Clinical impact of weight loss on mortality in patients with idiopathic pulmonary fibrosis: a retrospective cohort study

doi:10.21203/rs.3.rs-2214669/v1

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Clinical impact of weight loss on mortality in patients with idiopathic pulmonary fibrosis: a retrospective cohort study

https://doi.org/10.21203/rs.3.rs-2214669/v1

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published 08 Apr, 2023

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Background

Patients with idiopathic pulmonary fibrosis (IPF) often experience weight loss during the follow-up period. However, the prevalence and clinical impact of weight loss in these patients still need to be elucidated.

Methods

This retrospective single-center study reviewed 134 consecutive patients diagnosed with IPF. Clinical data of patients were compared according to the significant weight loss. We analyzed whether the clinical impact of significant weight loss differed regarding the pirfenidone dose.

Results

The median follow-up period was 22.1 months. Of the 134 patients, 42 (31.3%) experienced significant weight loss. Significant weight loss was independently associated with mortality (hazard ratio [HR]; 2.650; 95% confidence interval [CI], 1.108–6.341; p = 0.029) after adjusting for lung function and other significant risk factor (6-minute walk test distance: HR, 0.992; 95% CI, 0.992–0.987; p = 0.003) in multivariate analysis. The median survival of patients with significant weight loss (n = 26) was shorter than that of those without significant weight loss (n = 50) in the reduced dose pirfenidone group (28.3 ± 3.1 vs 41.8 ± 3.1 months, p = 0.013). Compared with patients without significant weight loss (n = 38), patients with significant weight loss (n = 15) also showed a marginally-significant shorter survival in the full-dose pirfenidone group (28.9 ± 3.1 vs 39.8 ± 2.6 months, p = 0.085).

Conclusions

Significant weight loss is a prognostic factor in patients with IPF regardless of pirfenidone dose. Vigilant monitoring might be necessary to detect weight loss during the clinical course in these patients.

Health sciences/Diseases

Health sciences/Medical research

Health sciences/Signs and symptoms

Idiopathic pulmonary fibrosis

Weight loss

Pirfenidone

Mortality

Idiopathic pulmonary fibrosis(IPF) is a specific form of interstitial lung disease characterized by chronic and progressive loss of lung function [1]. Although the clinical course of IPF varies widely, in general, the prognosis of IPF is poor, and the median survival is 3–5 years from the time of diagnosis [2].

Weight loss is a common problem in patients with IPF. Previous studies have reported that approximately 15–20% of patients with IPF lose \(\ge\)5% of their weight during the first year of the disease course. [3, 4]. Various factors such as disease progression, chronic inflammation, and physical inactivity have been suggested as the cause of weight loss in patients with IPF [5–7]. In addition, anti-fibrotic medications to treat IPF, especially pirfenidone might cause weight loss [8], often resulting in a dose reduction of these medications to minimize adverse effects [9].

Several studies have reported that weight loss and low body mass index (BMI) can adversely affect the prognosis of patients with IPF [3, 4, 10, 11]. However, other studies have shown conflicting results, depending on the confounding factor and study design [12, 13]. Large-scale studies on the prevalence and clinical impact of weight loss in patients with IPF are still needed, especially in the era of anti-fibrotic medication usage, which is an important confounding factor. Therefore, our study aimed to investigate the prevalence, risk factors, clinical impact of weight loss in patients with IPF, and whether the clinical effects of weight loss differ in regard to the dose of pirfenidone.

Study population

In this single-center retrospective cohort study, we analyzed the data of patients aged \(\ge\)40 years and diagnosed with IPF at Asan Medical Center, a tertiary referral hospital in Seoul, South Korea between January 1, 2018, and September 1, 2021. Patients with a follow-up duration of less than a year, and patients with no data on body weight at the time of diagnosis or a year after diagnosis were excluded from the study. Patients with a definite connective tissue disease or a history of exposure to the possible causes of interstitial lung disease were also excluded.

Diagnosis of IPF was made by the diagnostic criteria of the American Thoracic Society (ATS)/European Respiratory Society (ERS)/Japanese Respiratory Society/Latin American Thoracic Association in 2018 [14].

This study was conducted in compliance with the Declaration of Helsinki. The study protocol was endorsed by the Institutional Review Board of Asan Medical Center (IRB number: 2021 − 0736). Informed consent was waived because of the retrospective study design and anonymity of clinical data.

Clinical Data

Body weight was measured at the time of diagnosis and the outpatient visit or hospitalization thereafter. Significant weight loss was defined as a weight loss of \(\ge\)5% over 1 year after diagnosis [15, 16]. Data from the National Insurance Corporation were used to investigate deaths and their dates from the time of diagnosis to August 1, 2022. Consistent with ERS/ATS recommendations, spirometry was performed and, total lung capacity (TLC), and diffusing capacity for carbon monoxide (DLco) were measured [17, 18]. The 6-minute walk test (6MWT) was also performed according to these guidelines [19]. We used in-hospital data to investigate the demographics of the patients, whether they used pirfenidone, the dosage and side effects of pirfenidone, and the types of side effects. As used in Korea, full dose of pirfenidone was defined as 1800mg/d, and reduced dose of pirfenindone as < 1800mg/d [8, 20].

Statistical Analyses

For continuous variables, all values are presented as means ± standard deviations and categorical variables are presented as percentages. Student’s t-test or Mann–Whitney test was used to compare continuous variables, and the χ2 test or Fisher’s exact test was used to compare categorical variables.

The patients were divided into two groups: one with significant weight loss and one without. Logistic analysis was used to find risk factors for significant weight loss. Factors affecting mortality in patients with IPF were analyzed through the Cox proportional hazard analysis. Variables significant at a p value of \(\le\)0.2 in the univariable analysis were candidates in the multivariable analysis. Survival analysis was performed to determine a difference in mortality between the two groups using the Kaplan-Meier survival analysis and log-rank test.

All p-values were two-tailed, with statistical significance set at p \(\le\)0.05. SPSS 22.0 software (IBM Corporation, Armonk, NY, USA) was used for all statistical analyses.

Patients

A total of 134 patients were included in this study. The median follow-up duration was 22.1 months (interquartile range: 15.0–29.4 months). Table 1 presents the baseline characteristics of patients according to significant weight loss. Most participants were male (92.5%) and ever-smokers (86.6%). Of the total patients, 42 (31.3%) had a significant weight loss during the follow-up period, and 92 (68.7%) did not.

Table 1

Patient characteristics
	Total	Group with significant weight loss	Group without significant weight loss	p value
Patients, n	134	42	92
Age, years	67.3 ± 8.2	67.3 ± 9.3	67.3 ± 7.8	0.985
Male sex	124 (92.5)	41 (97.6)	83 (90.2)	0.171
Ever-smokers	116 (86.6)	39 (92.9)	77 (83.7)	0.149
Baseline body weight, kg	69.2 ± 10.6	70.4 ± 11.2	68.6 ± 10.3	0.366
Baseline BMI, kg/m²	25.5 ± 3.06	25.9 ± 3.37	25.3 ± 2.90	0.294
Weight change, kg/year	-2.14 ± 4.99	-7.83 ± 3.81	0.45 ± 2.84	< 0.001
IPF diagnosis
Clinical IPF	103 (76.9)	31 (73.8)	72 (72.2)	0.571
Biopsy proven IPF	31 (23.1)	11 (26.2)	20 (27.8)
KL-6, U/mL (116, 36/80)	1014.4 ± 874.9	922.3 ± 692.2	1055.8 ± 951.9	0.452
Baseline Albumin, g/dL (126, 40/86)	3.67 ± 0.43	3.58 ± 0.45	3.72 ± 0.41	0.108
Pulmonary function test
FVC, % predicted (129, 41/88)	75.6 ± 13.7	72.5 ± 15.1	77.0 ± 13.0	0.086
DLco, % predicted (124, 39/85)	58.6 ± 16.8	53.9 ± 16.1	60.7 ± 16.8	0.035
TLC, % predicted (112, 35/77)	74.5 ± 12.4	73.0 ± 13.3	15.2 ± 12.1	0.393
6MWD, meter	423.4 ± 99.9	414.0 ± 95.1	427.7 ± 102.8	0.468
6MWT, lowest SpO₂, %	90.4 ± 5.8	89.7 ± 5.5	90.8 ± 6.0	0.356
Data presented as mean ± standard deviation, median (interquartile range), or n (%), unless otherwise indicated. If a variable could not be measured in all patients, the number of patients for whom the variable was measured in total population and each group is indicated in parentheses next to the variables in the first column.
BMI: body mass index; FVC: forced vital capacity; DLco: diffusing capacity of the lung for carbon monoxide; IPF: idiopathic pulmonary fibrosis; TLC: total lung capacity; 6MWD: 6-minute walk test distance; 6MWT: 6-minute walk test; SpO₂: peripheral oxygen saturation.

Baseline characteristics were similar between the two groups; however, the DLco was significantly lower in the weight loss group (p = 0.035) than in the other group. Baseline body weight and BMI were not significantly different between two groups (p = 0.366, p = 0.294, respectively). Baseline Forced vital capacity (FVC) and albumin levels were lower in the significant weight loss group; however, the differences were marginally significant (FVC: p = 0.086, albumin: p = 0.108).

Use of pirfenidone and associated side effects

Most patients (96.3%, 129 of 134) received pirfenidone, and no significant difference was observed between the two groups regarding the pirfenidone dose and pirfenidone discontinuation (p = 0.478, p = 0.963 respectively, Table 2). Of all patients, 40.3% had gastrointestinal, 58.9% had skin, and 11.6% had both side effects. There was no significant difference in the frequency of each side effect according to significant weight loss (p = 0.570, p = 0.522, p = 0.774 for gastrointestinal, skin, and both side effects, respectively).

Table 2

Use of pirfenidone and associated side effects in subgroups of patients by weight loss
	Total	Group with significant weight loss	Group without significant weight loss	P value
Patients, n	129	41	88
Pirfenidone full dose	53 (41.1)	15 (36.6)	38 (43.2)	0.478
Pirfenidone reduced dose	76 (58.9)	26(63.4)	50 (56.8)
Discontinuation of treatment	28 (27.7)	9 (22.0)	19 (21.6)	0.963
Side effect
GI	52 (40.3)	18 (43.9)	34 (38.6)	0.570
Skin	76 (58.9)	43 (31.7)	33 (37.5)	0.522
GI and skin	15(11.6)	4 (9.8)	11 (12.5)	0.774
Data presented as mean ± standard deviation or n (%) unless otherwise indicated. GI: gastrointestinal

Risk factors related to significant weight loss

No baseline characteristics including age, sex, smoking history, BMI, baseline albumin, and 6MWT showed a relevant relation with significant weight loss. Although DLco was identified as a statistically relevant risk factor for significant weight loss (odds ratio [OR] = 0.975, p = 0.038) in the univariate analysis, the multivariate analysis showed no statistical significance (OR = 0.983, p = 0.195) (Table 3).

Table 3

Logistic regression analysis of risk factors for weight loss
Variable	OR	95% CI	P value
Univariate analysis
Age, years	1.000	0.956–1.045	0.985
Male sex	4.446	0.545–36.290	0.164
Ever smokers	2.532	0.692–9.274	0.161
Baseline BMI, kg/m²	1.065	0.947–1.199	0.294
Baseline albumin, g/dL Pulmonary function test	0.496	0.208–1.182	0.113
FVC, % predicted	0.975	0.948–1.004	0.089
DLco, % predicted	0.975	0.952–0.999	0.038
TLC, % predicted	0.986	0.954–1.018	0.389
6MWD, meter	0.999	0.995–1.002	0.465
6MWT, lowest SpO₂, %	0.972	0.914–1.033	0.355
Multivariate analysis
Male sex	2.391	0.110-52.213	0.580
Ever smokers	1.924	0.210-17.588	0.562
Baseline albumin, g/dL	0.519	0.195–1.386	0.191
FVC, % predicted	0.990	0.959–1.021	0.525
DLco, % predicted	0.983	0.957–1.009	0.195
6MWD: 6-minute walking distance; BMI: body mass index; CI: confidence interval; DLco: diffusing capacity of the lung for carbon monoxide; FVC: forced vital capacity; OR: odds ratio; SpO2: peripheral oxygen saturation; TLC: total lung capacity.

Factors affecting mortality and survival analysis

Table 4 demonstrates the Cox regression analysis of risk factors for mortality. The univariate Cox analysis showed that significant weight loss (hazard ratio [HR], 3.208; 95% confidence interval [CI], 1.452–7.089; p = 0.004), baseline albumin (HR, 0.394; 95% CI, 0.199–0.781; p = 0.008), FVC (HR, 0.974; 95% CI, 0.945–1.003; p = 0.075), DLco (HR, 0.954; 95% CI, 0.928–0.980; p < 0.001), 6-minute walking distance [6MWD] HR, 0.993; 95% CI, 0.990–0.997; p < 0.001), and lowest oxygen saturation (SpO₂) in 6MWT (HR, 0.928; 95% CI, 0.879–0.979; p = 0.006) were associated with mortality in patients with IPF.

Table 4

Cox regression analysis of risk factors for mortality
Variable	HR	95% CI	p value
Univariate analysis
Significant weight loss	3.208	1.452–7.089	0.004
Age, years	0.997	0.952–1.043	0.890
Male sex	0.970	0.288–3.267	0.961
Ever smokers	1.739	0.520–5.816	0.369
Baseline BMI, kg/m²	0.938	0.818–1.075	0.357
Baseline albumin, g/dL Pulmonary function test	0.394	0.199–0.781	0.008
FVC, % predicted	0.974	0.945–1.003	0.075
DLco, % predicted	0.954	0.928–0.980	< 0.001
TLC, % predicted	0.974	0.944–1.005	0.101
6MWD, meter	0.993	0.990–0.997	< 0.001
6MWT, lowest SpO₂, %	0.928	0.879–0.979	0.006
Use of pirfenidone	0.858	0.115–6.374	0.881
Multivariate analysis
Significant weight loss	2.650	1.108–6.341	0.029
Baseline albumin, g/dL	0.462	0.197–1.083	0.076
FVC, % predicted	0.987	0.958–1.017	0.383
DLco, % predicted	0.970	0.937–1.004	0.086
6MWD, meter	0.992	0.987–0.997	0.003
6MWT, lowest SpO₂, %	1.015	0.931–1.107	0.737
Among the significant variables in the univariate analysis, TLC (r = 0.974, p = 0.101) was excluded in the multivariate analysis due to close correlation with FVC. HR: hazard ratio; CI: confidence interval; BMI: body mass index; FVC: forced vital capacity; DLco: diffusing capacity of the lung for carbon monoxide; TLC: total lung capacity; 6MWD: 6-minute walking distance; SpO₂: peripheral oxygen saturation.

In the multivariate analysis, significant weight loss was independently associated with mortality (HR, 2.650; 95% CI, 1.108–6.341; p = 0.029) after adjusting other significant risk factors (6MWD: HR, 0.992; 95% CI, 0.987–0.997; p = 0.003). A comparison of survival curves between the patients with and without weight loss is shown in Fig. 1. The median survival of patients with weight loss was shorter than that of those without weight loss (29.4 ± 2.3 vs 41.4 ± 2.1 months, respectively, p = 0.002).

Clinical impact of weight loss according to the pirfenidone dosage

We analyzed whether the effect of significant weight loss on mortality differed according to the pirfenidone dose. The 129 patients treated with pirfenidone were divided into full-dose (1800 mg/d, 53 patients) and reduced-dose groups (\(<\) 1800 mg/d, 76 patients). Survival analysis was performed, and a Kaplan-Meier curve was plotted (Fig. 2). The median survival of patients with relevant weight loss was significantly shorter than that of those without significant weight loss in the reduced dose pirfenidone group (28.3 ± 3.1 vs 41.8 ± 3.1 months, p = 0.013, Fig. 2 − 1). In the full-dose group, the medial survival was marginally significantly shorter in the weight loss group (28.9 ± 3.1 vs 39.8 ± 2.6 months, p = 0.085, Fig. 2–2).

In this study, 42 of 134 (31.3%) patients showed significant weight loss during the follow-up period. There were no differences in the usage and dosage of pirfenidone between the groups with and without significant weight loss. Significant weight loss had an independent effect on mortality even after adjusting for lung function and exercise capacity, and the subgroup analysis according to the pirfenidone dose showed similar results.

Although the exact mechanism of these findings needs to be clarified, oxidative stress, chronic inflammation, physical inactivity, and poor general condition are proposed causes of weight loss in patients with IPF [5, 6, 21, 22]. In this study, proportion of patients who had significant weight loss (31.3%) was higher than that of previous studies [3, 10]. Nakatsuka et al. reported that the prevalence of significant weight loss in patients with IPF was 21.8% (27 of 124) in the Japanese cohort and 15.1% (13 of 86) in the English cohort [3]. Similarly, a retrospective cohort study by Jouneau et al. showed that 20.1% (85 of 423) of patients with IPF who took a placebo rather than nintedanib showed significant weight loss [10].

The following factors likely contributed to a higher proportion of patients having significant weight loss in our study compared with previous studies: first, in the general population, Asians have a lower body weight than Caucasians [23]; second, the number of patients who took anti-fibrotic drugs in our study was higher than that of the previous study (96.3% of patients in our study took pirfenidone; 28.2% and 23.3% took pirfenidone in the Japanese and English cohorts by Nakatsuka et al., respectively; and 60.1% took nintedanib in the study by Jouneau et al.); and finally, the exclusion of patients who followed-up for \(\le\) 1 year from the study design might have affected the prevalence. Among patients with IPF, Asians also have a higher proportion of underweight patients than do Caucasians, suggesting regional and racial differences in the clinical course of IPF [10, 24].

Several previous studies have shown that weight loss might be associated with poor prognosis in patients with IPF. In Nakatsuka et al.’s retrospective cohort study of 210 patients, a weight loss of \(\ge\)5% was a significant risk factor for mortality (HR = 2.51, 95% CI, 1.01–6.23, p = 0.047). Weight loss suggested a worse outcome even when FVC was normal [3]. Pugashetti et al., in a study with 225 patients with interstitial lung disease, reported that every 1% yearly decrease in BMI was associated with a 5% increase in mortality risk [4]. Furthermore, a recent report revealed that malnutrition is common in patients with IPF and associated with hospitalization and mortality, supporting the inference that weight loss adversely affects the prognosis of patients with IPF [25]. Similar to the previous findings, significant weight loss was associated with poor outcomes in our study. It was associated with a poor prognosis even after adjusting for well-known prognostic factors such as 6MWD, baseline albumin levels, and lung function [1, 26, 27]. Therefore, it can be suggested that careful monitoring of weight loss is necessary when treating patients with IPF.

Although anorexia and weight loss are known side effects of pirfenidone [7], there was no significant difference in the pirfenidone dose and the frequency of side effects between the significant and non-significant weight loss groups in our study. Moreover, in both the full and low dose pirfenidone groups, significant weight loss was associated with increased mortality, suggesting that weight loss is still an important prognostic factor in patients with IPF using anti-fibrotic drugs. Similarly, Jouneau et al. conducted a post hoc analysis of previous pirfenidone-related studies and suggested that patients whose BMI is \(\le\) 25\(\text{k}\text{g}/{\text{m}}^{2}\) or who experienced weight loss in the placebo group showed a faster rate of FVC decline and worse prognosis [28]. Similarly, in the pirfenidone-treated group, patients with significant weight loss showed a worse prognosis than did those without significant weight loss [28]. However, nintedanib, another anti-fibrotic agent, showed different results in a previous study [10]. Although in the placebo group, the rate of FVC decline was faster in patients with a baseline BMI \(\le\) 25 \(\text{k}\text{g}/{\text{m}}^{2}\) than in patients with a BMI of 25\(\text{k}\text{g}/{\text{m}}^{2}\) or more, FVC changes between each BMI group were similar in the nintedanib group [10]. Likewise, patients with significant weight loss suffered a relevantly faster decrease in FVC in the placebo group; however, the rate of FVC decline was not significantly different depending on significant weight loss in the nintedanib group [10]. Although some conflicting results have been reported between the two anti-fibrotic agents, weight loss might be an important composite outcome in patients with IPF who receive anti-fibrotic agents.

This study had several limitations. First, this was a single-center and retrospective study. Due to the retrospective design, we could not include all variables that could potentially affect mortality. Second, we could not specifically investigate the nutritional status and quality of life of the patients. However, we measured serum albumin level and used it as a surrogate for nutrition status. Third, in Korea, nintedanib is rarely used because it is not covered by health insurance; therefore, a detailed analysis of nintedanib could not be conducted in this study. Lastly, most of the patients included in this study took pirfenidone; therefore, we could not analyze the effect of weight loss on patients with IPF who did not take pirfenidone.

Our study suggests that significant weight loss might be an important prognostic factor in patients with IPF. Therefore, a vigilant monitoring is required to detect weight loss during the clinical course in patients with IPF.

IPF: idiopathic pulmonary fibrosis, FVC: forced vital capacity, DLco: diffusing capacity for carbon monoxide, TLC: total lung capacity, PFT: pulmonary function test, BMI: body mass index, 6MWD: 6-minute walk test distance, 6MWT: 6-minute walk test, SpO2: peripheral oxygen saturation, GI: gastrointestinal, HR: hazard ratio, CI: confidence interval OR: odds ratio.

Supplementary information

None.

Acknowledgements

Not applicable.

Author contributions

HCK takes responsibility for the content of the manuscript, including the data and analysis. JKL and HCK conceived and designed the study. JKL, CC, JK, and HSC collected the data and reviewed medical records. JKL, CC, JK, HSC, and HCK analysed and interpreted the data. JKL and HCK drafted the initial manuscript. All authors discussed the results and reviewed the manuscript.

Funding

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2022R1C1C1005736).

Availability of data and materials

The datasets generated and/or analyzed during this study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

The study protocol was endorsed by the Institutional Review Board of Asan Medical Center (IRB number: 2021-0736). This study was conducted in compliance with the Declaration of Helsinki. Informed consent was waived because of the retrospective study design and anonymity of clinical data.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no conflicts of interest related to this study.

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No competing interests reported.

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published 08 Apr, 2023

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Editorial decision: Major revision
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Clinical impact of weight loss on mortality in patients with idiopathic pulmonary fibrosis: a retrospective cohort study

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Journal Publication

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Abstract

Background

Methods

Results

Conclusions

Figures

Background

Methods

Study population

Clinical Data

Statistical Analyses

Results

Patients

Use of pirfenidone and associated side effects

Risk factors related to significant weight loss

Factors affecting mortality and survival analysis

Clinical impact of weight loss according to the pirfenidone dosage

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1