Rising stars of DPLD survival: FVC and exercise desaturation (a single-center study)

Abstract

Background/aim:
Diffuse parenchymal lung diseases (DPLDs) comprise a broad, heterogeneous group of diseases with common
functional characteristics and a common final pathway, usually leading to irreversible fibrosis. We investigated the effects of the
physiological and functional parameters and of pulmonary hypertension (PH) on survival in DPLDs.

Materials and methods:
The study included 158 patients with DPLDs. Patient data were examined retrospectively, and survival status
was obtained through phone calls.

Results:
Patients were divided into five groups according to their diagnosis: idiopathic pulmonary fibrosis (IPF), non-IPF idiopathic
interstitial pneumonias, connective tissue diseases, sarcoidosis, and other DPLDs. Median survival was 42.9 months. The significant
negative effects of older age, presence of delta saturation (DeltaSat; difference between oxygen saturation at rest and after the 6-min
walking test), 6-min walking distance (<350 m), systolic pulmonary artery pressure (sPAP; ≥50 mmHg), and baseline percentage of
diffusing capacity of the lungs for carbon monoxide (<80%) with percentage of forced vital capacity (FVC%; <80%) were detected on
survival (P < 0.05). A one-unit decrease in FVC% was related to a 6% increase in mortality. Another unique finding indicated that higher
DeltaSat (>10%) correlated strongly with sPAP (>50 mmHg) and thus with a worse survival rate.

Conclusion:
The current study determined that FVC% is important in the prediction of mortality. Moreover, it demonstrated a strong
relationship between exercise desaturation and PH.

Full text

826
http://journals.tubitak.gov.tr/medical/
Turkish Journal of Medical Sciences
Turk J Med Sci
(2018) 48: 826-832
© TÜBİTAK
doi:10.3906/sag-1802-196
Rising stars of DPLD survival: FVC and exercise desaturation (a single-center study)
Ayperi ÖZTÜRK1,*, Oya KAYACAN2
1Department of Interventional Pulmonology, Atatürk Chest Diseases and oracic Surgery Training and Research Hospital,
Health Sciences University, Ankara, Turkey
2Department of Chest Diseases, School of Medicine, Ankara University, Ankara, Turkey
* Correspondence: drayperi@yahoo.com
1. Introduction
Diuse parenchymal lung disease (DPLD) is a
heterogeneous category consisting of more than 200
diseases with similar clinical, radiological, and laboratory
properties. ese diseases lead to parenchymal lung injury
and severe accumulation of interstitial protein and cells,
associated with known or unknown causes (1,2). Although
DPLD classication is somewhat complicated, a consensus
report published by the American oracic Society
(ATS) and the European Respiratory Society classied
it into four main groups (3): DPLDs of known causes
(collagen vascular diseases [CVDs], etc.), idiopathic
interstitial pneumonias (IIPs), granulomatous DPLD (e.g.,
sarcoidosis), and other forms of DPLD (histiocytosis-X
[HX], lymphangioleiomyomatosis [LAM], etc.). Idiopathic
pulmonary brosis (IPF), which represents about half
of the cases of IIPs, is a chronic progressive disease
with poor treatment response and prognosis. Although
sarcoidosis is a multisystemic granulomatous disease
involving mostly the lungs and intrathoracic lymph
nodes, it has a good prognosis. However, pulmonary
parenchymal involvement is a poor prognostic factor in
CVD; for example, life expectancy has been reported to
decline by 3.5–4.9 years when pulmonary involvement is
identied in cases with rheumatoid arthritis (4–6). Many
survival studies have been conducted with subjects with
IIPs and particularly with IPF. In these studies, factors
such as diusion capacity (DLCO), hypoxia (at room
temperature and during exercise), exercise capacity,
and pulmonary hypertension have an important eect
on survival (7,8). e 6-min walking test (6MWT) is a
simple, inexpensive, reproducible, and well-tolerated
submaximal exercise test that is typically used in COPD
and vascular diseases. In IIP patients (particularly
severe cases), this test is also considered highly reliable
and reproducible (9). Oxygen desaturation during the
6MWT according to cardiopulmonary exercise testing
(CPET), even in the absence of resting hypoxia, is more
Background/aim: Diuse parenchymal lung diseases (DPLDs) comprise a broad, heterogeneous group of diseases with common
functional characteristics and a common nal pathway, usually leading to irreversible brosis. We investigated the eects of the
physiological and functional parameters and of pulmonary hypertension (PH) on survival in DPLDs.
Materials and methods: e study included 158 patients with DPLDs. Patient data were examined retrospectively, and survival status
was obtained through phone calls.
Results: Patients were divided into ve groups according to their diagnosis: idiopathic pulmonary brosis (IPF), non-IPF idiopathic
interstitial pneumonias, connective tissue diseases, sarcoidosis, and other DPLDs. Median survival was 42.9 months. e signicant
negative eects of older age, presence of delta saturation (DeltaSat; dierence between oxygen saturation at rest and aer the 6-min
walking test), 6-min walking distance (<350 m), systolic pulmonary artery pressure (sPAP; ≥50 mmHg), and baseline percentage of
diusing capacity of the lungs for carbon monoxide (<80%) with percentage of forced vital capacity (FVC%; <80%) were detected on
survival (P < 0.05). A one-unit decrease in FVC% was related to a 6% increase in mortality. Another unique nding indicated that higher
DeltaSat (>10%) correlated strongly with sPAP (>50 mmHg) and thus with a worse survival rate.
Conclusion: e current study determined that FVC% is important in the prediction of mortality. Moreover, it demonstrated a strong
relationship between exercise desaturation and PH.
Key words: Desaturation, diuse parenchymal lung diseases, forced vital capacity, survival, pulmonary hypertension
Received: 28.02.2018 Accepted/Published Online: 23.06.2018 Final Version: 16.08.2018
Research Article
is work is licensed under a Creative Commons Attribution 4.0 International License.

827
ÖZTÜRK and KAYACAN / Turk J Med Sci
oen observed in IIP (10,11). Desaturation to 88% or less
during baseline 6MWT is a more consistent and powerful
predictor of mortality in IIP than desaturation during
CPET (10,12,13). Exercise-induced desaturation has been
identied as an important factor for predicting mortality
(10–14). In an IPF-related study, a correlation was found
between the 6MWT and pulmonary artery pressure
(PAP). Pulmonary hypertension (PH) has recently been
considered a potential complication of DPLD (15–17).
is is encountered frequently in IPF, DPLD associated
with CVD (particularly scleroderma and rheumatoid
arthritis), sarcoidosis, and HX. PH development is a poor
prognostic factor for determining mortality (18). Hence,
current DPLD studies focus mainly on PH.
e goal of this retrospective study was to evaluate the
eects of physiological and functional parameters and of
PH on survival of DPLD patients.
2. Materials and methods
2.1. Patients’ characteristics
e medical les of 158 patients who were admitted with
the diagnosis of DPLD to the Interstitial Lung Disease
Unit of Ankara University’s Department of Chest Diseases
from 2000 to 2008 were retrospectively evaluated.
Patient data on sex, age, diagnosis, and dates of
diagnosis were recorded. Results of spirometric tests
(FVC%, FEV1%, FEV1%/FVC%, FEF25–75, PEF) and
results of single-breath carbon monoxide diusion tests
(DLCO, DLCO/VA) obtained in the upright sitting position
at room temperature were recorded, as were arterial blood
gas (pH, PaO2, PaCO2, SaO2) levels obtained at rest.
Walking distance covered during the 6MWT, which was
performed in a smooth corridor according to the ATS
guidelines, was recorded. SaO2 was measured by a nger
probe at rest and at the end of the test, and the dierence
(delta saturation [DeltaSat]) was recorded. e Borg
dyspnea index was recorded at both the beginning and the
end of the 6MWT.
Patients were divided into ve groups according to
diagnosis: IPF, non-IPF IIP, CVD, sarcoidosis, and other
forms of DPLD. Patients were compared by grouping
them as follows: age >65 years vs. <65 years; FVC <80%
vs. >80% of predicted; DLCO <80% vs. >80% of predicted;
FVC/DLCO ratio of <1.4 vs. >1.4; PaO2 <80 mmHg vs.
>80 mmHg; 6MWT <350 m vs. >350 m; DeltaSat <4% (no
desaturation), 4%–10%, and >10%.
e presence of PH was evaluated by the noninvasive
method of echocardiography. On transthoracic
echocardiography, systolic pulmonary artery pressure
(sPAP) was calculated using the tricuspid regurgitation
ow. Subjects with sPAP above 35 mmHg were diagnosed
with PH, and patients were grouped according to sPAP as
follows: <35 mmHg, 35–50 mmHg, and ≥50 mmHg.
e survival of patients was determined by phone calls
and recorded.
is study was approved by the Ethics Committee of
Ankara University.
2.2. Statistical evaluation
Statistical analysis was performed using SPSS 13.0
for Windows. Results were presented as mean ±
SD. Comparison of parameters between groups was
performed using the Mann–Whitney U test, Wilcoxon
test, and Student t-test. Patient and diagnostic groups were
compared using the chi-square test (Pearson chi-square
and Fisher exact test). P < 0.05 was considered statistically
signicant. Survival rate analysis was performed using the
Kaplan–Meier and Cox regression analysis tests.
3. Results
3.1. Demographic characteristics and variables
Of the 158 patients enrolled in the study, 91 (57.6%) were
female and 67 (42.4%) were male. e mean age was
58.9 ± 14.02 years, and the mean survival time was 42.9
± 35.7 months. Baseline demographic characteristics and
variables of the study population are shown in the Table.
e Kaplan–Meier test was used to evaluate the factors
aecting the survival rate. Male and female subjects did
not dier with respect to survival rate. Older patients
(>65 years) survived for a signicantly shorter time than
did younger patients (<65 years): 98.18 months vs. 147.74
months, respectively (P < 0.05). An evaluation of the
survival rate of patients with regard to diagnosis showed
Tab le. Baseline demographic characteristics and variables of
study population (n =158).
Variables Valu es
Age (years) 59 ± 14
Male/female 67/91 (42%/58%)
Resting cardiopulmonary
parameters
FVC% predicted 80.8 ± 24.1
FEV1% predicted 82 ± 24.3
FVC/DLCO 1.61 ± 0.6
DLCO% predicted 57.8 ± 24.7
SpO2 at rest (%) 95.1 ± 6.5
Exercise capacity, desaturation,
and pulmonary hypertension
6MWT (m) 372.5 ± 132.8
∆SpO2 (%) 10.1 ± 5.3
sPAP (mmHg) 31.5 ± 15.9

828
ÖZTÜRK and KAYACAN / Turk J Med Sci
that IPF patients’ survival was signicantly worse than
that of patients in the other DPLD groups (P < 0.05). Most
cases of death were registered in the IPF group, whereas no
deaths were reported in the sarcoidosis group.
3.2. Physiological and functional parameters
Of the spirometric tests, two parameters considered
valuable in the follow-up of such patients are FVC% of
predicted and DLCO% of predicted. e subjects with FVC
<80% of predicted survived for a shorter period of time
than those with >80% predicted: 118.5 months vs. 144.19
months, respectively (P < 0.05, Figure 1a). Similarly, the
subjects with lower DLCO (<80% of predicted) survived
for a shorter period of time than those with higher
DLCO (>80% of predicted) (P < 0.05, Figure 1b). We also
investigated the eect of FVC/DLCO (≥1.4 and <1.4) on
survival, but no dierence was found.
Subjects with hypoxemia (<80 mmHg) have a decreased
survival rate compared to normoxemic ones (>80 mmHg)
(P < 0.05, Figure 1c). Dierent levels of PaO2 (<40 mmHg,
40–60 mmHg, 60-80 mmHg, and >80 mmHg) were also
compared with respect to survival, but no signicant
dierence was found.
e patients who walked less than 350 m in the 6MWT
survived for a shorter period of time than those who
walked more than 350 m: 115.7 months vs. 145.9 months,
respectively (P < 0.05, Figure 1d). e desaturation level
of the subjects in the 6MWT was also evaluated. Seventy-
nine participants (50%) desaturated during the 6MWT. Of
these, 49% desaturated by 4%–10%, and 51% desaturated
200.00150.00100.0050.000.00
Survival rate
1.0
0.8
0.6
0.4
0.2
0.0
>80%
<80%
FVC%
P < 0.05
200.00150.00
100.0050.00
0.00
1.0
0.8
0.6
0.4
0.2
0.0
>80%
<80%
DLCO %
P < 0.05
200.00150.00100.0050.000.00
1.0
0.8
0.6
0.4
0.2
0.0
>80mmHg
<80mmHg
PaO2
200.00150.00100.0050.000.00
1.0
0.8
0.6
0.4
0.2
0.0
>350m
<350m
6MWD
Survival rate
Survival rate
Survival rate
P < 0.05 P < 0.05
A
B
CD
Figure 1. a) Relationship between FVC% and survival rate in all patients. b) Relationship between DLCO% and survival rate in all
patients. c) Relationship between hypoxia and survival rate. d) Relationship between 6MWT and survival rate in all patients.

829
ÖZTÜRK and KAYACAN / Turk J Med Sci
by >10%. e subjects with less desaturation (DeltaSat
4%–10%) and those with higher desaturation (DeltaSat
>10%) diered signicantly in terms of survival: 153.1 vs.
125.9 months, respectively (P < 0.01, Figure 2).
3.3. Pulmonary hypertension
e survival rate was better in subjects without PH (sPAP
<35 mmHg) than in those with PH (sPAP 35–50 mmHg
and >50 mmHg): 141.4 months vs. 99.96 months vs. 93.86
months, respectively (P < 0.01, Figure 3).
A strong relationship between DeltaSat and sPAP was
found. Accordingly, more than 10% DeltaSat suggests PH
(sPAP >50 mmHg) (Figure 4, P < 0.001).
All factors that we considered to have an eect on
patients’ survival rates, including age, sex, FVC%, DLCO%,
FVC/DLCO, PaO2, 6MWT, presence of desaturation
aer 6MWT, and sPAP values, were evaluated using Cox
regression analysis. Among all these parameters, only
FVC% had an eect on survival rate (predicting factor
for mortality). e most remarkable result indicated that
mortality increased by a rate of 6.3% when FVC% decreased
by one unit in DPLD and by 6.4% in IPF patients.
4. Discussion
is is the rst and largest single-center study in Turkey
addressing the eect of physiological changes on the
survival of DPLD patients. One of the unique ndings of
this study is that a one-unit decrease in FVC% increases
the mortality rate by more than 6% in DPLD and IPF
patients. It is known that restrictive ventilatory defects are
commonly encountered in DPLD due to brosis. Lung
function tests are used in DPLD to identify the severity
of the disease, follow up on the course of the disease,
evaluate treatment responses, and predict the mortality
rate of patients. ere is no similar study in the literature
that has established the relationship between the degree of
decrease in FVC% and mortality in IIPS. Previous studies
have reported only that a decrease in FVC and DLCO in
patients with IIP predicts mortality (19–23). e British
oracic Society (BTS) reported that 6–12 months of
follow-up of patients with IPF demonstrated that a ≥10%
decrease of FVC% or a ≥15% decrease in DLCO% led to an
increase in mortality (24).
Consistent with previous ndings, sex did not have
any eect on survival; however, younger patients survived
longer than older patients, as expected (19). e survival
of IPF patients was signicantly shorter than that of the
other DPLD patients.
e detection of a specic threshold value that would
help to dierentiate the results for respiratory function is
an expected factor (24). Consistent with previous studies,
the current study found a low basal PaO2, FVC%, and
6MWT in patients with DLCO% <80; found that they
were desaturated at the end of exercise; and found that
patients with DLCO% <80 survived for shorter periods of
time than those with DLCO% >80 (19,23).
Multivariate linear analysis showed that in determining
the development of PH, the FVC%-to-DLCO% ratio had a
positive predictive value of 71% and a negative predictive
value of 81% (25); another study demonstrated that a
DLCO% of <55 and a FVC%-to-DLCO% ratio of >1.4
indicated a relationship with PH (26). In light of these
reports, we also investigated the FVC%-to-DLCO% ratio.
Similarly, PH was more prevalent in subjects with a higher
ratio in the present study. However, no relationship was
found between this ratio and survival rate.
P < 0.01
200
150
100500
1.0
.8
.6
.4
.2
0.0
Deltasaturatio
n
absence
presence
Survival rate
Figure 2. Relationship between the presence of DeltaSat and
survival rate.
Figure 3. Relationship between sPAP values and survival rate in
all patients.
200.00150.00100.0050.000.00
1.0
0.8
0.6
0.4
0.2
0.0
35-50mmHg
>50mmHg
<35mmHg
sPAP group
P < 0.01
Survival rate

830
ÖZTÜRK and KAYACAN / Turk J Med Sci
We compared mortality rates between the patients
with no desaturation and those with 4%–10% and
>10% desaturation. e patients with more than 10%
desaturation survived for shorter time periods than
the other patients. Although arterial oxygen saturation
is normal at rest in cases with interstitial lung disease
(ILD), desaturation is generally observed during exercise.
Desaturation is oen associated with anatomical shunt
development and decrease in diusion capacity (27). In
the context of DPLD, although the 6MWT is a simple test,
only a few studies have shown its prognostic signicance
in IPF (12–14,28) and one study has done so in a mixed
cohort of IPF and nonspecic interstitial pneumonia (11).
None of the previous studies reported a constant threshold
value for the 6MWT in meters and oxygen desaturation
degree. In these studies, 350 m or 400 m for the 6MWT
and >4% value for oxygen desaturation were oen used
(29–31). Even though dierent views of the relationship
between 6MWT and mortality have been reported, there
was a consensus that desaturation (>4%) is a strong factor
in predicting mortality in IPF (12,13). Oxygen desaturation
in IPF patients at baseline 6MWT was also shown to be a
stronger prognostic factor compared to lung function tests
in the BTS Guidelines on ILD (Evidence C) (24).
e most remarkable result of the present study is that
in PH (in which sPAP was ≥50 mmHg), DeltaSat (≥10%)
was more prevalent. To the best of our knowledge, this is
a unique nding in English-language research. Although
PH is the most well-known complication of interstitial
lung disease, it has not been adequately investigated
(16,17). Recent pathophysiological studies have revealed
the role of PH in the course of ILD and the benets of
specic treatments. PH is most commonly observed in
diseases such as IPF, CVD, and sarcoidosis. In our study,
patients with sPAP >35 mmHg were also observed more
commonly in the IPF and CVD groups. e development
of PH increases mortality risk in DPLD (31,32). Consistent
with previous studies, subjects with increased sPAP had a
lower life expectancy. Additionally, in a sarcoidosis study,
the authors did not nd any relationship between 6MWT
and increased sPAP, but desaturation in the 6MWT
(DeltaSat) was reported to be an independent factor in
the determination of PH (33). Furthermore, DLCO% of
<35, observation of DeltaSat (>10%), and the need for
oxygen supply have been demonstrated as predictive
factors for PH (28,31–37). PH was suggested to have a
poor prognosis, and mean life expectancy was reported to
be less than 1 year in patients with sPAP >50 mmHg (32).
However, no study has evaluated the relationship between
PH and DeltaSat rates. is result indicates that signicant
DeltaSat (especially >10%) at 6MWT points to PH, thereby
hindering further laboratory research and thus reducing
medical expenditure.
Studies have argued for dierent decreased values
of FVC% during a 6- or 12-month follow-up period
(10% or 15%) in IIPs (22,38). In addition, some authors
investigating only biopsy-proven IPF patients suggested
that the presence of a honeycomb image at the end of a
3-year follow-up indicates a decrease in survival (39).
Flaherty et al. showed that within a group that desaturated
below 88%, serial decline in DLCO was the strongest
predictor of mortality. is study also demonstrated an
increased mortality risk in the group that maintained
SpO2 above 88% when there was a serial decline in forced
vital capacity (FVC) or increasing desaturation (13). In
studies with IPF, age, male sex, low body mass index,
signicant increase in dyspnea, severe physiological
abnormalities, high degree of brosis, and poor treatment
response as well as frequent hospitalization and also a
few biomarkers (matrix metalloproteinase-7, surfactant
protein-D, Krebs von den Lungen-6, surfactant protein-A,
etc.) were reported as predictive factors for a decreased
survival rate (19,39–43). Consistent with the literature,
in this study, older age, observation of DeltaSat, sPAP
≥35 mmHg, 6MWT <350 m, and FVC <80% were also
predictive factors for a decreased survival rate.
e retrospective nature of the present study and the small
number of subjects in each group of DPLD patients are
this study’s limitations. In conclusion, this study conrms
that FVC is an important predictor of mortality. DeltaSat
(>10%) is another important predictor of mortality and it
is also strongly indicative of PH.
62
21
17
88
12
0
0 10 20 30 40 50 60 70 80 90 100
Desaturation & sPAP
sP
AP 35 -50 mmHg
sPAP <50 mmHg
Absence of
desaturation
Presence of
desaturation
sP
AP >50 mmHg
Figure 4. Relationship between DeltaSat and sPAP values.

831
ÖZTÜRK and KAYACAN / Turk J Med Sci
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