Dyspnea in Idiopathic Pulmonary Fibrosis: A Systematic Review

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Journal of Pain and Symptom Management

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Review Article

Dyspnea in Idiopathic Pulmonary Fibrosis: A Systematic Review Christopher J. Ryerson, MD, DorAnne Donesky, PhD, RN, Steven Z. Pantilat, MD, and Harold R. Collard, MD Department of Medicine (C.J.R., S.Z.P., H.R.C.), School of Medicine, and Department of Physiological Nursing (D.D.), School of Nursing, University of California at San Francisco, San Francisco, California, USA

Abstract Context. Little is known about the treatment and correlates of dyspnea in idiopathic pulmonary fibrosis (IPF). Objectives. The objective of this systematic review was to summarize the literature regarding the treatment and correlates of dyspnea in IPF. Methods. MEDLINE, EMBASE, and all Evidence-Based Medicine Reviews were searched for publications that evaluated treatment or correlates of dyspnea in IPF. Reference lists and recent review articles also were searched. Results. The heterogeneity of included studies did not permit meta-analysis. Dyspnea improved in studies of sildenafil, pulmonary rehabilitation, and prednisone with colchicine. Additional studies of these three treatments, however, found discordant results. One study suggested that assisted ventilation delivered by facemask improved exertional dyspnea. Oxygen and opioids improve dyspnea in other chronic lung diseases, but data in IPF are limited. Correlates of dyspnea included functional and physiological measures and comorbid diseases. Conclusion. Sildenafil and pulmonary rehabilitation should be considered as potential therapies for dyspnea in selected patients with IPF. Supplemental oxygen and opioids may be additional potential therapies; however, the evidence supporting their use is weak. Additional research should focus on the management of functional status and comorbidities as potential treatments for dyspnea. J Pain Symptom Manage 2012;43:771e782. Ó 2012 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Dyspnea, idiopathic pulmonary fibrosis, systematic review

Introduction Address correspondence to: Christopher J. Ryerson, MD, 505 Parnassus Avenue, Box 0111, San Francisco, CA 94143, USA. E-mail: [email protected] Accepted for publication: April 27, 2011. Ó 2012 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved.

Interstitial lung disease (ILD) is a diverse group of conditions that are characterized by inflammation and fibrosis of the pulmonary parenchyma. Idiopathic pulmonary fibrosis (IPF) is one of the most common ILDs, with 0885-3924/$ - see front matter doi:10.1016/j.jpainsymman.2011.04.026

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a prevalence of up to 227 per 100,000 among those aged 75 years or older.1 IPF is characterized by relentless progression, with a three-year mortality of up to 50%.2,3 Because of these features, IPF has been the focus of most of the clinical research conducted in ILD. IPF is a disease with high morbidity, with 90% of patients reporting dyspnea at the time of diagnosis.2 The clinical significance of dyspnea in IPF is illustrated by its strong correlation with quality of life (QOL)4 and mortality.5 Relief of dyspnea is, therefore, an important goal in the management of IPF. Disease-modifying pharmacotherapy is of marginal benefit,6,7 highlighting the need for complementary symptom-based management strategies. One such approach is to investigate the treatment of correlates of dyspnea, as some of these correlations also may represent causation. Common management approaches to dyspnea in IPF include pulmonary rehabilitation, supplemental oxygen, and opioids.8 In this article, we review the evidence for these and other treatments of dyspnea in IPF and provide recommendations for dyspnea management based on the available evidence. We also review the correlates of dyspnea in IPF and suggest that directing treatment toward independent correlates of dyspnea could improve symptoms.

Methods Data Sources and Searches We performed a systematic search of the literature using MEDLINE, EMBASE, and all Evidence-Based Medicine Reviews. The search was designed to capture all studies relating to both dyspnea and IPF. Search terms for dyspnea included ‘‘dyspn*’’ and ‘‘breath*’’ to return all variations of the terms dyspnea, breathlessness, and shortness of breath. The medical subject heading in each database for pulmonary fibrosis was used to capture all studies relevant to IPF. Additional search terms included IPF, lung fibrosis, fibrosing alveolitis, idiopathic interstitial pneumon*, usual interstitial pneumon*, UIP, and IIP. No limits were applied. Details of the search strategy are available in Appendix I at jpsmjournal.com. We considered articles and conference abstracts published from database inception

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through November 2010 (MEDLINE from 1950, EMBASE from 1980). In addition, we examined bibliographies of retrieved articles and other major review articles to identify additional articles. The literature search was performed independently by two authors (C. J. R. and D. D.) using predefined criteria. All discrepancies were resolved by iteration and consensus.

Study Selection Studies were eligible if they were published in English and reported treatments or correlates of dyspnea in 10 or more adults with IPF. There was no restriction on study design, quality, duration, or type of treatment. Studies were included if the diagnosis of IPF was based on the American Thoracic Society/European Respiratory Society diagnostic criteria or if equivalent criteria were described.9,10 Studies that included subjects with other forms of ILD were acceptable if subjects with IPF were reported separately. Studies published only in abstract form were included if sufficient information was available to satisfy inclusion criteria.

Data Extraction and Quality Assessment Data were extracted from selected studies using data abstraction forms with predefined criteria. Two authors (C. J. R. and D. D.) collected information regarding study design, subject characteristics, and study results as they pertained to the prespecified endpoints. Discrepancies were resolved by iteration and consensus. Trial quality was assessed using the Cochrane Collaboration’s tool for assessing methodological quality and risk of bias.11

Data Synthesis and Analysis We compared baseline study characteristics using Chi-squared or t-tests. For treatment results, we reported the available data for treatment approaches that were identified in the search or were determined a priori to be commonly used in clinical practice (i.e., pulmonary rehabilitation, supplemental oxygen, and opioids). Two authors (C. J. R. and H. R. C.) used the grading system developed by the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) working group to provide a recommendation (for or against, weak or strong).12 This system

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grades the strength and quality of the available evidence, and these grades may change as more and better quality data become available. For correlates of dyspnea, we report ranges for the correlation coefficients (r values). Data were grouped for some variables (e.g., actual and percent predicted forced vital capacity) to facilitate reporting and interpretation. The sign of the correlation coefficient was reversed for variables associated with the baseline dyspnea index, the dyspnea component of the Chronic Respiratory Questionnaire, and the oxygen cost diagram because decreasing scores on these metrics correspond to increasing dyspnea severity. Thus, for the remainder of this review a positive correlation coefficient indicates that an increase in the value of a variable corresponds to increased dyspnea.

Results The initial search revealed 3490 peerreviewed citations; 122 citations were identified for full-text review (Fig. 1). Of these, 26 studies satisfied inclusion criteria. Examination of reference lists and other major review articles yielded three additional studies. A total of 29 studies were included in the final review, including 14 studies that evaluated potential

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treatments of dyspnea6,13e25 and 15 studies that evaluated correlates of dyspnea.26e40 The heterogeneity of the selected studies precluded meta-analysis. Dyspnea severity was measured with nine metrics (Appendix II at jpsmjournal.com). Only the dyspnea component of the Composite Clinical, Radiographic, and Physiological scoring system was designed specifically for use in an ILD population.41 Most metrics were developed in populations with chronic obstructive pulmonary disease (see references in Appendix II).

Treatment of Dyspnea Fourteen studies evaluated the treatment of dyspnea in IPF (Table 1). Study quality was variable, with the Cochrane methodological quality score ranging from 3 to 6 out of 6 for the seven randomized trials. The evidence for potential treatments of dyspnea is summarized below. Based on available evidence, recommendations for the treatment of dyspnea in IPF are provided in Fig. 2.

Disease-Modifying Treatments No potential disease-modifying treatment (i.e., treatment aimed at modifying the underlying pathogenesis of IPF) has been shown to reliably

Fig. 1. Study selection (*studies could be excluded for multiple reasons during full-text review).

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Table 1 Summary of Trials Evaluating the Response of Dyspnea to Treatment in IPF Study

n

Intervention (Study Design)

Potential disease-modifying therapies 107 Pirfenidone 600 mg PO TID Azuma et al., for nine months (RCT) 200513

King et al., 200916 Raghu et al., 200417 Raghu et al., 200818 Selman et al., 1998a,19

Non-disease-modifying therapies 11 Sildenafil 20e50 mg PO TID Collard et al., for 12 weeks (open study, 200720 no control) 29 Sildenafil 20 mg PO TID for Jackson et al., 24 weeks (RCT) 201021

64

89

91

81

58

61

63

72

65

66

44

NR

65

57

NR

NR

NR

64

65

73

NR

68

42

55

66

71

71

72

65

63

69

NR

59

65

68

100

52

43 >33

Dyspnea

Primary Endpoint

No effect on dyspnea (Chronic Respiratory Questionnaire, dyspnea subscale) No effect on CRP dyspnea score

No effect on change from baseline to lowest SpO2 during a six-minute steady-state exercise test Improved VC 0.18 L (P ¼ 0.02), DLCO 0.75 mmol/min/kPa (P ¼ 0.003) Improved CRP dyspnea score No effect on total CRP 2.1 points in prednisone þ score colchicine arm (P ¼ 0.001)

No effect on six-MWD

47

No effect on BDI/TDI or Borg dyspnea index after six-MWT No effect on UCSD SOBQ

64

37

No effect on BDI/TDI

No effect on progressionfree survival

NR

64

37

No effect on BDI/TDI

36

NR

38

NR

No effect on four-point dyspnea scale

No effect on FVC, DLCO, P(A-a)O2 Not specified

72

57

71

70

32

71

79

86

62

42

No effect on modified Borg dyspnea index during six-MWT No effect on Borg dyspnea score before or after six-MWT

No effect on overall survival time

six-MWD improved 49 m (P < 0.05) No effect on six-MWD

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826 Interferon gamma 200 mcg SC 3x/wk for median 64 weeks (RCT) 330 Interferon gamma 200 mcg SC 3x/wk for minimum 48 weeks (RCT) 87 Etanercept 25 mg SC 2x/wk for 48 weeks (RCT) 56 Colchicine 1 mg/d þ prednisone 1 mg/kg/d, D-penicillamine 600 mg/ d þ prednisone 1 mg/kg/ d, D-penicillamine þ colchicine þ prednisone, prednisone for 104 weeks (open study, no control)

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Demedts et al., 155 Acetylcysteine 600 mg PO TID for one year, added to 20056 prednisone and azathioprine (RCT) 30 Prednisone 1 mg/kg/d, Fiorucci et al., 14 prednisone 0.5 mg/kg/ 2008 d þ cyclophosphamide 100 mg/d, prednisone 0.5 mg/kg/d þ colchicine 1 mg/d for 78 weeks (open study, no control) 154 Bosentan 125 mg PO BID for King et al., 15 minimum 52 weeks (RCT) 2008

% Surgical Mean % % Ever Mean FVC Mean DLCO Biopsy Age Male Smoked (% Predicted) (% Predicted)

Ozalevli et al., 201025

Nishiyama et al., 200824

IPF ¼ idiopathic pulmonary fibrosis; FVC ¼ forced vital capacity; DLCO ¼ diffusing capacity of carbon monoxide; PO ¼ orally; TID ¼ three times daily; RCT ¼ randomized controlled trial; SpO2 ¼ oxygen saturation by pulse oximetry; CRP ¼ clinical radiologic and physiologic scoring system; NR ¼ not reported; BID ¼ twice daily; VC ¼ vital capacity; BDI/TDI ¼ baseline/transitional dyspnea index; MWD ¼ minute walk distance; MWT ¼ minute walk test; UCSD SOBQ ¼ University of California San Diego Shortness of Breath Questionnaire; P(A-a)O2 ¼ alveolararterial oxygen gradient; CPAP ¼ continuous positive airway pressure; MRC ¼ Medical Research Council dyspnea scale. a Did not use ATS/ERS diagnostic criteria.

Not specified Improved MRC 0.9 points (P ¼ 0.003) 63 NR

67

40

72

68

Not specified No effect on BDI/TDI 54 67 NR 66 NR

75

46 79 NR 61 100 Moderno et al., 201023

IPF Network, 201022

180 Sildenafil 20 mg PO TID for 12 weeks (RCT), followed by open-label extension of additional 12 weeks 10 Proportional assisted ventilation during exercise, CPAP, no ventilatory assistance (crossover study) 28 Pulmonary rehabilitation 2x/ wk for 10 weeks (randomized trial, unclear control) 17 Home-based pulmonary rehabilitation for 12 weeks (open study, no control)

69

40

Dyspnea in Idiopathic Pulmonary Fibrosis

NR

83

76

57

26

Improved UCSD SOBQ 6.58 No effect on six-MWD points (P ¼ 0.006); no effect on Borg dyspnea score Improved Borg dyspnea score Not specified during bicycle exercise test (P < 0.05)

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improve dyspnea.6,13e19 The combination of prednisone and colchicine was studied in two unblinded trials.14,19 One trial randomized 30 subjects to receive 78 weeks of prednisone alone, prednisone plus cyclophosphamide, or prednisone plus colchicine.14 Dyspnea score improved in the 10 subjects who received prednisone and colchicine but worsened in the other treatment arms (P ¼ 0.001). A second unblinded study found no improvement of dyspnea in 19 subjects after treatment with prednisone and colchicine for 104 weeks.19 No other endpoints improved in either study. No other potential diseasemodifying treatment improved dyspnea.

Non-Disease-Modifying Treatments Treatment of Pulmonary Hypertension. Three included studies directly or indirectly evaluated the impact of treating pulmonary hypertension in patients with IPF. A small randomized controlled trial found no effect of sildenafil on dyspnea in 29 subjects with a pulmonary artery systolic pressure of 25e50 mm Hg by echocardiography.21 A second small open-label cohort study found sildenafil had no effect on dyspnea but did improve walk distance in 11 subjects with pulmonary hypertension confirmed by right heart catheterization.20 A third study randomized 180 subjects with advanced IPF (defined by a diffusing capacity of carbon monoxide [DLCO] < 35% predicted) to 12 weeks of placebo or sildenafil (a diagnosis of pulmonary hypertension was not required for inclusion).22 Sildenafil therapy improved resting dyspnea, some measures of QOL, DLCO, and oxygenation, with no increase in serious adverse reactions. There were no studies identified that evaluated treatment of any other comorbid disease. Pulmonary Rehabilitation. Two studies of pulmonary rehabilitation satisfied inclusion criteria. One randomized controlled study of 28 subjects found no benefit of pulmonary rehabilitation on dyspnea.24 A second uncontrolled cohort study of 17 subjects evaluated change in dyspnea after a 12-week home-based pulmonary rehabilitation program.25 Dyspnea improved (P ¼ 0.003) in the 15 subjects who completed the program, as did walk distance and QOL. Nine additional studies of pulmonary rehabilitation were identified in our search but were excluded for various reasons (definition of

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Fig. 2. Treatment considerations for dyspneic patients with IPF.

pulmonary fibrosis not provided, n ¼ 3;42e44 IPF not reported separately, n ¼ 3;45e47 and not published in English, n ¼ 348e50). Dyspnea improved in eight of these nine studies, but most of these studies had significant methodological deficiencies. One randomized study did not report subjects with IPF separately,45 but a subsequent Cochrane review retrieved the original data and reported findings for the IPF subgroup.51 This analysis was underpowered, with a small but nonsignificant improvement in dyspnea in subjects with IPF

(standardized mean difference 0.56, 95% confidence interval 1.26 to 0.14). Noninvasive Ventilatory Assistance. One study of 10 subjects was included that evaluated noninvasive ventilatory assistance during exercise, an intervention similar to bilevel positive airway pressure.23 Exertional dyspnea was improved compared with no ventilatory assistance and treatment with continuous positive airway pressure (CPAP). Exercise tolerance and some markers of cardiovascular and

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ventilatory function also improved with assisted ventilation. The effects of this intervention on resting dyspnea and long-term dyspnea were not evaluated.

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IPF, with only six subjects having diagnosis confirmed by computed tomography and only eight having restrictive physiology.

Correlates of Dyspnea Fifteen studies evaluated correlates of dyspnea (Table 2). Seventy unique variables were tested (Appendix III at jpsmjournal.com). Most variables were evaluated in only one or two studies. Dyspnea showed statistically significant correlation with numerous variables using bivariate analysis, including functional and physiological measures (e.g., six-minute walk distance [six-MWD]) and comorbid disease (i.e., depression) (Fig. 3). Multivariate analysis was performed in six studies, showing independent association of dyspnea with several variables (Table 3).

Supplemental Oxygen. We did not identify any studies of supplemental oxygen that met inclusion criteria. One study reported the impact of oxygen on dyspnea in patients with IPF, but this study was excluded because of an inadequate definition of IPF and its small size.52 Compared with control, oxygen improved dyspnea in 10 subjects with ILD (eight IPF, one hypersensitivity pneumonitis, one amiodarone-induced ILD) (P < 0.05). Opioids. Two studies reported the impact of opioids on dyspnea in patients with IPF, but both studies were excluded. A study of six subjects with ILD (three with IPF) showed no impact of nebulized morphine on dyspnea compared with placebo.53 A second study of 11 subjects with IPF and severe breathlessness showed that dyspnea decreased significantly with subcutaneous diamorphone (P < 0.0001), without any respiratory depression or other significant adverse effects.54 This study was excluded because of an inadequate definition of

Discussion Dyspnea in IPF can potentially be treated by effective disease modification, lung transplantation, and symptom-based therapy. Diseasemodifying treatments have shown a limited impact on dyspnea. Although dyspnea improved in a small unblinded study of prednisone and colchicine,14 there was no

Table 2 Summary of Trials Evaluating Correlations of Dyspnea in IPF % Surgical Biopsy

Mean Agea

% Male

100 38 NR

60 65 64

47 NR 21 19 51

% Ever Smoked

Mean FVC (% Predicted)

42 71 37

NR 76 NR

78 64 NR

50 51 45

57 78 67 66 64

65 68 79 95 85

NR 52 65 81 83

NR 78 72 73 77

NR 46 42 49 59

85 59 100 90 54.3

NR 63 66 61 63.6

58 65 84 60 69.5

46 41 NR NR 67.6

79 75 69 70 73.2

49 49 71 42 50.6

Studies that did not use the ATS/ERS diagnostic criteria for IPF 34 BDI/TDI 79 Martinez et al., 200039 18 CRP 67 Meliconi et al., 199040 Total/weighted mean 52 74.8

58 56 57.3

59 67 61.8

NR NR d

62 64 62.7

NR 53 53.0

n Studies that used the ATS/ERS Daniil et al., 200526 Daniil et al., 200827 De Vries et al., 200128 Glaser et al., 200929 Manali et al., 201030 Mura et al., 200631 Mura et al., 200632 Nishiyama et al., 2005, 200733,34,b Papiris et al., 200535 Papiris et al., 200736 Tzanakis et al., 200537 Zimmermann et al., 200738 Total/weighted mean

Dyspnea Tools

diagnostic criteria for IPF 12 MRC 21 MRC 41 Bath breathlessness scale 34 Borg 25 MRC 34 MRC 42 MRC 41 BDI/TDI, Borg 26 27 25 20 323

MRC MRC Borg, MRC, OCD BDI/TDI

Mean DLCO (% Predicted)

IPF ¼ idiopathic pulmonary fibrosis; FVC ¼ forced vital capacity; DLCO ¼ diffusing capacity of carbon monoxide; ATS ¼ American Thoracic Society; ERS ¼ European Respiratory Society; MRC ¼ Medical Research Council dyspnea scale; NR ¼ not reported; BDI/TDI ¼ baseline/transitional dyspnea index; OCD ¼ oxygen cost diagram; CRP ¼ clinical radiologic and physiologic scoring system. a P < 0.05 for difference between studies that used and did not use the ATS/ERS diagnostic criteria for IPF. b Nishiyama et al. reported findings from the same population in two studies. These studies are combined for this table.

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Fig. 3. Schema of statistically significant correlates of dyspnea severity in IPF.

improvement in a larger study of similar design.19 There are several possible explanations for the absence of benefit with disease-

modifying therapies. First, the treatments studied may be ineffective treatments for IPF, as suggested by the absence of convincing

Table 3 Correlates of Dyspnea in IPF Using Multivariate Analysis Variables Included in Final Model (P-value for Variable)

R2 of Model (P-value for Model)

Study

n

Manali et al., 201030

25

Six-MWD (P < 0.05)

Mura et al., 200631

34

DLCO % predicted (P < 0.05) HRCT score (P < 0.05)

0.28 (P ¼ 0.008)

Mura et al., 200632

42

Extent of fibrosis/fibrosis score (P < 0.05) Extent of emphysema (P < 0.05)

0.17 (P ¼ 0.063)

Nishiyama et al., 200734

0.27 (P ¼ 0.0005)

NR

41

SpO2 at end of six-MWT (P ¼ 0.0005)

35

Papiris et al., 2005

26

PaCO2 (P ¼ 0.02) FVC% predicted (P ¼ 0.004)

NR

Papiris et al., 200736

27

CD8 þ T lymphocyte count (BAL) (P ¼ 0.042)

NR

IPF ¼ idiopathic pulmonary fibrosis; MWD ¼ minute walk distance; NR ¼ no response; DLCO ¼ diffusing capacity of carbon monoxide; HRCT ¼ high-resolution computed tomography; SpO2 ¼ oxygen saturation by pulse oximetry; MWT ¼ minute walk test; PaCO2 ¼ arterial partial pressure of carbon dioxide; FVC ¼ forced vital capacity; BAL ¼ bronchoalveolar lavage.

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benefit in the primary endpoints in most studies. Second, dyspnea was not a primary endpoint in most of the reviewed studies, and some studies were underpowered to evaluate change in dyspnea. Finally, most dyspnea metrics used in these studies were developed in non-ILD populations and may not be as accurate or sensitive to change in patients with ILD. We did not identify any studies that evaluated the impact of lung transplant on dyspnea. Lung transplantation is likely an appropriate treatment for dyspnea in patients with endstage IPF, but it is a costly and limited resource that is not suitable for many patients. Given the absence of effective disease-modifying therapies and the limited availability and appropriateness of lung transplantation, symptom-based therapy for dyspnea remains an important potential alternative.

Treatment of Comorbid Disease Pulmonary hypertension is present in up to 46% of patients with severe IPF55 and is an important predictor of mortality.56,57 Although the largest study of sildenafil in patients with severe IPF did not require subjects to have pulmonary hypertension, the hypothesized mechanism of action was via the effects of sildenafil on the pulmonary vasculature, rather than the underlying fibrotic process.22 Although sildenafil did not improve the primary endpoint of six-MWD, there was statistically significant and clinically meaningful improvement in resting dyspnea. The results of this large, randomized, placebo-controlled trial (180 subjects) must be balanced against the negative results from two much smaller studies of sildenafil (total of 40 subjects). Overall, the balance of evidence suggests that sildenafil may have a role in the treatment of dyspnea in selected patients with severe IPF. We did not identify any studies that evaluated the impact of treating other comorbidities, such as emphysema or cardiovascular disease, in patients with IPF. Some patients with IPF have more emphysema than fibrosis, suggesting that symptoms may improve by treating obstructive lung disease. Similarly, cardiovascular disease is common in IPF,58 but the effect of treating cardiovascular disease in IPF has not been examined. The impact of treating comorbidities, such as emphysema and cardiovascular disease in IPF warrants additional study.

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Other Symptomatic Therapies Studies of pulmonary rehabilitation in general populations of ILD patients (which contained large numbers of IPF patients) have generally shown that pulmonary rehabilitation improves dyspnea and other important endpoints including walk distance.42e47 The balance of these studies in patients with ILD suggests that pulmonary rehabilitation may be beneficial in managing dyspnea in IPF despite the discordant IPF specific studies. No studies of supplemental oxygen and opioid therapy in IPF satisfied inclusion criteria for this systematic review. Limited evidence from excluded studies and extrapolation from another chronic respiratory disease (i.e., chronic obstructive pulmonary disease) suggests that these therapies may be useful. Clearly, additional research is needed. Although proportional assisted ventilation during exercise did improve exercise capacity and exertional dyspnea in one small study, this treatment is cumbersome and impractical for most patients. Additional therapies directed at other mechanisms of dyspnea also warrant further investigation.

Correlates of Dyspnea The pathogenesis of dyspnea in IPF likely results from complex interactions of pulmonary, cardiovascular, neuromechanical, and psychological inputs. Identification of a variety of correlates of dyspnea supports this multidimensional model of dyspnea in IPF. Future studies should investigate the treatment of correlates of dyspnea, as some of these correlations also may represent causation. Deconditioning and depression correlate with dyspnea in IPF and are promising candidates for this approach. The impact of pulmonary rehabilitation in ILD may well be a result of extrapulmonary effects, such as cardiovascular and peripheral muscle function, rather than improvements in ventilatory restriction and gas exchange.24,44,45 Similarly, dyspnea is a common somatic symptom of depression, suggesting that treatment of depression, when present, may have a secondary effect of improving dyspnea. This systematic review highlights the limitations of the current literature regarding correlates and potential contributors to dyspnea in IPF. Only six studies used multivariate analysis,

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and these analyses were performed on small cohorts, limiting the ability to adjust for potential confounders. An important area of future research is to examine the correlates of dyspnea using a multivariate approach that incorporates a wider variety of potentially modifiable factors.

Limitations There are limitations to this review. First, we were unable to assess for publication bias. However, the objective of this review was to identify effective treatments for dyspnea in patients with IPF, and studies showing such effects are more likely to be published. Second, we were unable to provide summary estimates because of the temporal and methodological heterogeneity of the included studies. Several dyspnea tools were used, and these metrics have unique characteristics that may contribute to the inconsistent results observed for some treatments. Third, we only reviewed articles published in English. Notwithstanding these limitations, this review is the first to systematically examine the treatment and correlates of dyspnea in IPF, providing an important summary of the existing literature and gaps in knowledge.

Conclusion This systematic review summarizes what is currently known about the treatment of dyspnea in IPF, provides recommendations for the treatment of dyspnea in IPF, and suggests areas for further research in this field. Sildenafil and pulmonary rehabilitation are potential therapies for dyspnea in selected patients with IPF. Supplemental oxygen and opioids may be additional potential therapies; however, the evidence supporting their use is weak. Additional research should focus on the management of functional status and comorbidities as potential treatments for dyspnea.

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The initial draft of the manuscript was prepared by C. J. R. and H. R. C. All authors read and approved the final manuscript, and all authors take responsibility for the integrity of the work as a whole.

Appendix Supplementary Material Supplementary data associated with this article can be found, in the online version, at 10.1016/j.jpainsymman.2011.04.026.

References 1. Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2006;174:810e816. 2. Bjoraker JA, Ryu JH, Edwin MK, et al. Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1998;157:199e203. 3. Hubbard R, Johnston I, Britton J. Survival in patients with cryptogenic fibrosing alveolitis: a population-based cohort study. Chest 1998;113:396e400. 4. Swigris JJ, Kuschner WG, Jacobs SS, Wilson SR, Gould MK. Health-related quality of life in patients with idiopathic pulmonary fibrosis: a systematic review. Thorax 2005;60:588e594. 5. King TE Jr, Schwarz MI, Brown K, et al. Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality. Am J Respir Crit Care Med 2001;164:1025e1032. 6. Demedts M, Behr J, Buhl R, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005;353:2229e2242. 7. Taniguchi H, Ebina M, Kondoh Y, et al. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 2010;35:821e829. 8. Ryerson CJ, Collard HR, Pantilat SZ. Management of dyspnea in interstitial lung disease. Curr Opin Support Palliat Care 2010;4:69e75.

Disclosures and Acknowledgments

9. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 2000;161(2 Pt 1):646e664.

No funding was received for this study. C. J. R., S. Z. P., and H. R. C. conceived the research question and study design. C. J. R. developed the search strategy. C. J. R. and D. D. performed the search and data extraction.

10. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of

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