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Original Research: DIFFUSE LUNG DISEASE |

Depression and Functional Status Are Strongly Associated With Dyspnea in Interstitial Lung Disease FREE TO VIEW

Christopher J. Ryerson, MD; Jane Berkeley, BA; Virginia L. Carrieri-Kohlman, RN, DNSc; Steven Z. Pantilat, MD; C. Seth Landefeld, MD; Harold R. Collard, MD, FCCP
Author and Funding Information

From the Department of Medicine (Drs Ryerson, Pantilat, Landefeld, and Collard and Ms Berkeley), School of Medicine, and Department of Physiological Nursing (Dr Carrieri-Kohlman), School of Nursing, University of California San Francisco, San Francisco, CA.

Correspondence to: Harold R. Collard, MD, FCCP, 505 Parnassus Ave, Box 0111, San Francisco, CA 94143; e-mail: hal.collard@ucsf.edu


Funding/Support: This study was supported by the Association of Specialty Professors/CHEST Foundation Geriatric Development Research Award.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2011 American College of Chest Physicians


Chest. 2011;139(3):609-616. doi:10.1378/chest.10-0608
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Background:  Little is understood about the characteristics of dyspnea in patients with interstitial lung disease (ILD), and its severity is likely influenced by multiple factors. Depression and functional status are known to influence dyspnea in patients with COPD. The aim of this study was to determine the relationship of dyspnea with clinical parameters, including depression and functional status, in patients with ILD.

Methods:  Dyspnea was measured with the Baseline Dyspnea Index and the University of California San Diego Shortness of Breath Questionnaire. Clinical parameters were recorded. Regression analysis was performed to determine independent correlates of dyspnea.

Results:  Fifty-two subjects were enrolled. The two dyspnea scales were strongly correlated (r = −0.79; P < .00005). The mean levels of dyspnea were 6.5 and 41.0, representing a moderate degree of dyspnea. Clinically meaningful depressive symptoms were found in 23% of subjects. Independent correlates of dyspnea severity for each dyspnea scale were depression score (P = .002 and P < .0005), 4-m walk time (P = .001 and P = .06), FVC (P = .07 and P = .004), and diffusing capacity of the lung for carbon monoxide (P = .007). BMI had borderline significant association with the Baseline Dyspnea Index (P = .10).

Conclusions:  In patients with ILD, dyspnea is associated with depression score, functional status, and pulmonary function. These results suggest that attention to depression and functional status is important in these patients and that treatment directed at these comorbidities may improve dyspnea and quality of life.

Trial registry:  ClinicalTrials.gov; No.: NCT00611182 ; URL: www. clinicaltrials.gov

Figures in this Article

Interstitial lung disease (ILD) is a diverse group of conditions that are characterized by inflammation and fibrosis of the pulmonary parenchyma. In general, the ILDs are chronic diseases that result in substantial morbidity and, in some instances, high mortality.1,2 In recognition of the significant morbidity and mortality associated with ILD, greater emphasis recently has been placed on assessing and improving the symptoms and quality of life of these patients.3-7

Dyspnea is common in patients with ILD. It is present at the time of diagnosis in 90% of patients with idiopathic pulmonary fibrosis (IPF), a common subtype of ILD.1,8 Importantly, dyspnea severity has been shown to have a strong correlation with quality of life and mortality in patients with IPF.9,10 Consequently, dyspnea is increasingly recognized as an important outcome for both prognostic and therapeutic purposes in ILD. Unfortunately, dyspnea often is refractory to currently available therapies.8

Although restriction and impaired gas exchange likely influence the presence and degree of dyspnea, other factors such as depression and functional status likely contribute to its severity8 and are known to influence dyspnea in patients with COPD.11,12 Identification of the key correlates of dyspnea in patients with ILD could provide important insight into its management.

In the present study, we sought to determine the relationship of dyspnea with the selected clinical variables of depression and functional status in patients with ILD. We hypothesized that the severity of dyspnea in patients with ILD is related to depression and decreased functional status, and that these relationships are independent of pulmonary function. We conducted a cross-sectional study of outpatients with ILD to examine these relationships.

Study Subjects

Subjects were prospectively identified through the University of California San Francisco (UCSF) ILD program between 2007 and 2009. Subjects were included if they had been given a diagnosis of ILD and the ability to provide informed consent. The final diagnosis was made by multidisciplinary review according to established criteria, taking clinical, radiologic, and pathologic findings into consideration.13-15 Subjects who were unable to read and write English were excluded. The study design was approved by the UCSF Committee on Human Research, and all subjects provided written informed consent.

Measurements

Data collection and testing was performed in the following order: demographic and clinical data, dyspnea, stress, anxiety, kyphosis index, gait speed, sleep, depression, pain, and grip strength. Baseline information was recorded, and all questionnaires were completed at the study visit. Baseline data included age, sex, ethnicity, smoking history, and BMI. Resting oxygen saturation was recorded. The physiologic assessment included standard techniques for the measurement of FVC, total lung capacity (TLC), and diffusing capacity of the lung for carbon monoxide (Dlco).16-18

Dyspnea was measured using the self-administered Baseline Dyspnea Index (BDI) and the University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ).19,20 The BDI evaluates dyspnea in three categories: functional impairment, magnitude of task, and magnitude of effort. Patients designate a score of 0 to 4 for each category, with a total possible range of 0 to 12. The UCSD SOBQ requires that patients rate the severity of dyspnea in 24 situations on a scale of 0 to 5, providing a total score of 0 to 120. A higher score indicates worse dyspnea for the UCSD SOBQ, and a lower score indicates worse dyspnea for the BDI. Both indices were used because neither has demonstrated superiority in patients with ILD.

Depression, sleep quality, anxiety, and pain were measured using established self-administered questionnaires. Depression was measured using the Center for Epidemiologic Studies Depression score.21 A score > 15 was considered a clinically meaningful indicator of depressed mood, and the referring physician was notified if a subject exceeded this score. Sleep quality was measured with the Pittsburgh Sleep Quality Index, with a score > 5 considered clinically meaningful.22 Anxiety was measured with the State-Trait Anxiety Inventory,23 with an anxiety score > 40 considered clinically meaningful. Pain was measured with the Brief Pain Inventory.24

Kyphosis was measured using a flexometer, and the kyphosis index was calculated.25 Muscle strength was measured using grip strength, an established geriatric metric of functional status.26 Grip strength was measured with a dynamometer (Jamar Hydraulic Hand Dynamometer model 5030J1; Sammons Preston; Bolingbrook, Illinois). The 4-m walk time, which is the time it takes to walk 4 m starting from a standing position, was used to assess muscle function.26 Subjects were permitted to use walking aids and supplemental oxygen. The 4-m walk time is a validated measure of functional status in the geriatric population26 and was used instead of the 6-min walk distance (6MWD) because it is easier to perform and less influenced by pulmonary and cardiovascular disease, thereby being a more accurate measure of peripheral muscle function in this population.

Statistical Analysis

Data are described using the mean and SD, unless otherwise noted. Intergroup comparisons were performed using parametric or nonparametric methods as appropriate. Spearman correlation coefficients were calculated for bivariate analyses. The IPF subgroup was analyzed as a distinct subgroup as specified a priori because it represented a large proportion of our cohort, is a common ILD, and likely has a unique pathophysiology.13 Backward stepwise linear regression analysis was performed using both the BDI and the UCSD SOBQ as dependent variables, incorporating variables from bivariate analysis with each dyspnea metric that had a P < .10. A P value cut-off point of .10 was chosen to rule out confounding with greater certainty. The following predefined independent variables were evaluated: age, sex, ethnicity, smoking history, BMI, resting oxygen saturation, use of supplemental oxygen, FVC, TLC, Dlco, kyphosis index, grip strength, 4-m walk time, depression score, sleep quality score, anxiety score, and pain score. No variables were forced into the model. All data analysis was performed using Stata, version 11.0 (StataCorp; College Station, Texas).

Study Subjects

Fifty-two subjects were enrolled. Their demographic and clinical characteristics are summarized in Table 1. The most common diagnosis was IPF (n = 20; 38% of the study population), followed by connective tissue disease-associated ILD (n = 17; 33%) and chronic hypersensitivity pneumonitis (n = 7; 13%). Other subtypes of ILD included sarcoidosis (n = 4), idiopathic nonspecific interstitial pneumonia (n = 3), and organizing pneumonia (n = 1). On average, subjects were aged 64 years, predominantly men, and predominantly current or former smokers. Subjects had a mild reduction in FVC (74% predicted) and TLC (74% predicted), with a moderate reduction in Dlco (51% predicted). Clinically meaningful depressive symptoms were found in 23% of subjects. Clinically meaningful anxiety symptoms and abnormalities in sleep quality were found in 27% and 58%, respectively. Subjects with IPF were significantly older and more likely to be men. No significant difference was found in lung function between subjects with and without IPF.

Table Graphic Jump Location
Table 1 —Baseline Characteristics

Data are presented as mean ± SD, unless otherwise indicated. P value is for the difference between subjects with and without IPF. Dlco = diffusing capacity of the lung for carbon monoxide; IPF = idiopathic pulmonary fibrosis; TLC = total lung capacity.

Dyspnea scores and measured clinical variables are shown in Table 2. Subjects had a wide range of dyspnea severity (Fig 1). The average level of dyspnea was 6.5 (out of 12) and 41.0 (out of 120) as measured by the BDI and UCSD SOBQ, respectively, representing a moderate degree of dyspnea. The mean BDI and UCSD SOBQ scores were similar between subjects with and without IPF (P = .13 and P = .30).

Table Graphic Jump Location
Table 2 —Dyspnea Scores and Measured Clinical Variables

Data are presented as mean ± SD, unless otherwise indicated. P value is for the difference between subjects with and without IPF. BDI = Baseline Dyspnea Index; BPI = Brief Pain Inventory; CES-D = Center for Epidemiologic Studies Depression score; PSQI = Pittsburgh Sleep Quality Index; STAI = State-Trait Anxiety Inventory; UCSD SOBQ = University of California San Diego Shortness of Breath Questionnaire. See Table 1 legend for expansion of other abbreviation.

Figure Jump LinkFigure 1. Distribution of dyspnea scores. A, Distribution using the BDI. B, Distribution using the UCSD SOBQ. BDI = Baseline Dyspnea Index; IPF = idiopathic pulmonary fibrosis; UCSD SOBQ = University of California San Diego Shortness of Breath Questionnaire.Grahic Jump Location
Correlation of Dyspnea and Clinical Variables

The BDI was strongly correlated with the UCSD SOBQ (r = 0.79; P < .00005) (Fig 2). This relationship was similar when analyzing only IPF. The BDI had significant correlation with depression, anxiety, 4-m walk time, and FVC (Table 3). The UCSD SOBQ was significantly correlated with depression, sleep quality, anxiety, pain, 4-m walk time, and sex. Of the variables tested, depression had the strongest correlation with both the BDI and the UCSD SOBQ (r = −0.43 and 0.50, respectively; P < .002) (Fig 3). Analysis of only subjects with IPF revealed similar relationships, as did analysis of subjects with non-IPF conditions (data not shown).

Figure Jump LinkFigure 2. Relation between the UCSD SOBQ and BDI scores. Significant correlation was observed in the dyspnea scores of all patients (r = −0.79; P < .00005) and in patients with IPF (r = −0.65; P = .002). See Figure 1 legend for expansion of abbreviations.Grahic Jump Location
Table Graphic Jump Location
Table 3 —Association of Dyspnea With Clinical Parameters

See Table 1 and 2 legends for expansion of abbreviations.

a 

Variables with P values obtained using a Student t test.

b 

Variables with P values obtained using one-way analysis of variance.

Figure Jump LinkFigure 3. Relation between the UCSD SOBQ and depression scores. Significant correlation was observed between dyspnea and depression scores in all patients (r = 0.50; P = .0002) and in patients with IPF (r = 0.57; P = .009). See Figure 1 legend for expansion of abbreviations.Grahic Jump Location
Multivariate Analysis

Variables associated with dyspnea using multiple regression analysis are shown in Table 4. Five variables were considered potential independent correlates of dyspnea as measured by the BDI: depression score, 4-m walk time, Dlco, FVC, and BMI. These five parameters had a cumulative r2 of 0.54 (adjusted r2 = 0.48). FVC and BMI had borderline statistically significant association with BDI. The strength of these associations were not altered by considering the possibility of threshold effects (eg, that only a BMI above a certain threshold affected dyspnea). Removal of FVC and BMI from the model did not alter the strength of association of BDI with the remaining three variables. Depression score, 4-m walk time, and FVC were independent correlates of dyspnea as measured by the UCSD SOBQ. These three parameters had a cumulative r2 of 0.40 (adjusted r2 = 0.35). The direction and degree of association of dyspnea with Dlco and BMI was similar using both dyspnea scales. The results were unchanged with backward or forward stepwise regression, when using transformed or nontransformed variables and when considering the impact of interactions among included variables.

Table Graphic Jump Location
Table 4 —Multivariate Models of Dyspnea

Data are presented from stepwise multiple regression analysis, incorporating variables from bivariate analysis that had a P < .10. Values not shown indicate variables that did not remain in the model following multivariate analysis. See Table 1 and 2 legends for expansion of abbreviations.

The 4-m walk time had the strongest association with the BDI (P = .001), and depression had the strongest association with the UCSD SOBQ (P < .0005). A 1-s increase in the 4-m walk time was associated with a 0.8 point (6.9%) decrease in the BDI score and a 5.2 point (4.3%) increase in UCSD SOBQ score. A one point (1.7%) increase in depression score was associated with a 0.10-point (0.8%) decrease in BDI score and a 1.3-point (1.0%) increase in UCSD SOBQ score.

This study demonstrates that dyspnea is common in patients with ILD and is strongly correlated with depression and 4-m walk time (a measure of functional status). Further, this study illustrates the prevalence of clinically significant depressive symptoms in patients with ILD. Depression and functional status may be common modifiable therapeutic targets in ILD, a disease group that often lacks effective disease-modifying therapy. Treatment directed at these targets may improve dyspnea and by extension, quality of life.

Studies in COPD have demonstrated a close relationship of dyspnea with depression and functional status.11,12 The consistency of these findings with our results suggests that factors modifying the severity of dyspnea may be similar in COPD and ILD. These similarities have important implications for the future study and treatment of dyspnea in chronic lung diseases, suggesting that strategies for the treatment of dyspnea in COPD may be applied to patients with ILD. This is of particular importance because the relatively small patient population with ILD limits the ability to perform large clinical trials. A shared treatment approach to dyspnea would be analogous to the treatment of chronic pain syndromes, which often are consistent across diseases with widely varying etiologies.27

Dyspnea and Depression

The prevalence of clinically meaningful depressive symptoms in the current study (23%) is similar to the prevalence in a previous study of IPF (23% to 27%)28 and above the expected prevalence for minor depression in a general population of elderly subjects (9.8%).29 More than 40% of patients with an above-average UCSD SOBQ score had clinically meaningful depressive symptoms compared with only 4% of patients with a below-average UCSD SOBQ score. These data suggest that patients with ILD and a moderate degree of dyspnea may have a high frequency of depression and that routine screening for depression may be justified.

We show a strong relationship between dyspnea and depression score. Dyspnea (measured using the Bath Breathlessness Scale) has previously been correlated on unadjusted (ie, bivariate) analysis with clinically meaningful depression in one of the four domains of the Beck Depression Inventory and two of the four domains of the Cognitive Depression Inventory.28 We build upon this study by demonstrating the independent nature and strength of the relationship between dyspnea and depression by adjusting for other important clinical variables. The strength of the relationship between depression and dyspnea suggests that treatment of depression could lead to improvement in dyspnea and quality of life in these patients. This hypothesis has important implications because dyspnea is the predominant symptom in ILD, is disabling, and often persists despite therapy. Further studies are required to determine whether treatment of depression in ILD will improve dyspnea and quality of life.

Dyspnea and Functional Status

This study reports the novel finding that dyspnea correlates with the 4-m walk time, a measure of lower-extremity muscle mass and function and an important marker of functional status.26 Prior studies of patients with ILD have demonstrated the correlation of dyspnea with other measures of functional status, including 6MWD and the 6-min step test.30,31 We chose to use the 4-m walk test instead of the 6MWD for several reasons. First, the 4-m walk test is an established metric of functional status in the geriatric population.26 Second, the 6MWD has been questioned as a reliable outcome measure in patients with ILD partly because of its sensitivity to change in nonpulmonary conditions (eg, cardiac or musculoskeletal disease).6,32 Third, in patients with ILD, the 6MWD is likely influenced by dyspnea (ie, not an independent variable), whereas the 4-m walk time is not.

Dyspnea and Pulmonary Function

We found that the severity of dyspnea correlated with the FVC and Dlco. This finding is consistent with previous studies that have evaluated the relationship between dyspnea and lung function.31,33,34 Interestingly, the correlation between dyspnea and pulmonary function is relatively weak, and this relationship does not explain the majority of variance in dyspnea.

Dyspnea and BMI

A high BMI had borderline association with worse dyspnea on bivariate and multivariate analysis when dyspnea was measured by the BDI but not when measured by the UCSD SOBQ. In ILD, the cumulative mechanical load placed on the lungs by parenchymal fibrosis and obesity would be expected to worsen dyspnea, which contrasts with the effects seen in COPD where obese subjects experience less dyspnea during exercise and achieve a higher peak oxygen consumption compared with nonobese subjects.35 This reduction in dyspnea may have been due to the mechanical effects of obesity that counterbalanced the hyperinflation typical of COPD, resulting in normalization of lung volumes. Despite what appear to be opposite effects on dyspnea, the impact of BMI on mortality is similar in COPD and IPF, with a lower BMI predicting higher mortality rates in both conditions.36,37 A relationship between dyspnea and BMI has not been reported previously in ILD, and the weak association with only one dyspnea index in the current study is insufficient to draw conclusions. However, these results do suggest that further research is warranted to better characterize the impact of BMI on dyspnea in ILD.

Limitations

There are several limitations to this study. First, because of its cross-sectional nature, we were able to comment on association but not on causation. We cannot comment directly on the effect of depression on the experience of dyspnea. We hypothesize that depression contributes to dyspnea severity, but it is also possible that worse dyspnea leads to worse depressive symptoms. Second, we used several indices and clinically meaningful values that have not been validated in patients with ILD. Although this may affect the prevalence of these abnormalities, this would not alter the correlative relationships. Third, subjects were recruited from a tertiary ILD clinic, and it is possible that the characteristics of these subjects are not representative of the general ILD population. Fourth, our analysis did not include all potential determinants of dyspnea; thus, it is possible that other factors (eg, pulmonary hypertension) could confound our findings. Finally, the sample size limits the analysis of subgroups, and it is possible that the relationships among the measured variables differ based on the type of ILD. However, both the IPF and the nonspecific interstitial pneumonia subgroups were large enough to permit bivariate analysis, showing similar relationships compared with the entire ILD population (data not shown).

In summary, dyspnea in ILD is common and strongly correlated with depression and functional status. Future longitudinal assessment of the interactions of dyspnea, depression, and functional status should investigate whether and how changes in these variables are interrelated and whether treatment of depression and functional status can improve quality of life. The strong association between dyspnea and depression suggests that treatment of depression in patients with ILD may improve not only mood but also dyspnea. The similar relationship among depression, functional status, and dyspnea in COPD and ILD suggests that effective strategies for dyspnea relief (eg, standardized exercise programs) in one pulmonary disease may be beneficial in other chronic lung diseases, regardless of etiology. With an improved understanding of dyspnea in patients with ILD, it is hoped that novel therapeutic interventions can be developed that positively affect clinically important outcomes.

Author contributions:Dr Ryerson: contributed to the data analysis and interpretation, writing of the initial draft of the manuscript, and approval of the final manuscript.

Ms Berkeley: contributed to the data analysis and interpretation and approval of the final manuscript.

Dr Carrieri-Kohlman: contributed to the conception of the study design, data analysis and interpretation, and approval of the final manuscript.

Dr Pantilat: contributed to the conception of the study design, data analysis and interpretation, and approval of the final manuscript.

Dr Landefeld: contributed to the conception of the study design, data analysis and interpretation, and approval of the final manuscript.

Dr Collard: contributed to the conception of the study design, data analysis and interpretation, writing of the initial draft of the manuscript, and approval of the final manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Collard has consulted for Actelion, Gilead, Genzyme, and InterMune. Drs Ryerson, Carrieri-Kohlman, Pantilat, and Landefeld and Ms Berkeley have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: The authors thank Talmadge E. King Jr for his thoughtful comments and review of the manuscript, Debra Koehler and the providers and staff of the UCSF Interstitial Lung Disease Program for their assistance in recruiting subjects for this study, the members of the UCSF Interstitial Lung Disease Consortium for their continued referral of patients to our center, and the patients with ILD who through their generosity and efforts allow us to conduct clinical research studies such as this in an effort to improve the lives of patients with ILD.

6MWD

6-minute walk distance

BDI

Baseline Dyspnea Index

Dlco

diffusing capacity of the lung for carbon monoxide

ILD

interstitial lung disease

IPF

idiopathic pulmonary fibrosis

TLC

total lung capacity

UCSD SOBQ

University of California San Diego Shortness of Breath Questionnaire

UCSF

University of California San Francisco

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Alakhras M, Decker PA, Nadrous HF, Collazo-Clavell M, Ryu JH. Body mass index and mortality in patients with idiopathic pulmonary fibrosis. Chest. 2007;1315:1448-1453. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Distribution of dyspnea scores. A, Distribution using the BDI. B, Distribution using the UCSD SOBQ. BDI = Baseline Dyspnea Index; IPF = idiopathic pulmonary fibrosis; UCSD SOBQ = University of California San Diego Shortness of Breath Questionnaire.Grahic Jump Location
Figure Jump LinkFigure 2. Relation between the UCSD SOBQ and BDI scores. Significant correlation was observed in the dyspnea scores of all patients (r = −0.79; P < .00005) and in patients with IPF (r = −0.65; P = .002). See Figure 1 legend for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 3. Relation between the UCSD SOBQ and depression scores. Significant correlation was observed between dyspnea and depression scores in all patients (r = 0.50; P = .0002) and in patients with IPF (r = 0.57; P = .009). See Figure 1 legend for expansion of abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Baseline Characteristics

Data are presented as mean ± SD, unless otherwise indicated. P value is for the difference between subjects with and without IPF. Dlco = diffusing capacity of the lung for carbon monoxide; IPF = idiopathic pulmonary fibrosis; TLC = total lung capacity.

Table Graphic Jump Location
Table 2 —Dyspnea Scores and Measured Clinical Variables

Data are presented as mean ± SD, unless otherwise indicated. P value is for the difference between subjects with and without IPF. BDI = Baseline Dyspnea Index; BPI = Brief Pain Inventory; CES-D = Center for Epidemiologic Studies Depression score; PSQI = Pittsburgh Sleep Quality Index; STAI = State-Trait Anxiety Inventory; UCSD SOBQ = University of California San Diego Shortness of Breath Questionnaire. See Table 1 legend for expansion of other abbreviation.

Table Graphic Jump Location
Table 3 —Association of Dyspnea With Clinical Parameters

See Table 1 and 2 legends for expansion of abbreviations.

a 

Variables with P values obtained using a Student t test.

b 

Variables with P values obtained using one-way analysis of variance.

Table Graphic Jump Location
Table 4 —Multivariate Models of Dyspnea

Data are presented from stepwise multiple regression analysis, incorporating variables from bivariate analysis that had a P < .10. Values not shown indicate variables that did not remain in the model following multivariate analysis. See Table 1 and 2 legends for expansion of abbreviations.

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