Sleep Medicine 14 (2013) 1139–1150

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Sleep Medicine
journal homepage: www.elsevier.com/locate/sleep

Original Article

Effects of continuous positive airway pressure therapy on systemic

inflammation in obstructive sleep apnea: A meta-analysis
XiaoMei Xie a,1, Lei Pan b,1, DunQiang Ren c,1, ChangJun Du d, YongZhong Guo d,⇑
a
Department of Radiotherapy, Xuzhou Central Hospital, Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou, China
b
Guangzhou Institute of Respiratory Diseases, State Key Lab of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical College, Guangzhou, China
c
Department of Respiratory Medicine, The Affiliated Hospital of Medical College Qingdao University, Qingdao, Shandong, China
d
Department of Respiratory Medicine, Xuzhou Central Hospital, Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou, China

a r t i c l e i n f o a b s t r a c t

Article history: Objectives: Our meta-analysis was performed to estimate the effect of continuous positive airway pres-
Received 2 February 2013 sure (CPAP) therapy on systemic inflammation in patients with obstructive sleep apnea (OSA).
Received in revised form 3 June 2013 Methods: A comprehensive literature search of PubMed and EMBASE was performed for literature pub-
Accepted 3 July 2013
lished up to January 2013. Standardized mean difference (SMD) was calculated to estimate the treatment
Available online 14 August 2013
effects of pre- and post-CPAP therapy.
Results: A total of 35 studies involving 1985 OSA patients were included in the meta-analysis. Each study
Keywords:
investigated one or more inflammatory markers: 24 studies on C-reactive protein (CRP), 16 studies on IL-
Obstructive sleep apnea
Continuous positive airway pressure
6, 3 studies on IL-8, and 12 studies on tumor necrosis factor a (TNF-a). The results showed that the SMD
Systemic inflammation (95% confidence interval [CI]) for CRP, IL-6, IL-8, and TNF-a were 0.452 (95% CI, 0.252–0.651), 0.299 (95%
C-reactive protein CI, 0.001–0.596), 0.645 (95% CI, 0.362–0.929), and 0.478 (95% CI, 0.219–0.736) in pre- and post-CPAP
Interleukin-6 therapy, respectively. The subgroup analyses seemed to support better benefits with therapy duration
Interleukin-8 of P3 months and more adequate compliance (P4 h/night).
Tumor necrosis factor-a Conclusions: CPAP therapy could partially suppress systemic inflammation in OSA patients, and substan-
Meta-analysis tial differences were present among the various inflammatory markers.
Ó 2013 Elsevier B.V. All rights reserved.

1. Introduction inflammation in cardiovascular disease, have been reported to be

Obstructive sleep apnea (OSA) is the most common sleep disor-
der in clinical practice. Its growing worldwide prevalence may be
due to the rising incidence of obesity in the public. OSA has been
increasingly recognized as a major public health issue, as it has a
significant influence on the incidence and prognosis of cardiovas-
cular diseases [1]. The underlying pathophysiologic mechanisms
on the influence of OSA to the development of cardiovascular dis-
ease have not been completely understood and may be multifacto-
rial in origin. Increasing evidence suggests that inflammatory
processes play a pivotal role in the pathogenesis of cardiovascular
disease in OSA [2,3]. Inflammatory markers, such as C-reactive pro-
tein (CRP), IL-6, IL-8, and tumor necrosis factor a (TNF-a), which
have been proposed to be linked to the pathogenesis of systemic
elevated in OSA patients [4].
Continuous positive airway pressure (CPAP) therapy is remark-
ably beneficial to the pathologic condition and prognosis of cardio-
vascular diseases in OSA but is inconsistent to systemic
inflammation. Previous meta-analyses based on small sample size
and studies indicated a significant decrease of CRP levels in OSA
patients under CPAP therapy with adequate compliance (P4 h/
night) [5,6]. However, the effects of CPAP therapy on the decrease
of other inflammatory factors and on those with poor compliance
(<4 h/night) has not been answered. To better address this issue,
a meta-analysis was performed to evaluate the effects of CPAP
therapy on the inflammatory markers CRP, IL-6, IL-8, and TNF-a
in OSA patients.
2. Methods

2.1. Literature search and selection

⇑ Corresponding author. Address: Department of Respiratory Medicine, Xuzhou
Central Hospital, Affiliated Xuzhou Hospital of Medical College of Southeast
We comprehensively searched PubMed and EMBASE databases
University; 199 South Jiefang Rd., Xuzhou, Jiangsu, 221009, China. Tel.: +86 1810
520 8862; fax: +86 516 83956013. for literature published up to January 2013. The search was limited
E-mail address: yongzhguo@sina.cn (Y. Guo). to human adults (aged P 18 years) with no language restrictions.
1
These authors equally contributed to this work. The following search terms were used to query the databases, with

1389-9457/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.sleep.2013.07.006
1140 X. Xie et al. / Sleep Medicine 14 (2013) 1139–1150

combined free-text and subject-based parameters: C-reactive pro- Meta-regression analyses also were conducted to explore if
tein, CRP, tumor necrosis factor alpha, tumor necrosis factor a, TNF-al- some variables, including the sample size, levels of inflammatory
pha, TNF-a, interleukin-6, IL-6, interleukin-8, IL-8, positive airway markers, therapy duration, age, BMI, AHI, Epworth Sleepiness Scale
pressure, CPAP, apnoea, and apnea. The reference lists of relevant scores, and lowest O2 saturation were the possible sources of
publications were manually searched for additional studies. heterogeneity.
Two investigators independently identified eligible studies. The Q and I2 statistics were used to examine statistical hetero-
Conflicting decisions were resolved by consensus with a third geneity among individual studies. Significant heterogeneity was
investigator. Studies were considered eligible if they met the fol- indicated by Pheterogeneity < .10 or I2 > 60%. Publication bias was
lowing criteria: (1) the diagnosis of OSA was made by polysomnog- visually evaluated using funnel plots and was statistically evalu-
raphy (apnea-hypopnea index [AHI] > 5); (2) the intervention was ated with Egger and Begg tests and the trim and fill method. A
an application of CPAP; (3) the value of serum CRP, TNF-a, IL-8, and two-tailed P value <.05 was considered statistically significant.
IL-6 needed to be reported for pre- and post-CPAP therapy; and (4)
the therapy duration was longer than 4 weeks. 3. Results
Abstracts, case reports, editorials, expert opinions, letters, ani-
mal studies, and reviews without original data were excluded. 3.1. Characteristics of included studies
Studies were considered ineligible when: (1) the diagnosis of
OSA was not made by AHI (AHI > 5); (2) values of inflammatory The selection process for studies included in the meta-analysis
factors were not reported for pre- and post-CPAP therapy, or insuf- is outlined in Fig. 1. A total of 35 studies were found eligible for
ficient information was available to compute these values; and (3) inclusion based on the set criteria for meta-analysis [9–43]; these
the therapy duration was less than 4 weeks. If multiple studies re- studies involved 1985 patients (men, 75.45%). Each study investi-
ported outcomes on the same patient group, the study with the gated one or more inflammatory markers: 24 studies on CRP
largest population was included. [9,11–13,15,16,18–22,25,27,28,32,34,36–42], 16 studies on IL-6
[11,13,17,23–26,28–33,35,42,43], 3 studies on IL-8 [10,17,43],
2.2. Quality assessment and data extraction and 12 studies on TNF-a [14,15,17,23,25,26,29,30,32,35,42,43].
The characteristics of included studies for different inflammatory
The Downs and Black checklist was used to assess study quality markers are provided in Tables 1–4, respectively.
[7]. Because not all items in the checklist were relevant to the stud-
ies included in our meta-analysis, a modified version of the check-
3.2. Results for CRP
list was used. The modified checklist had 14 items, including items
1–4, 6–10, 16, 18–20, and 26 from the original list, with a maxi-
The pooled results showed that CPAP therapy significantly de-
mum score of 14 points (higher points indicated superior quality).
creased CRP levels (SMD, 0.452 [95% confidence interval {CI},
The assessment of study quality was performed by 2 independent
0.252–0.651]; z = 4.43; P = .000; Fig. 2). The sensitivity analyses
investigators; conflicting assessments were resolved by consensus
with a third investigator.
Data extracted from each study included the name of first
author, year of publication, nation, patient inclusion and exclusion
criteria, sample size, gender distribution, mean age, baseline body
mass index (BMI), Epworth Sleepiness Scale scores, AHI, lowest O2
saturation, therapy duration, and markers assays. If the study pro-
vided medians and interquartile ranges instead of means and stan-
dard deviations [SDs], the corresponding means and SDs were
calculated according to the method described by Hozo et al. [8].

2.3. Statistical analysis

The meta-analysis was conducted using Stata statistical soft-

ware (version 10.0; Stata Corporation, College Station, TX, USA).
Because the inflammatory markers were measured and reported
differently in various laboratories, the standardized mean differ-
ence (SMD) was used to compute the summary estimates rather
than the absolute levels of the inflammatory markers. These SMDs
were derived by dividing the mean difference of specific inflamma-
tory markers levels by its corresponding SDs during the pre- and
post-CPAP therapy of each study [6]. In studies in which data were
separately provided based on patient compliance (<4 and P4 h/
night), we pooled these data as independent studies. As the pres-
ence of study diversity, the random-effects model was used for
the pooled estimate analysis. Sensitivity analyses were conducted,
including omitting one study at a time and changing the eligibility
criteria to explore the robustness of pooled results.
Planed subgroup analyses using the random-effects model were
conducted to evaluate the effects of some relevant variables
including area (Asian vs non-Asian patients), therapy duration
(<3 months vs P3 months) and compliance (<4 h/night vs P4 h/
night) on CPAP therapy and to explore the possible sources of
heterogeneity. Fig. 1. Flow diagram of study selection.
Table 1
Characteristics of 24 included studies for C-reactive protein.

Study National Number of Inclusion criteria Exclusion Therapy Daily Marker Quality Patient characteristics
patients (W) criteria duration duration measurement scores
Age BMI AHI ESS LowSO2
Chin et al. (2000) [9] Japan 23 (0) AHI > 20 Have 1 mo >5.0 ELISA 9 51.0 29.0 52.0 9.6 62.0
(11.0) (5.0) (16.0) (4.8) (13.0)
Yokoe et al. (2003) Japan 17 (0) AHI P 20 Have 1 mo NR LPEI 12 47.7 31.7 57.5 12.6 67.5
[11] (10.3) (3.0) (16.9) (5.8) (2.7)
Barcelo et al. 2004 Spain 31 (0) Men with OSA NR 3 mo 5.4 (1.9) Chemiluminescent 10 NR 30.0 43.5 12.5 NR
[12] assays (4.3) (14.2) (5.1)
Harsch et al. (2004) Germany 20 (0) AHI > 30; ESS > 10 Have 8 wk 5.3 (3.0) ELISA 10 58.6 32.1 48.6 12.1 NR
[13] (9.6) (6.9) (19.2) (2.8)
Kobayashi et al. Japan 35 (5) AHI > 30 Have 3 mo NR ELISA 10 51.4 27.9 52.3 NR NR
(2006) [15]# (13.1) (3.6) (14.8)
Minoguchi et al. Japan 20 (0) AHI P 15 Have 3 mo 4.8 (1.3) LPEI 12 49.3 28.9 46.5 13.1 70.9
(2006) [16] (3.5) (0.6) (9.8) (2.8) (7.9)
Drager et al. (2007) Brazil 12 (0) AHI > 30 Have 4 mo 6.6 (0.6) LPEI 11 44 (6.7) 29.9 56.0 14.0 74.0
[18] (3.0) (22.0) (4.0) (11.0)
Iesato et al. (2007) Japan 36 (0) AHI P 20 Have 3 mo P4.0 NR 8 NR NR 57.5 NR 70.5
[19] (23.4) (1.8)
Patruno et al. (2007) Italy 16 (3) AHI > 20; diurnal NR 3 mo 6.0 (1.0) LPEI 9 47.0 35.2 46.0 14.1 70.0

X. Xie et al. / Sleep Medicine 14 (2013) 1139–1150

[20] hypersomnolence; ESS > 12 (10.7) (4.0) (14.6) (1.7) (11.7)
Ryan et al. (2007) [21] Ireland 49 (0) AHI, 14–73 Have 6 wk 4.6 (1.3) NM 9 40.0 34.0 37.0 15.0 NR
(8.0) (6.0) (14.8) (5.0)
Steiropoulos et al. Greece 20 (4) AHI > 15 Have 6 mo 4.7 (0.6) NM 12 46.8 36.4 56.7 13.0 69.8
(2007) [22]a (11.5) (9.8) (27.6) (6.5) (12.2)
Steiropoulos et al. Greece 19 (0) AHI > 15 Have 6 mo 2.4 (1.1) NM 11 45.0 32.3 64.0 11.7 72.4
(2007) [22]b (10.1) (5.1) (25.5) (5.4) (8.75)
Dorkova et al. (2008) Slovakia 16 (1) AHI > 30; metabolic syndrome Have 8 wk P4.0 CLIA 13 51.3 32.8 64.7 12.6 66.5
[25]a (9.5) (4.4) (23.3) (3.4) (15.6)
Dorkova et al. (2008) Slovakia 15 (5) AHI > 30; metabolic syndrome Have 8 wk <4.0 CLIA 12 56.1 37.3 63.2 13.9 56.8
[25]b (9.5) (6.9) (18.8) (5.6) (22.2)
Sánchez et al. (2008) Spain 21 (NR) AHI P 30; ESS > 10 Have 6 mo P4.0 LPEI 12 48.4 30.0 64.4 10.6 NR
[27] (12.2) (2.3) (22.9) (4.5)
Takahashi et al. Japan 27 (2) AHI > 20 Have 1 mo >4.0 NM 12 48.3 30.1 48.2 NR 65.2
(2008) [28] (10.7) (4.6) (14.8) (16.5)
Carneiro et al. (2009) Brazil 7 (0) AHI > 30; BMI P 40; daytime Have 3 mo 6.6 (1.1) CLIA 10 NR 46.1 91.0 10.5 71.2
[32] sleepiness (19.6) (25.7) (2.7) (5.3)
Ishida et al. (2009) Japan 40 (8) AHI > 20 NR 6 mo NR LAI 9 57.0 29.3 47.8 NR 77.0
[34]a (12.6) (7.0) (27.2) (12.6)
Ishida et al. 2009 Japan 15 (3) AHI > 20 NR 6 mo NR LAI 12 50.0 31.5 46.3 NR 78.0
[34]b (15.5) (5.0) (24.8) (11.6)
Nena et al. (2010) Greece 62 (9) AHI > 15 Have 6 mo 4.7 (0.7) NM 13 46.4 33.9 57.4 11.6 72.5
[36] (11.3) (6.9) (27.5) (5.7) (9.9)
Schiza et al. (2010) Greece 436 (184) AHI > 20 Have 12 mo 4.6 (0.4) LPEI 13 53.2 35.3 43.3 17.1 75.9
[37]a (11.7) (7.1) (23.9) (4.7) (9.6)
Schiza et al. (2010) Greece 92 (40) AHI > 20 Have 12 mo NR LPEI 12 43.0 30.1 27.2 11.6 86.8
[37]b (13.1) (5.6) (13.9) (4.5) (4.8)
Chung et al. (2011) Korean 25 (3) AHI P 15 Have 90–250 d P4.0 Turbidimetric 13 51.4 27.7 64.9 NR 69.9
[38] (60%) immunoassay (11.5) (3.7) (20.0) (9.3)
Kasai et al. (2011) Japan 27 (0) AHI P 15 Have 1 mo 5.1 (1.1) LPEI 11 50.9 27.5 49.9 12.1 75.5
[39] (12.3) (3.6) (21.7) (5.6) (9.6)
Mermigkis et al. Greece 436 (184) AHI > 15 Have 6 mo >4.0 LPEI 13 53.2 35.2 44.5 16.7 75.1
(2012) [40] (11.7) (7.3) (23.1) (4.9) (9.6)
Colish et al. (2012) Canada 47 (15) AHI > 15; ESS > 10 Have 12 mo >4.5 AAPRR 13 51.0 38.0 63.0 14.0 78.0
[41] (10.0) (9.0) (30.0) (3.0) (8.0)
Karamanli et al. (in Turkey 35 (14) AHI P 15 Have 3 mo 5.8 NR 13 52.5 NR 45.6 NR 72.1
press) [42] (10.3) (22.1) (13.0)

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1142 X. Xie et al. / Sleep Medicine 14 (2013) 1139–1150

showed that the SMD for CRP ranged from 0.393 (95% CI, 0.201–
assay; ESS, Epworth Sleepiness Scale; LAI, latex agglutination immunoassay; LowSO2, lowest arterial oxygen saturation; LPEI, latex particle–enhanced immunoturbidimetry; mo, month; NM, nephelometry; NR, not reported; W,
Abbreviations: AAPRR, antigen antibody precipitant rate reaction; AHI, apnea-hypopnea index; BMI, body mass index; CLIA, chemiluminescent immunoassay; d, days; EL, enzyme-linked; ELISA, enzyme-linked immunoabsorbent

0.585) after omitting the study of Ishida et al. (<4 h/night) [34] to
0.480 (95% CI, 0.281–0.679) after omitting the study of Barceló
et al. [12]. The patients in the studies of Schiza et al. [37] and
Mermigkis et al. [40] seemed to be from the same patient group.
That is, removing the study of Mermigkis et al. [40], which had
fewer patients, did not significantly change the results (SMD,
0.428 [95% CI, 0.217–0.639]). After removal of the 4 studies
[13,15,21,39] in which the means and SDs were extracted by read-
ing a graph or calculating medians and interquartile ranges, the
significantly decreasing trend of CRP did not change (SMD, 0.517
[95% CI, 0.308–0.726]). Additional sensitivity analysis was per-
formed by restricting the analysis to the studies that had no signif-
icant change in BMI at pre- and post-CPAP therapy
[11,16,22,27,34,36,38,39]; significant results were obtained (SMD,
0.618 [95% CI, 0.294–0.942]).
Subgroup analyses suggested a significant decrease from longer
therapy duration (P3 months) adequate compliance, and no sig-
nificant difference between Asian vs non-Asian patients (Table 5).
Sources of heterogeneity were not found by meta-regression (Ta-
ble 6) and subgroup analyses.
No publication bias was observed from the funnel plots (Fig. not
shown). However, the Egger and Begg tests suggested the presence
of publication bias (P = .026). The trim and fill method indicated
that there were no additional studies needed to identify and cor-
rect funnel plot asymmetry. Compared with the random-effects
model estimate, the fixed-effects model estimate for CRP was more
significant, which indicated the minimal effect of publication bias
on estimation of treatment effects.

3.3. Results for IL-6

The pooled result for IL-6 is presented in Fig. 3 (SMD, 0.299 [95%
CI, 0.001–0.596]; z = 1.97; P = .049). By omitting one study at each
run, the sensitivity analyses produced nonrobust results. The SMD
ranged from 0.228 (95% CI, 0.057 to 0.513) after omitting the
study of Yamamoto et al. [31] to 0.353 (95% CI, 0.061–0.654) after
omitting the study of Dorkova et al. [25] (>4 h/night). After re-
moval of the 2 studies [13,43] in which the means and SDs were
extracted by reading a graph or calculating from medians and
interquartile ranges, a decreasing trend was observed. However,
this trend was not statistically significant (SMD, 0.271 [95% CI,
0.013 to 0.555]). By restricting the analysis to the studies that
clearly showed no significant changes in BMI at pre- and post-
CPAP therapy [11,17,23,30,31,35], a decreasing trend was demon-
strated, which was not significant (SMD, 0.200 [95% CI, 0.288 to
0.688]).
Subgroup analyses suggested that no significant differences
were present when grouped by therapy duration and compliance,
and a significant decrease of IL-6 in Asian patients (Table 5).
Sources of heterogeneity were not found by meta-regression (Ta-
Indicated data from the whole study population.
Indicated treatment duration of P4 h per night.
Indicated treatment duration of <4 h per night.

ble 6) and subgroup analyses. No publication bias was observed.

3.4. Results for IL-8

Indicated data from reading a graph.
Values are mean (standard deviation).

Three studies reported a decrease in the IL-8 levels [10,17,43],

Daily duration indicated as hours.
AHI indicated as events per hour.

the same pooled result was obtained from the fixed-effects and
random-effects model (SMD, 0.645 [95% CI, 0.362–0.929];
z = 4.46; P = .000; Fig. 4).Because of the limitation of the number
BMI indicated as kg/m2.

LowSO2 indicated as %.
Age indicated as years.

ESS indicated as score.

of studies, subgroup and meta-regression analyses and assessment

women; wk, week.

of publication bias were not conducted.

3.5. Results for TNF-a

A significant result also was observed for TNF-a (SMD, 0.478

b
#

[95% CI, 0.219–0.736]; z = 3.62; P = .000; Fig. 5). By omitting one

Table 2
Characteristics of 16 included studies for IL-6.

Study National Number of Inclusion criteria Exclusion Therapy Daily Marker Quality Patient characteristics
patients (W) criteria duration duration measurement scores
Age BMI AHI ESS LowSO2
Yokoe et al. (2003) Japan 17 (0) AHI P 20 Have 1 mo NR ELISA 12 47.7 31.7 57.5 12.6 67.5
[11] (10.3) (3.0) (16.9) (5.8) (2.7)
Harsch et al. (2004) Germany 20 (0) AHI > 30; ESS > 10 Have 8 wk 5.3 (3.0) ELISA 10 58.6 32.1 48.6 12.1 NR
[13] (9.6) (6.9) (19.2) (2.8)
Ryan et al. (2006) [17] Ireland 49 (0) AHI > 5 NR 6 wk 4.6 (1.3) ECL 14 NR NR 37.0 15.0 NR
(14.7) (5.0)
Arias et al. (2008) [23] Spain 25 (0) AHI > 10; ESS > 11 Have 12 wk 6.2 (1.1) ELISA 12 52.0 30.2 43.8 NR 72.0
(13.0) (4.4) (27.0) (15.0)
Burioka et al. (2008) Japan 9 (0) AHI > 30 Have 3 mo 5.0 (0.4) ELISA 13 48.2 25.8 53.6 13.3 74.7
[24] (15.0) (2.1) (17.4) (3.3) (10.2)
Dorkova et al. (2008) Slovakia 16 (1) AHI > 30; metabolic Have 8 wk P4.0 ELISA 13 51.3 32.8 64.7 12.6 66.5
[25]a syndrome (9.5) (4.4) (23.3) (3.4) (15.6)
Dorkova et al. (2008) Slovakia 15 (5) AHI > 30; metabolic Have 8 wk <4.0 ELISA 12 56.1 37.3 63.2 13.9 56.8
[25]b syndrome (9.5) (6.9) (18.8) (5.6) (22.2)
Li et al. (2008) [26] China 33 (NR) AHI > 5 NR 2 mo NR ELISA 11 NR NR 45.7 NR 62.0
(24.9) (14.8)
Takahashi et al. (2008) Japan 27 (2) AHI > 20 Have 1 mo >4.0 CLIA 12 48.3 30.1 48.2 NR 65.2

X. Xie et al. / Sleep Medicine 14 (2013) 1139–1150

[28] (10.7) (4.6) (14.8) (16.5)
Tomiyama et al. Japan 29 (0) AHI P 15 Have 3 mo NR ELISA 10 NR NR NR NR NR
(2008) [29]#
Vgontzas et al. (2008) Greece 16 (0) Obese; AHI > 20 Have 3 mo 4.6 (0.4) ELISA 12 48.1 37.5 53.3 12.1 72.4
[30] (5.6) (4.7) (28.0) (4.4) (8.4)
Yamamoto et al. Japan 11 (0) AHI > 5 Have 3 mo 5.1 (1.8) ELISA 12 NR 29.0 49.9 NR NR
(2008) [31]# (6.6) (median)
Carneiro et al. (2009) Brazil 7 (0) AHI > 30; BMI P 40; daytime Have 3 mo 6.6 (1.1) Immunometric 10 NR 46.1 91.0 10.5 71.2
[32] sleepiness (19.6) (25.7) (2.7) (5.3)
Drummond et al. Portugal 98 (0) AHI > 20 Have 6 mo 5.8 (1.6) ELISA 13 55.3 33.2 51.7 NR 70.8
(2009) [33] (10.7) (5.0) (21.3) (9.7)
Steiropoulos et al. Greece 32 (0) AHI > 5; daytime symptoms Have 6 mo 4.7 (0.6) ELISA 13 45.6 34.6 61.1 11.9 71.0
(2009) [35]a (10.7) (8.9) (28.3) (5.6) (9.4)
Steiropoulos et al. Greece 20 (0) AHI > 5; daytime symptoms Have 6 mo 1.4 (1.5) ELISA 12 46.6 33.6 50.7 9.6 74.7
(2009) [35]b (9.9) (4.5) (26.3) (5.6) (11.0)
Karamanli et al. (in Turkey 35 (14) AHI P 15 Have 3 mo 5.8 ELISA 13 52.5 NR 45.6 NR 72.1
press) [42] (10.3) (22.1) (13.0)
Oyama et al. (2012) Japan 32 (13) AHI > 20; metabolic Have 3 mo P4.0 ELISA 11 53.9 26.7 56.2 17.4 NR
[43]# syndrome (60%) (8.6) (3.6) (21.6) (5.3)

Abbreviations: AHI, apnea-hypopnea index; BMI, body mass index; CLIA, chemiluminescent immunoassay; ECL, electrochemiluminescence assay; ELISA, enzyme-linked immunoabsorbent assay; ESS, Epworth Sleepiness Scale;
LowSO2, lowest arterial oxygen saturation; mo, month; NR, not reported; W, women; wk, week.
Values are mean (standard deviation).
Age indicated as years.
AHI indicated as events per hour.
BMI indicated as kg/m2.
Daily duration indicated as hours.
ESS indicated as score.
LowSO2 indicated as %.
#
Indicated data from reading graph.
Indicated data from the whole study population.
a
Indicated treatment duration of P4 h per night.
b
Indicated treatment duration of <4 h per night.

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1144 X. Xie et al. / Sleep Medicine 14 (2013) 1139–1150

Table 3
Characteristics of 3 included studies for IL-8.

Study National Number of Inclusion Exclusion Therapy Daily Marker Quality Patient characteristics
patients (W) criteria criteria duration duration measurement scores
Age BMI AHI ESS LowSO2
Ohga et al. Japan 20 (0) Men with OSA NR 1 mo NR ELISA 9 47.8 29.4 38.9 NR NR
(2003) (9.8) (6.3) (13.9)
[10]#
Ryan et al. Ireland 49 (0) AHI > 5 NR 6 wk 4.6 (1.3) ECL 14 NR NR 37.0 15.0 NR
(2006) (14.7) (5.0)
[17]
Oyama et al. Japan 32 (13) AHI > 20; Have 3 mo P4.0 ELISA 11 53.9 26.7 56.2 17.4 NR
(2012) metabolic (60%) (8.6) (3.6) (21.6) (5.3)
[43]# syndrome

Abbreviations: AHI, apnea-hypopnea index; ECL, electrochemiluminescence assay; ELISA, enzyme-linked immunoabsorbent assay; LowSO2, lowest arterial oxygen satura-
tion; mo, month; NR, not reported; W, women; wk, week.
Values are mean (standard deviation).
Age indicated as years.
AHI indicated as events per hour.
Body mass index indicated as kg/m2.
Daily duration indicated as hours.
ESS indicated as score.
LowSO2 indicated as %.
#
Indicated data from reading graph.

study at a time, sensitivity analyses showed that the pooled SMD
for TNF-a ranged from 0.391 (95% CI, 0.188–0.594) after omitting
the study of Li et al. [26] to 0.519 (95% CI, 0.257–0.782) after omit-
ting the study of Dorkova et al. (>4 h/night) [25]. After the omission
of the 3 studies [15,29,43] in which data were extracted by reading
a graph, similar results were obtained (SMD, 0.406 [95% CI, 0.095–
0.717]). By restricting the analysis to the studies that clearly
showed no significant change in BMI at pre- and post-CPAP ther-
apy [14,17,23,30,35], a significant result was obtained (SMD,
0.518 [95% CI, 0.115–0.920]).
Subgroup analyses showed that the decrease in TNF-a levels
were found in less than 3 months therapy duration and poor com-
pliance and were more pronounced in more than 3 months and
adequate compliance (Table 5). Similarly, the possible sources of
heterogeneity and publication bias were not observed.
4. Discussion
Our meta-analysis assessed the effects of CPAP therapy in OSA
patients on several inflammatory markers namely, CRP, IL-6, IL-8,
and TNF-a. We chose these inflammatory markers because they
have been widely studied and may closely link OSA with cardiovas-
cular diseases; genetic variants of CRP, TNF-a, and IL-6 have been
associated with OSA [44–47]. The pooled results indicated that
CPAP therapy could significantly decrease the levels of CRP, IL-6,
IL-8, and TNF-a in OSA patients. Sensitive analysis produced non-
robust results for IL-6. However, the decreasing trend remained
unchanged in the results. The meta-analysis identified levels of
systemic inflammation in the included studies, which could be par-
tially suppressed by CPAP therapy in patients with OSA. Further-
more, substantial differences were present among the various
inflammatory markers.
Accumulating evidence shows that OSA is a local disorder of the
respiratory system which may be characterized by the develop-
ment of low-grade systemic inflammation. The relationship be-
tween systemic inflammation and OSA is complex; reciprocal
induction may account for the capacity of OSA to activate systemic
inflammation [48]. Conversely systemic inflammation can aggra-
vate OSA [49]. The development of systemic inflammation in OSA
patients and its effective treatment remains unclear. Current evi-
dence suggests that the intermittent hypoxia induced by upper air-
way obstruction during sleep can directly activate systemic
inflammation. Thus CPAP therapy corrects intermittent hypoxia
by mechanically opening the upper airway, thereby decreasing
systemic inflammation. Therefore, the results of our meta-analysis
revealed that CPAP therapy could possibly decrease systemic
inflammation in patients with OSA. Decreased systemic inflamma-
tory levels also were reported in surgery-treated OSA patients, and
this finding is consistent with our meta-analysis [26,50–52].
To our surprise, the sensitive analysis afforded nonrobust re-
sults for IL-6, as IL-6 is considered to be a contributing factor in
the pathogenesis of OSA. Several studies have suggested that IL-6
had an independent effect on OSA [11] and that it is the strongest
predictor of AHI change [26]. Subgroup analysis showed a signifi-
cant benefit in Asian patients, thereby a disparity in the effective-
ness of CPAP therapy for different race and ethnicity. However, no
evidence supports such a disparity to date, thereby implying that
such an interpretation is questionable. Our results for IL-6 may
be due to 2 possible reasons. First, the small sample size may not
have had sufficient power to disclose all potential benefits of the
therapy. Second, CPAP therapy may have had a lack of substantial
effects. Additional well-designed large-scale clinical studies are
necessary to confirm this hypothesis.
Multiple factors influence the effectiveness of CPAP therapy.
Among these factors, the duration of therapy and compliance are
clinically important in decreasing the levels of inflammatory mark-
ers. Our results indicated improved benefits on the CRP levels after
therapy of 3 months or more and adequate compliance (P4 h/
night). By contrast, TNF-a levels benefited from therapy of less
than 3 months and poor compliance (<4 h/night). However, the
trend for TNF-a could be false or spurious, as the results were
not consistent. Furthermore, most of the previous studies sup-
ported the opposite conclusion [22,25,34,35,37,41]. No significant
differences were found in the IL-6 levels based on the therapy
duration and compliance. These inconsistent results may cater to
an important question raised in the title of the report by Drager
et al. [53]: ‘‘Effects of CPAP on inflammation in patients with
OSA: is it a matter of time or a matter of marker?’’ The most effec-
tive duration of therapy and compliance for reversing systemic
inflammation in OSA patients remains uncertain. A longer therapy
duration [37,41] and adequate compliance [22,25,34,35] could
more effectively decrease systemic inflammation. Several studies
reported a significant decrease of systemic inflammation with a
month or less of CPAP therapy [10,11,28] but not after 6 months
or more [27,33,41]. However, the differences in CPAP therapy on
Table 4
Characteristics of 12 included studies for TNF-a.

Study National Number of Inclusion criteria Exclusion Therapy Daily Marker Quality Patient characteristics
patients (W) criteria duration duration measurement scores
Age BMI AHI ESS LowSO2
Minoguchi et al. Japan 12 (0) AHI > 20 Have 1 mo 5.6 (0.9) ELISA 12 49.2 29.1 59.2 13.5 68.4
(2004) [14] (11.7) (2.2) (14.7) (3.2) (9.4)
Kobayashi et al. (2006) Japan 35 (5) AHI > 30 Have 3 mo NR ELISA 10 51.4 27.9 52.3 NR NR
[15] # (13.1) (3.6) (14.8)
Minoguchi et al. Japan 12 (0) AHI > 20 Have 1 mo 5.6 (0.9) ELISA 12 49.2 29.1 59.2 13.5 68.4
(2004) [14] (11.7) (2.2) (14.7) (3.2) (9.4)
Kobayashi et al. (2006) Japan 35 (5) AHI > 30 Have 3 mo NR ELISA 10 51.4 27.9 52.3 NR NR
[15]# (13.1) (3.6) (14.8)
Ryan et al. (2006) [17] Ireland 49 (0) AHI P 5 NR 6 wk 4.6 (1.3) ELISA 14 NR NR 37.0 15.0 NR
(14.7) (5.0)
Arias et al. (2008) [23] Spain 25 (0) AHI > 10; ESS > 11 Have 12 wk 6.2 (1.1) ELISA 12 52.0 30.2 43.8 NR 72.0
(13.0) (4.4) (27.0) (15.0)
Dorkova et al. (2008) Slovakia 16 (1) AHI > 30; metabolic Have 8 wk P4.0 ELISA 13 51.3 32.8 64.7 12.6 66.5
[25]a syndrome (9.5) (4.4) (23.3) (3.4) (15.6)
Dorkova et al. (2008) Slovakia 15 (5) AHI > 30; metabolic Have 8 wk <4.0 ELISA 12 56.1 37.3 63.2 13.9 56.8
[25]b syndrome (9.5) (6.9) (18.8) (5.6) (22.2)
Li et al. (2008) [26] China 33 (NR) AHI > 5 NR 2 mo NR ELISA 11 NR NR 45.7 NR 62.0

X. Xie et al. / Sleep Medicine 14 (2013) 1139–1150

(24.9) (14.8)
Tomiyama et al. (2008) Japan 29 (0) AHI P 15 Have 3 mo NR ELISA 10 NR NR NR NR NR
[29]#
Vgontzas et al. (2008) Greece 16 (0) Obese; AHI > 20 Have 3 mo 4.6 (0.4) ELISA 12 48.1 37.5 53.3 12.1 72.4
[30] (5.6) (4.7) (28.0) (4.4) (8.4)
Carneiro et al. (2009) Brazil 7 (0) AHI > 30; BMI P 40; daytime Have 3 mo 6.6 (1.1) Immunometric 10 NR 46.1 91.0 10.5 71.2
[32] sleepiness (19.6) (25.7) (2.7) (5.3)
Steiropoulos et al. Greece 32 (0) AHI > 5; daytime symptoms Have 6 mo 4.7 (0.6) ELISA 13 45.6 34.6 61.1 11.9 71.0
(2009) [35]a (10.7) (8.9) (28.3) (5.6) (9.4)
Steiropoulos et al. Greece 20 (0) AHI > 5; daytime symptoms Have 6 mo 1.4 (1.5) ELISA 12 46.6 33.6 50.7 9.6 74.7
(2009) [35]b (9.9) (4.5) (26.3) (5.6) (11.0)
Karamanli et al. (in Turkey 35 (14) AHI P 15 Have 3 mo 5.8 ELISA 13 52.5 NR 45.6 NR 72.1
press) [42] (10.3) (22.1) (13.0)
Oyama et al. (2012) Japan 32 (13) AHI > 20; metabolic Have 3 mo P4.0 ELISA 11 53.9 26.7 56.2 17.4 NR
[43]# syndrome (60%) (8.6) (3.6) (21.6) (5.3)

Abbreviations: AHI, apnea-hypopnea index; BMI, body mass index; ELISA, enzyme-linked immunoabsorbent assay; ESS, Epworth Sleepiness Scale; LowSO2, lowest arterial oxygen saturation; mo, month; NR, not reported; W,
women; wk, week.
Values are mean (standard deviation).
Age indicated as years; AHI indicated as events per hour.
BMI indicated as kg/m2.
Daily duration indicated as hours.
ESS indicated as score.
LowSO2 indicated as %.
#
Indicated data from reading graph.
Indicated data from the whole study population.
a
Indicated treatment duration of P4 h per night.
b
Indicated treatment duration of <4 h per night.

1145
1146 X. Xie et al. / Sleep Medicine 14 (2013) 1139–1150

Fig. 2. Comparison of C-reactive protein levels before and after continuous positive airway pressure therapy in the 24 included studies. Abbreviations: SMD, standardized
mean difference; CI, confidence interval. (a) and (b) indicated treatment duration of P4 and <4 h per night, respectively.

Table 5
The results of subgroup analyses.

Subgroup CRP IL-6 TNF-a

Number of studies/ Heterogeneity Number of studies/patients Heterogeneity Number of studies/ Heterogeneity
patients patients
SMD (95% CI) (P value; I2 (%); SMD (95% CI) (P value; I2 (%); SMD (95% CI) (P value; I2 (%);
Psubgroup) Psubgroup) Psubgroup)
Area
Asia 10/265; 0.731 (0.337–1.126) .000; 78.9; 0.583 6/126; 0.952 (0.483–1.422) .013; 65.5; 0.000 5/141; 0.900 (0.451–1.348) .014; 68.1; 0.000
Non-Asian 18/1432; 0.308 (0.065–0.552) .000; 86.7 12/365; 0.004 ( 0.299 to 0.291) .000; 71.6 9/215; 0.258 (0.067–0.449) .467; 0.0
Therapy duration (mo)
<3 8/1944; 0.336 ( 0.036 to 0.707) .002; 68.2; 0.000 8/202; 0.215 ( 0.295 to 0.725) .000; 83.6; 0.739 6/150; 0.579 (0.095–1.063) .002; 74.2; 0.219
P3 20/1503; 0.493 (0.264–0.723) .000; 85.9 10/289; 0.355 ( 0.021 to 0.730) .000; 76.1 8/206; 0.402 (0.106–0.699) .036; 53.3
Daily duration (h)
<4 11/338; 0.274 ( 0.001 to 0.549) .001; 65.0; 0.000 9/292; 0.299 ( 0.187 to 0.785) .000; 86.2; 0.602 6/181; 0.642 (0.156–1.129) .000; 79.4; 0.012
P4 17/1359; 0.553 (0.312–0.794) .000; 85.0 9/199; 0.299 ( 0.047 to 0.644) .005; 63.9 8/175; 0.303 (0.092–0.515) .623; 0.0

Abbreviations: AHI, apnea-hypopnea index; BMI, body mass index; CI, confidence interval; ESS, Epworth Sleepiness Scale; h, hours; mo, months; SMD, standardized mean
difference; TNF-a, tumor necrosis factor a.

various inflammatory markers may be plausible according to pre-
vious studies [13,32,35,39] and from the results of our meta-anal-
ysis. In addition meta-regression analyses showed that differences
in the baseline inflammatory markers levels, therapy duration,
mean age, BMI, AHI, and lowest O2 saturation were not predictors
of the treatment difference based on systemic inflammatory re-
sponse. Thus none of the factors mentioned above could indepen-
dently predict the effectiveness of CPAP therapy on systemic
inflammation. Results of the meta-analysis should be cautiously
interpreted, as the subgroups were defined post hoc and the study
means rather than the individual patients were used as data points.
Aside from OSA, obesity has been recognized as an important
factor that induces and aggravates systemic inflammation in pa-
tients with OSA, though the independent factors remain controver-
sial [39,54–57]. The results from our meta-analysis showed that
restricting the analysis to studies that showed no significant
change of BMI pre- and post-CPAP therapy did not significantly
change the results of the analyses. Similarly Barceló et al. [12]
 X. Xie et al. / Sleep Medicine 14 (2013) 1139–1150 1147

Table 6
The results of meta-regression analyses.

Variable CRP IL-6 TNF-a

Number of studies/patients P value Number of studies/patients P value Number of studies/patients P value
Sample size 28/1697 .166 17/491 .866 14/356 .288
Inflammatory markers levels# 28/1697 .322 17/491 .183 14/357 .024
Therapy duration 28/1697 .708 17/491 .476 14/358 .398
Age 24/1574 .925 13/362 .385 9/206 .87
BMI 25/1577 .592 13/334 .197 9/178 .191
AHI 28/1697 .755 16/451 .843 12/295 .875
ESS 20/1386 .007 11/233 .162 8/167 .333
LowSO2 22/1443 .213 12/318 .761 9/179 .407

Abbreviations: AHI, apnea-hypopnea index; BMI, body mass index; CRP, C-reactive protein; ESS, Epworth Sleepiness Scale; LowSO2, lowest arterial oxygen saturation; NR, not
reported; TNF-a, tumor necrosis factor a.
#
The value in before continuous positive airway pressure therapy.

Fig. 3. Comparison of IL-6 levels before and after continuous positive airway pressure therapy in the 16 included studies. Abbreviations: SMD, standardized mean difference;
CI, confidence interval. (a) and (b) indicated treatment duration of P4 and <4 h per night, respectively.

did not find significant changes in CRP levels between obese and
nonobese patients with OSA after 3 months of CPAP therapy [12].
CPAP therapy often results in weight gain rather than weight loss.
Thus the results from our meta-analysis suggest the role of OSA on
the development of systemic inflammation in patients with OSA,
one which is independent of obesity.
A few caveats should be noted when interpreting the findings
from our meta-analysis. First, significant heterogeneity was ob-
served in our report, but no consistent determinant was identified.
Second, the primary outcome assessed in most of the studies was
not the effect of CPAP therapy on systemic inflammation. Further-
more, the sample size was relatively small, especially for IL-8,
thereby making the results prone to selective bias. Third, the stud-
ies included in our meta-analysis were not controlled, with levels
of evidence lower than those of randomized controlled studies. Be-
cause the randomization of risk factors in controlled trials involv-
ing patients with confirmed and untreated OSA is unethical, only
the potential changes in systemic inflammation may be observed.
There were only 2 randomized controlled studies that explored
the effect of CPAP therapy on systemic inflammation and reported
inconsistent results [18,58]. Fourth, measures of inflammatory
markers in all studies are unique, which makes the influence of
acute inflammation unavoidable. Fifth, although most studies at-
tempted to control the potential confounders which could influ-
ence levels of inflammatory markers, the substantial degree of
disparity was noted among factors including the patients’ charac-
teristics, medications, measurement of markers, treatment models,
and therapy duration. Finally, the means and SDs were extracted
by reading a graph or calculating results from nonnormally distrib-
uted statistics (median and interquartile ranges) in some studies
[13,15,21,29,31,39,43]. Thus these data did not represent the true
values obtained from the actual studies, which may be a potential
cause of error. All of these caveats could lead to false or spurious
results, decrease statistical power, or even negate our conclusions.
Despite these disadvantages, our analysis presents several nota-
ble findings. First, CPAP therapy could suppress systemic inflam-
mation in OSA patients, and substantial changes were observed
in the levels of various inflammatory markers. Second, the results
1148 X. Xie et al. / Sleep Medicine 14 (2013) 1139–1150

Fig. 4. Comparison of IL-8 levels before and after continuous positive airway pressure therapy in the 3 included studies. Abbreviations: SMD, standardized mean difference;
CI, confidence interval.

Fig. 5. Comparison of TNF-a levels before and after continuous positive airway pressure therapy in the 12 included studies. Abbreviations: SMD, standardized mean
difference; CI, confidence interval. (a) and (b) indicated treatment duration of P4 and <4 h per night, respectively.

of our meta-analysis support the hypothesis that heightened sys-
temic inflammatory levels are present in OSA and are independent
of obesity, despite the inconclusive results. In addition, no single
factor was found to independently predict the effectiveness of
CPAP therapy on systemic inflammation. Finally, the SDs of inflam-
matory markers in most studies were relatively large, thereby sug-
gesting the wide distribution of levels of inflammatory markers in
individual patients. To avoid this influence, we recommend the use
of percentage change instead of the absolute value of the inflam-
matory markers in future research.
The results of our meta-analysis showed that CPAP therapy
influences the decrease of systemic inflammation. More benefits
are gained from longer durations and adequate compliance, though
significant heterogeneity was observed among the included stud-
ies. By considering the close relationship between OSA and cardio-
vascular disease, future research should identify the effects of
decreased systemic inflammation on the amelioration of cardio-
vascular risk associated with OSA and should determine the mag-
nitude of these effects.
Conflict of interest
The ICMJE Uniform Disclosure Form for Potential Conflicts of
Interest associated with this article can be viewed by clicking
 X. Xie et al. / Sleep Medicine 14 (2013) 1139–1150 1149

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