Impact of emphysema on mortality in idiopathic pulmonary fibrosis: A systematic review and meta-analysis

Abstract

Background

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrosing interstitial lung disease. The effects of emphysema on mortality in IPF remains unclear.

Methods

MEDLINE, Embase and Cochrane Library databases were searched. Studies were included if they compared mortality in IPF patients with and without emphysema. In included studies, the diagnosis with IPF or IPF combined emphysema was according to the ATS and ERS statements. From eligible studies, we extracted HR and 95% CI, if HRs were not reported, they were extracted based on Kaplan–Meier curves.

Results

A total of 2605 patients across 15 cohort studies were included in the systematic review and meta-analysis. Emphysema was associated with increased risk of all-cause mortality with a pooled HR 1.37 (95% CI, 1.04-1.80) and I² = 64%. However, the level of evidence was ‘very low’ according to GRADE criteria. Subgroup analysis according to IPF with emphysema patients revealed that DL_CO%pre<40 (HR 1.75 (95% CI, 1.02-3.01) and I² = 74%), FVC%pre<80 (HR 1.81 (95% CI, 1.24-2.64) and I² = 61%), location on North America and Europe (HR 2.00 (95% CI, 1.09-3.67) and I² = 76%), and Smoking Pack-years<40 (HR 1.38 (95% CI, 1.02-1.87) and I² = 15%) were risk factors for all-cause mortality. Sensitivity analysis revealed that one study had a disproportional effect on the pooled rate.

Conclusions

Our findings suggested emphysema increased the risk of all-cause mortality in patients with IPF. This conclusion should be re-evaluated by a large-scale randomized controlled trial.

Trial Registration

PROSPERO: CRD42022378699; https://www.crd.york.ac.uk/prospero/.

Keywords

idiopathic pulmonary fibrosis emphysema combined pulmonary fibrosis and emphysema

Introduction

The term idiopathic pulmonary fibrosis (IPF) refers to a chronic and progressive fibrosing interstitial lung disease with an unknown cause, characterized by radiologic and histopathologic findings consistent with usual interstitial pneumonia (UIP).^1,2 The incidence of IPF ranges from 3 to 9 cases per 100,000 person-years, predominantly affecting the elderly.³ Its prognosis is poor with median survival of 3 years from the time of diagnosis.⁴ IPF combined with comorbidities such as emphysema,⁵ lung cancer⁶ and pulmonary arterial hypertension⁷ usually has distinguished characteristics.

The term combined pulmonary fibrosis and emphysema (CPFE) refers to the coexistence of emphysema and fibrotic interstitial lung disease,⁵ which was first proposed as a disease entity by Cottin et al⁸ in 2005. About 26%–54% reported patients are diagnosed with IPF(5, 9), so we consider IPF combined with emphysema is its common clinical phenotype.⁹ CPFE has some distinguished characteristics compared to IPF such as higher frequency in smokers, almost normal forced vital capacity (FVC), lower diffuse capacity of the lung for carbon monoxide (DLco).⁵ The prognosis of IPF combined emphysema is also poor, previous researches revealed that its mortality could be better,¹⁰ similar,¹¹ or poorer¹² compared to IPF alone. Hence, whether existing emphysema affects mortality in IPF is still unclear.

In this systematic review and meta-analysis, we aimed to explore whether existing emphysema could affect mortality in IPF.

Methods

Flow diagram indicating the search strategy of this systematic review and meta-analysis is depicted in Figure 1. The protocol was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.¹³ The protocol was registered with PROSPERO:CRD42022378699;https://www.crd.york.ac.uk/prospero/

Figure 1.

Study selection algorithm.

Search strategy and study selection

MEDLINE, Embase and Cochrane Library databases were searched from January 1st, 1956 to October 29, 2022. The search strategy was using the term “(((CPFE) OR (Emphysema)) OR (Combined Pulmonary Fibrosis and Emphysema)) AND ((((Idiopathic Pulmonary Fibrosis) OR (IPF)) OR (Cryptogenic fibrosing alveolitis)) OR (CFA))” (Supplemental document 1).

Inclusion criteria

We included studies with (1) patients diagnosed with IPF and IPF combined emphysema according to the American Thoracic Society (ATS) and European Respiratory Society (ERS) statements,^1,5 (2) at least 5 patients were included in each group, (3) language was not restricted.

Exclusion criteria

The titles and abstracts of all retrieved articles were independently reviewed by three investigators (Yanhong Wang, RuYi Zou, and Yu Yao). Studies were excluded if: (1) a complete article was not available for review; (2) they involved animal or in vitro studies; (3) they were case reports or reviews; (4) there was an absence of control group; (5) there was overlapping data among the articles. After assessments of 57 studies, a total of 42 were excluded. 38 studies were excluded because of not having sufficient survival data to extract HR. 4 studies were excluded due to IPF with emphysema group included non-IPF patients. Finally, 15 eligible studies were included and analyzed in this systematic review and meta-analysis.

Data extraction

Data were independently extracted by three investigators (Yanhong Wang, RuYi Zou and Cheng Tang). The following variables were extracted from each study: names of the authors, year of publication, duration of study enrollment, participant characteristics (number, age, sex, smoking history, smoking pack-years, baseline pulmonary function tests) and hazard ratio (HR) for all-cause mortality and 95% confidence interval (CI). HRs were not reported in some studies and were extracted using the method developed by Parmar et al¹⁴ based on Kaplan–Meier curves. Disagreement between two researchers were settled by arbitration of the principal investigator (Minjie Lin and Jing Luo).

Quality assessment

All the studies included are observational studies, risk of bias assessment was evaluated using the Newcastle-Ottawa scale.¹⁵ Three investigators (Yanhong Wang, RuYi Zou and Yu Yao) independently evaluated the risk of bias for all studies. Disagreement between three researchers were settled by arbitration of the principal investigator (Minjie Lin and Jing Luo). The threshold for categorizing studies as having a ‘low risk of bias’ was set at a score of ≥5 on the Newcastle-Ottawa scale, while studies with scores <5 were classified as having a ‘high risk of bias’.

Outcomes

The primary outcome of this study was to compare the risk of all-cause mortality between patients with IPF who have emphysema and those without emphysema. The effect size was estimated as hazard ratio (HR) with 95% confidence interval (CI).

Statistics

From eligible studies, we extracted HR and 95% CI, if HRs were not reported, they were extracted using the method developed by Parmar et al¹⁴ based on Kaplan–Meier curves. The data were aggregated through the utilization of random-effect meta-analyses

The statistical heterogeneity of effect size across the included studies was evaluated using both the Cochrane Q test and the I² statistic. A p-value below 0.1 on the Q test was deemed to be statistically significant. Furthermore, I² values ranging from 0% to 50% were indicative of acceptable levels of heterogeneity, while values between 51% and 100% denoted a high degree of heterogeneity.¹⁶ Sensitivity analysis was carried out via conducting leave-one-out sensitivity test. Further subgroup analysis was conducted in patients with IPF and emphysema to evaluate the variables that may be associated with mortality and identify potential sources of study heterogeneity. The variables included DL_CO %pre (<40 vs≥40), FVC %pre (<80 vs≥80), geographical distribution (Asia vs North America and Europe) and Smoking Pack-years (<40 vs≥40). The presence of publication bias was evaluated through the utilization of funnel plot. All statistical analyses were conducted utilizing RevMan 5.4. Confidence assessment in the body of evidence for an outcome was conducted via GRADEprofiler 3.6.

Results

Out of the 2473 articles identified in our initial search, 2416 articles were excluded based on meticulous scrutiny of their titles and abstracts. Following full-text review, 57 articles remained for consideration, ultimately 15 articles were included in the final meta-analysis.^{9–12, 17–27} (Figure 1).

Characteristics of the included studies

The included studies comprised exclusively of cohort studies. A total of 871 IPF patients with emphysema and 1734 IPF patients without emphysema were enlisted in the meta-analysis. Included patients came from Asia, Europe and North America and the majority were male (80%). IPF with emphysema patients in our meta-analysis were usually male, >60 years old, having smoking history, heavy smoking pack-years, almost normal FVC% pre and severe impairment of DL_CO% pre. The quality of the cohort studies evaluated using the Newcastle-Ottawa scale varied between 5 and 8 (Table1 and Supplemental Table 1).

Table 1.

Summary of included studies.

Studies	Geographical distribution (country)	Public time	Study enrolment period	IPF with emphysema								IPF alone								Newcastle-ottawa scale
Studies	Geographical distribution (country)	Public time	Study enrolment period	Sample size	Sex (M)	Age	Smoking history (%)	Smoking Pack-years	FVC % pre	DLCO % pre	Median follow-up duration	Sample size	Sex (M)	Age	Smoking history (%)	Smoking Pack-years	FVC % pre	DLCO % pre	Median follow-up duration	Newcastle-ottawa scale
Akagi et al¹⁷	Asia (Japan)	2009	1988-2007	26	23	65.1±8.5	92.3	59.5±36.7	NA	45.3±15	4.67±2.15 (years)	33	22	66.5±9.2	75.5	39.9±32.5	NA	60.7±19.8	3.73±2.42 (years)	8
Jacob et al¹⁸	Europe (UK)	2017	2007-2011	105	85	66	86.6	35±24.2	76.8±19.9	35.6±12.0	NA	167	126	67	50.9	21±14.6	62.9±19.1	36.7±13.4	NA	7
Kim et al¹⁹	Asia (Korea)	2014	2000-2013	26	23	67.6±2.2	92.3	28.3±4.1	79.3±4.0	76.5±6.1	48.9±6.8 (months)	42	24	68.2±1.7	45.2	10.7±2.5	79.7±3.0	82.8±4.3	62.1±6.7 (months)	7
Kurashima et al¹⁰	Asia (Japan)	2010	1997-2006	221	209	71.1±7.7	74.5	55.3±24.9	87.1±17.0	65.2±20.9	NA	439	336	72.9±8.1	100	36.5±27.6	71.8±19.4	74.3±20.1	NA	7
Li et al²⁰	Asia (China)	2022	2018-2020	44	44	68±6	100	40	77.26±12.08	39.7 (31.00∼43.70)	21 (months)	57	45	67±8	58	30	67.45±13.77	54.5 (39.50∼62.38)	21 (months)	6
Ma et al²¹	Asia (China)	2013	2002-2007	23	21	63±8	95.7	28±18	NA	44±12	NA	33	27	64±8	75.8	18±16	NA	54±16	NA	8
Mejía et al¹²	North America (Mexico)	2009	1996-2006	31	30	67±7	77.4	5 (0–60)	62.1±15.6	NA	NA	79	49	63±10	45.6	0 (0–78)	58.7±18	NA	NA	6
Moon et al²²	Asia (Korea)	2019	2003-2018	107	104	70.1±7.1	96.3	46.4±26.4	82.8±17.4	64.8±17.9	18.6±25.5 (months)	176	165	70.4±8.4	91.5	35.6±23.8	83.3±18.8	78.0±21.5	24.1±24.1 (months)	8
Ryerson et al¹¹	North America (USA)	2013	2000-2010	29	20	69.9	100	46.4	79.8	37.1	NA	336	239	69	71	16.1	65	44.4	NA	8
Sangani et al²³	North America (USA)	2021	2015-2019	49	32	73.9±10.42	93.9	49.09±29.58	73.76±15.65	38.35±15.45	4.45±2.39 (years)	60	35	78.2±9.46	53.3	15.39±14.84	75.83±18.79	51.09±15.96	4.64±3.26 (years)	7
Sato et al²⁴	Asia (Japan)	2016	2001-2012	55	53	71.8±7.3	N [24]A	61.8	96.4±20.2	54.8±10.4	NA	45	38	69.9±7.1	NA	50.7	91.0±19.5	55.2±8.3	NA	7
Sato et al⁹	Asia (Japan)	2016	2008-2010	12	NA	NA	NA	NA	NA	NA	NA	5	NA	NA	NA	NA	NA	NA	NA	5
Sugino et al²⁵	Asia (Japan)	2014	2003-2010	46	43	73.7±6.7	97.8	59.9	93.9±22.4	49.8±14.1	NA	62	46	71.4±6.3	79	33	73.9±19.1	53.9±17.9	NA	7
Takahashi et al²⁶	North America (USA)	2021	2011-2016	27	23	63±6	NA	NA	65±22	19±5	NA	145	106	61±8	NA	NA	48±18	24±9	NA	8
Ye et al²⁷	Asia (China)	2014	2006-2009	70	68	64±9	97.1	30 (0–160)	72±17	NA	NA	55	38	66	50.9	2	71±20	NA	NA	7

FVC = forced vital capacity, DLCO = diffuse capacity of the lung for carbon monoxide.

Effect of emphysema on all-cause mortality

For the analysis of all-cause mortality, pooled HR was 1.37 (95% CI, 1.04-1.80) and I² = 64% (Figure 2). Sensitivity analysis revealed that one study had a disproportional effect on the pooled rate after conducting leave-one-out sensitivity test (Table 2). We performed additional subgroup analysis according to IPF with emphysema patients stratified by lung function, geographical distribution and smoking index, which revealed that DL_CO%pre<40 (HR 1.75 (95% CI, 1.02-3.01) and I² = 74%), FVC%pre<80 (HR 1.81 (95% CI, 1.24-2.64) and I² = 61%), North America and Europe distribution (HR 2.00 (95% CI, 1.09-3.67) and I² = 76%), and Smoking Pack-years<40 (HR 1.38 (95% CI, 1.02-1.87) and I² = 15%) were risk factors for all-cause mortality in IPF with emphysema (Figures 3–6).

Figure 2.

Forest plot for pooled hazard ratio for all-cause mortality.

Table 2.

Sensitivity analysis.

Removed studies	Tests for overall effect			Tests for heterogeneity
Removed studies	p	HR	95%CI	p	I²
Akagi et al	0.001	1.42	1.08-1.88	0.0004	I²= 65%
Jacob et al	0.004	1.41	1.02-1.93	0.0002	I² = 66%
Kim et al	0.004	1.34	1.01-1.76	0.0004	I² = 65%
Kurashima et al	<0.0001	1.49	1.16-1.90	0.02	I² = 48%
Li et al	0.004	1.37	1.02-1.84	0.0002	I² = 66%
Ma et al	0.002	1.39	1.04-1.84	0.0002	I² = 66%
Mejía et al	0.007	1.31	1.00-1.73	0.0007	I² = 63%
Moon et al	0.004	1.41	1.02-1.93	0.0002	I² = 66%
Ryerson et al	0.07	1.20	0.97-1.47	0.10	I² = 35%
Sangani et al	0.005	1.35	1.01-1.80	0.0003	I² = 66%
Sato et al	0.002	1.41	1.05-1.88	0.0002	I² = 66%
Sato et al	0.002	1.37	1.04-1.80	0.0002	I² = 66%
Sugino et al	0.005	1.35	1.01-1.79	0.0003	I² = 66%
Takahashi et al	0.002	1.38	1.04-1.81	0.0005	I² = 62%
Ye et al	0.003	1.32	1.02-1.72	0.0002	I² = 67%
Kurashima et al and ryerson et al	0.003	1.27	1.08-1.48	0.70	I² = 0

Figure 3.

Forest plot for pooled hazard ratio for all-cause mortality in subgroup analysis according to IPF with emphysema patients stratified by DL_CO %pre. (1.1.1) DL_CO%pre ≥ 40; (1.1.2) DL_CO %pre <40.

Figure 4.

Forest plot for pooled hazard ratio for all-cause mortality in subgroup analysis according to IPF with emphysema patients stratified by FVC %pre. (1.1.1) FVC %pre ≥ 80; (1.1.2) FVC %pre <80.

Figure 5.

Forest plot for pooled hazard ratio for all-cause mortality in subgroup analysis according to IPF with emphysema patients stratified by geographical distribution. (1.1.1) Asia; (1.1.2) North America and Europe.

Figure 6.

Forest plot for pooled hazard ratio for all-cause mortality in subgroup analysis according to IPF with emphysema patients stratified by smoking pack-years. (1.1.1) Smoking pack-years≥40; (1.1.2) Smoking pack-years< 40.

Evaluation of publication bias

The funnel plot revealed an asymmetry in the distribution of publication contributions, suggesting a potential bias among the 15 studies (Supplemental Figure 1).

Certainty of evidence for all-cause mortality

The meta-analysis revealed that the presence of emphysema significantly augmented the risk of all-cause mortality in patients with IPF. Considering that all the studies included were cohort studies, which might introduce publication bias, the certainty ratings for effect size were deemed to be at a very low level of evidence according to GRADE criteria. The GRADE criteria showed no imprecision, no indirectness, no inconsistency, potential publication bias but risk of information bias. (Table 3).

Table 3.

Summary of results for outcome and quality of evidence.

Outcome	No. Of participants	HR	95% CI	Quality of evidence (GRADE)
All-cause mortality (15 cohort studies)	2605	1.37	1.04-1.80	⊕○○○ very low

Discussion

This systematic review and meta-analysis included 2605 patients from 15 studies (871 IPF with emphysema and 1734 IPF patients) and found emphysema appeared to increase the risk of all-cause mortality with pooled (HR 1.37 (95% CI, 1.04-1.80) and I² = 64%). Sensitivity analysis revealed that one study had a disproportional effect on the pooled rate after conducting leave-one-out sensitivity test. Subgroup analyses according to IPF with emphysema patients revealed that DL_CO %pre<40 (HR 1.75 (95% CI, 1.02-3.01) with I² = 74%), FVC %pre<80 (HR 1.81 (95% CI, 1.24-2.64) with I² = 61%), North America and Europe population (HR 2.00 (95% CI, 1.09-3.67) and I² = 76%), and Smoking Pack-years<40 Pack-years (HR 1.38 (95% CI, 1.02-1.87) and I² = 15%) were associated with inferior outcome in IPF with emphysema.

Whether existing emphysema increases the mortality of IPF remained controversial. Jiang et al²⁸ conducted a meta-analysis to assess the survival rate of CPFE versus IPF alone and the results showed similar prognosis. Subgroup analysis by 1, 3 and 5-year follow-up time also showed no difference between the two groups. However, CPFE included pulmonary fibrosis of various etiology⁵ and the outcome can be influenced due to confounding bias. Hence, implement a systematic review and meta-analysis to compared IPF with emphysema to IPF alone is necessary. To our knowledge, this is the first systematic review and meta-analysis to compare the prognosis of IPF with emphysema versus IPF alone. Our research revealed that existing emphysema increases the mortality of IPF, which suggested the mortality of IPF with emphysema may decreased if we actively to treat the emphysema. Dong et al ’s²⁹ study revealed that the utilization of inhaled corticosteroids (ICS)/long-acting beta2-agonists (LABA) therapy enhanced lung function parameters among patients with IPF accompanied by emphysema. Additionally, it reduced the frequency and severity of acute disease outbreaks during episodes. Therefore, for IPF with emphysema, our research suggests that in addition to antifibrotic therapy, the use of ICS/bronchodilators for inhalation therapy or lung rehabilitation, mechanical lung volume reduction, and so on, similar to those used for emphysema and chronic obstructive pulmonary disease are necessary. However, more high-quality researches should be implemented in the future.

The heterogeneity observed in our pooled analysis of all-cause mortality risk was substantial, prompting a sensitivity analysis to investigate potential underlying factors. We found removing Kurashima et al¹⁰’s or Ryerson et al¹¹’s research could significantly decrease heterogeneity and when we removed them both I² decreased to 0%. We reviewed the above two researches again and found they had the biggest sample size in our meta-analysis, heterogeneity in these researches could be amplified. In Kurashima et al¹⁰’s research, the inclusion criteria didn’t contain the extent of emphysema and DL_CO % pre was higher than the other researches. So, we hypothesized IPF with emphysema patients in this article tended to be mild, which underestimated the influence of emphysema on mortality. As for Ryerson et al¹¹’ research, the number of IPF with emphysema patients was much smaller than IPF alone compared to the other researches, we speculated this article might have different method to assess the extent of emphysema, which could underestimate the number of IPF with emphysema patients and result in information bias.

Subgroup analysis according to IPF with emphysema patients stratified by lung function, smoking pack-years and geographical distribution showed that DLCO %pre<40, FVC %pre<80, smoking pack-years<40 and North America and Europe location was associated with increased risk of mortality. The results of subgroup analysis did not meet our expectation as previous studies revealed that IPF with emphysema usually had lower FVC %pre and higher smoking pack-years, which are usually associated with severe emphysema.^30,31 Lower DL_CO %pre was consistent with previous research, which was attributed to the additive effect of emphysema and pulmonary fibrosis on gas exchange.³² The difference between North America, Europe and Asia has not been described before, which required further exploration. Additionally, all the included studies might have selection bias because critical patients could not complete pulmonary function tests, so the included patients tended to be mild, which might explain some subgroup analysis outcome against our experience.

There are several limitations to our study. First, pooled analysis of cohort studies had high heterogeneity and sensitivity analysis showed two researches might contribute to the heterogeneity. Second, all studies included were cohort studies, which could lead to various bias and don’t have as high level of evidence as randomized controlled trial (RCT) researches or individual participant data meta-analysis.³³ In addition, most included studies don’t display their subgroup average/median follow-up duration, which could also contribute to the heterogeneity. Finally, the sensitivity analysis showed altered pooled outcome after removing one study, which suggested our result was not very robust.

Conclusions

Our findings suggest that the presence of emphysema significantly increases the risk of all-cause mortality in patients with IPF (HR 1.37 (95% CI, 1.04-1.80)). However, it is important to acknowledge the limitation of study heterogeneity in our pooled analysis, although the prognosis remains consistent across subgroup analyses. Therefore, we eagerly anticipate high-quality researches will be carried out in this field.

Supplemental Material

Supplemental Material - Impact of emphysema on mortality in idiopathic pulmonary fibrosis: A systematic review and meta-analysis

Supplemental Material for Impact of emphysema on mortality in idiopathic pulmonary fibrosis: A systematic review and meta-analysis by Yanhong Wang, Ruyi Zou, Yu Yao, Cheng Tang, Jing Luo and Minjie Lin in European Journal of Inflammation

Footnotes

Author contributions

YHW, JL and MJL contributed to the conception, methodology design, and writing of the manuscript. RYZ, YY, CT and YHW took responsibilities for data abstraction and accuracy of data analysis. All authors are guarantors of this work.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was funded by National Natural Science Foundation of China, grant number 82203561.

ORCID iD

Minjie Lin

Data availability statement

All data generated or analyses in this study are included in this article. Further enquiries can be directed to the corresponding author.*

Supplemental Material

Supplemental material for this article is available online.

Appendix

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