Data are presented as median
followed by interquartile range (IQR 25, 75). Significance
level was set at 0.05.
Overall, nine IPF patients, of whom eight received
antifibrotic treatment were studied. The median treatment
duration with antifibrotics at baseline was 7 months
(IQR 3.5, 10.8). The median GAP-Score at baseline was
4.0 points (IQR 3.0, 5.0), corresponding to GAP-Stage 2
]. At the time of data collection all participants were
in a clinically stable state. A summary of the baseline
characteristics and lung function data are shown in
Table 1. Out of the planned 45 24-h RPs 37 RPs were
analyzed (n = 6 technical failure, n = 2 refused by
IPF duration at time of first RP (months)
Wakefulness and sleep
The median cough-index over 24 h was high with 9.55/h
(median absolute cough count 229 per 24 h). Cough was
significantly more prevalent during wakefulness (median
overall cough-index awake 14.8/h (IQR 10.9, 16.8) than
asleep (median overall cough-index asleep 1.6/h (IQR
1.32, 2.75); p = 0.0039). This was also found in the RPs
at baseline, after 8 months and for the overall cough
count and cough index across all valid RPs. RR and heart
rate were more elevated during wakefulness compared
with sleep, while oxygenation showed no significant
difference. Results of oxygenation during wakefulness and
sleep are displayed in Additional file 1: Table S1.
Course of the respiratory and clinical parameters over time
Over time the median awake RR increased significantly
from 25.7/min (IQR 19.8, 26.6) to 32.2/min (IQR 26.5,
40.9), p = 0.0273 (Fig. 1) and remained stable during
sleep (median RR asleep at baseline 20.1/min (IQR 18.9,
21.3); follow up median RR asleep 20.2/min (IQR 18.3,
23.4), p = 0.2109). PFT, 6MWT, oxygenation parameters,
BNP and the SGRQ score remained stable. These results
are summarized in Additional file 1: Table S2.
Respiratory rate and FVC – Comparison between
survivors and non-survivors
Patients were followed up for survival from study inclusion
until March 15th 2017 (median follow-up time 13 months
(IQR 11, 23). Five patients survived (55.6%). The median
overall RR awake of all RPs was significantly higher in the
non-survivors [33.1/min (IQR 24.4, 40.3)] than in the
survivors [25.0/min (IQR 20.4, 30.4)], p = 0.0335 (Additional file 1:
Figure S1 in the) while the median FVC was significantly
lower in the non-surviving patients (2.1 L (IQR 1.9, 3.0) /
52% predicted (IQR 50.3, 74.0) compared to the survivors
(FVC 2.8 L (IQR 2.7, 3.2) / 70% predicted (IQR 57.3, 79.8),
p = 0.0035 / p = 0.0077.
The most important findings of this study are a
significantly higher cough-index during wakefulness in
IPF patients and an increase in the awake RR over
time despite stable oxygenation parameters and
pulmonary function tests.
Cough is frequent in IPF and the cough indices in IPF
patients subjectively complaining about cough in our
study are in line with the data of Key et al. who also found
a median daytime cough-index of 14.6/h and significantly
less coughing at night with 1.9/h [
]. The exact
mechanisms by which cough is caused in IPF is not entirely
known, but the pronunciation of cough during
wakefulness indicates a possible mechanical influence of speech
and/or physical activity and potentially increased cough
reflexes that may then be diminished during sleep [
We assume that the differences between wakefulness
and sleep seen in oxygenation and heart rate with
increases in heart rate and slightly worse oxygenation can
be attributed to an increase in physical activity during
In our observational study, as an interesting finding
RR during wakefulness showed a progressive and
significant increase while all oxygenation parameters and
pulmonary function tests, even FVC – to date the most
powerful predictor of disease progression in IPF
remained stable over the study period. The overall
elevated RRs are in line with former physiological studies
that showed a higher resting minute ventilation in
patients with IPF compared to healthy controls. This
increase in resting minute ventilation was achieved by a
significant increase in RR with more severe disease,
while the tidal volume decreased progressively [
FVC being inversely correlated with the RR and directly
with the tidal volume . One more recent laboratory
study found a different breathing pattern with an
increase in minute ventilation in IPF patients caused by an
increase in tidal volume in daytime measurements at
rest, while the RR remained stable [
]. The current
study was performed in a real-life scenario with the
patients being able to perform their usual daily routine
while being monitored by RP at home. We could thus
avoid a bias, as a study setting will inevitably influence
the breathing pattern due to explicit direction of the
patients’ concentration on respiration.
Until now different predictors of prognosis in IPF have
been identified, including demographical, clinical,
physiological and radiological aspects as well as the impact of
certain comorbidities as pulmonary hypertension,
emphysema, gastroesophageal reflux and lung cancer [
GAP-Score has been developed as a model for predicting
1-year-mortality . The observed progressive increase in
RR during wakefulness in this study raises the question, if
RR could serve as an additional and maybe more reliable
follow-up-parameter and predictor for mortality in IPF. In
the acute setting the RR is a valuable vital sign, as baseline
tachypnea or an increasing RR during hospitalization are
well-established predictors of critical illness or potentially
upcoming life-threatening events as acute respiratory
failure or even cardiopulmonary arrest [
]. Thus, RR is
part of several risk assessment scores for different medical
conditions, i.e. the CURB-65 for community acquired
pneumonia  or the Pulmonary Embolism Severity
Index (PESI) [
]. In COPD patients a temporary increase
in RR is also one of the earliest signs of an exacerbation
and could possibly be helpful in early detection of
]. The baseline RR at rest or during exercise
has not been found to have a prognostic value for IPF in
the study by King et al. [
], but the course of RR in IPF
has not been reported so far. Monitoring RR in
IPFpatients might provide valuable additional information on
acute disease progression and over a longer period of time.
The fact, that the RR in the non-survivors was
significantly higher might be an expression of a more severe
restrictive lung defect and indicates, that a rise in RR could
be predictive of disease progression, although this cannot
be proven by means of this small pilot study.
Although our study has included only nine patients,
the number of available RPs strengthens our
observations. A limitation is the lack of a control group with
healthy subjects or patients with other lung diseases to
evaluate disease specific development of the parameters
in more detail. The 24-h-RP provides information over a
whole day. Thus, physical activity will influence the RR.
As people were instructed to continue their normal daily
routine, this could be considered as a systematical error,
not influencing the course of RR. A major limitation is
the use of oxygen by some patients during the RPs that
is falsifying the oxygenation parameters and the results
of exercise-testing. But for ethical concerns it would not
have been appropriate to withdraw oxygen for 24 h in a
hypoxemic and symptomatic patient. Besides having
studied a population with more severe lung functional
limitations and less sleep apnea this might also explain
in part why in our patients the sleep desaturations did
not exceed that of normal daytime activity, which has
been reported before [
]. Nevertheless, despite the
application of supplemental oxygen, the significant increase
in RR is still detectable.
Although antifibrotic drugs reduce the decline of
FVC in IPF-patients the mortality remains high.
Additional parameters are needed to monitor disease
progression and predict mortality [
]. RR during
wakefulness might be a potential follow-up parameter, but
further studies with a larger sample size and longer
follow-up periods are needed to confirm our findings
and test their clinical implication.
Additional file 1: Table S1. Respiratory parameters and cough during
wakefulness and sleep. Table S2. Respiratory parameters, exercise tests
and quality of life over time. Figure S1. Comparison of respiratory rate
and FVC between survivors and non-survivors (DOCX 49 kb)
Supported by the Research Fund of the Swiss Lung Association, Bern.
Availability of data and materials
The datasets analyzed during the current study are available from the
corresponding author on reasonable request.
AS, MFC and AKB designed the study. AS analyzed all respiratory polygraphies.
Data analyses were performed by AS and AKB. All authors contributed to the
interpretation of the data and writing of the manuscript, read and approved the
Ethics approval and consent to participate
The study was approved by the Cantonal Ethics Committee Bern (REC-No:
002/14). All participants provided written informed consent.
Consent for publication
A.S. and A-K.B. have no real or perceived conflict of interest with the reported
work. M.F-C. received research grants and M.F-C. and T.G. received speaker’s fees
from Roche and Boehringer Ingelheim.
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