1. NAVIGATING the NEW ERA in IPF: Comorbidities and Complications
3/28/2014
NAVIGATING the NEW ERA in IPF: Comorbidities and Complications
FACULTY
Title
Affiliation

2. Learning Objectives
Identify approaches to IPF management that are covered in current guidelines, taking into account the strength of relevant recommendations
Formulate a plan, based on available data and expert consensus, for addressing acute exacerbations of IPF
Explain the impact and treatment of common comorbidities of IPF
PILOT Learning Objectives
Explain the considerations associated with clinical evaluation, imaging, and surgical biopsy, in terms of differentially diagnosing IPF.
Identify opportunities for interdisciplinary collaboration and consultation and key aspects of guideline recommendations that can facilitate early and accurate IPF diagnosis.
Summarize the current understanding of the IPF disease process and strategies that can help measure disease progression and treatment response.
Identify approaches to IPF management that are covered in current guidelines, taking into account the strength of relevant recommendations.
Formulate a plan, based on available data and expert consensus, for addressing acute exacerbations of IPF.
Evaluate clinical trial data on available and emerging treatments for IPF.
Formulate a plan for regular and relevant communication with and education of patients and families regarding both pharmacologic and nonpharmacologic aspects of care.
Explain the impact and treatment of common comorbidities of IPF.
Identify opportunities for referral to others as part of the multidisciplinary IPF management plan.

3. Common Complications and Comorbidities of IPF
GERD
Pulmonary hypertension
Emphysema
Acute exacerbation
OSA
CVD and Thromboembolism
Depression

4. IPF and GERD Lee JS, et al. Am J Med. 2010;123(4):304-311.
Am J Med Apr;123(4): doi: /j.amjmed
Does chronic microaspiration cause idiopathic pulmonary fibrosis?
Lee JS1, Collard HR, Raghu G, Sweet MP, Hays SR, Campos GM, Golden JA, King TE Jr.
Author information
Abstract
Idiopathic pulmonary fibrosis is a diffuse fibrotic lung disease of unknown etiology with no effective treatment. Emerging data support a role for chronic microaspiration (ie, subclinical aspiration of small droplets) in the pathogenesis and natural history of idiopathic pulmonary fibrosis. However, the precise relationship between chronic microaspiration and idiopathic pulmonary fibrosis remains unknown. Gastroesophageal reflux, a presumed risk factor for microaspiration, has been strongly associated with idiopathic pulmonary fibrosis with an estimated prevalence of up to 90%. This review aims to describe the relationship between chronic microaspiration and idiopathic pulmonary fibrosis by laying out the clinical and biologic rationale for this relationship and exploring the scientific evidence available. The gaps in our current understanding of the diagnosis of chronic microaspiration and idiopathic pulmonary fibrosis and the ongoing uncertainties in management and treatment will be highlighted. Defining the role of chronic microaspiration in idiopathic pulmonary fibrosis is essential as it has potential clinical, pathobiological, and treatment implications for this deadly disease.
Lee JS, et al. Am J Med. 2010;123(4):

5. Gastroesophageal Reflux Disease (GERD)
Definition: Symptoms or complications resulting from the reflux of gastric contents into the esophagus or beyond, into the oral cavity (including larynx) or lung
Risk factor for IPF
Common in patients with IPF
Clinically silent in the majority of cases
May have nonacid components (alkaline GERD)
Etiology unknown
Contribution to IPF pathology unknown
Katz PO, et al. Am J Gastroenterol. 2013;108(3):
Raghu G, et al. Am J Respir Crit Care Med. 2011;183(6):

6. GERD Diagnosis Treatment Barium swallow Esophageal manometry
24 hour pH probe
Treatment
PPI’s
Nissen fundoplication
WRAP-IPF trial
ClinicalTrials.gov: NCT
Raghu G, et al. Eur Respir J. 2006;27:

7. GERD Prevalence Normal: 10-20%1 IPF: 90%2 COPD: 60%3
Cystic Fibrosis: 35 to 81%4
Eur Respir J 2006; 27: High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis
G. Raghu1, T. D. Freudenberger1, S. Yang2, J. R. Curtis1, C. Spada1, J. Hayes1, J. K. Sillery3, C. E. Pope, II3 and C. A. Pellegrini3 1
The aim of this prospective study was to determine the prevalence and characteristics of acid gastro-oesophageal reflux (GER) in patients with idiopathic pulmonary fibrosis (IPF).
Sixty-five consecutive patients with well-defined IPF were subjected to 24-h pH monitoring and oesophageal manometry. A total of 133 consecutive patients with intractable asthma and symptoms of GER were used as comparisons.
The prevalence of abnormal acid GER in IPF patients was 87%, with 76% and 63% demonstrating abnormal distal and proximal oesophageal acid exposures, respectively. Abnormal acid GER was significantly more common in IPF patients than asthma patients. Only 47% of IPF patients experienced classic GER symptoms. Despite treatment with standard doses of proton pump inhibitors (PPIs), 12 out of 19 patients receiving PPIs during the 24-h pH monitoring had abnormal oesophageal acid exposures by pH probe. There was no correlation between IPF severity and acid GER severity.
In conclusion, abnormal acid gastro-oesophageal reflux is highly prevalent, but often clinically occult in patients with idiopathic pulmonary fibrosis. Standard doses of proton pump inhibitors may not suppress the acid gastro-oesophageal reflux in this population. Therefore, further studies are needed to determine if acid abnormal gastro-oesophageal reflux represents an important risk factor for idiopathic pulmonary fibrosis development or progression, and if optimal suppression of acid gastro-oesophageal reflux slows the progression of idiopathic pulmonary fibrosis and/or decreases episodic exacerbations of idiopathic pulmonary fibrosis.
Increased gastro-oesophageal reflux disease in patients with severe COPD
C. Casanova1, J.S. Baudet1, M. del Valle Velasco1, J.M. Martin1, A. Aguirre-Jaime1, J. Pablo de Torres1 and B.R. Celli2 1 Depts of Pulmonary Medicine and Gastroenterology, Medical Research Unit, Hospital Universitario La Candelaria, Tenerife, Spain. 2 Pulmonary and Critical Care Division, St. Elizabeth's Medical Center, Tufts University, Boston, USA
The prevalence and clinical consequences of gastro-oesophageal reflux disease (GERD) in chronic obstructive pulmonary disease (COPD) are not well characterised.
The present study prospectively studied 42 males with COPD (forced expiratory volume in one second % predicted: 35%, range 20–49) and 16 healthy volunteers of similar age without respiratory or gastro-oesophageal symptoms. The diagnosis of GERD was confirmed using oesophageal 24 h pH monitoring. In the current study group, reflux symptoms were measured using the Vigneri score, cough and dyspnoea with the modified Medical Research Council questionnaire, and pulmonary function with bronchodilator response and health status using St George's Respiratory Questionnaire.
Pathological reflux was documented in 26 out of 42 patients (62%) and in three volunteers (19%). In patients with GERD, 15 patients (58%) did not report any reflux symptoms. There were no differences in symptoms, health status, bronchodilator treatment and pulmonary function test between patients with and without GERD. Oxygen desaturation coincided with episodes of increased oesophageal acidity in 40% of patients with GERD.
Patients with severe chronic obstructive pulmonary disease have a high prevalence of asymptomatic gastro-oesophageal reflux. The association between this reflux and oxygen desaturation deserves further attention.
Katz PO, et al. Am J Gastroenterol. 2013;108(3):
Raghu G, et al. Eur Respir J. 2006;27,
Kempainen RR, et al. Chest. 2007; 131:
Robinson NB, et al. Ann Am Thorac Soc. 2014;11(6):

8. GERD Acid GERD prevalent in IPF (87%)
47% experience classic GERD symptoms
GERD and IPF severities not correlated:
DLCO
FVC
Distal % Reflux Time ln
GERD
Gastroesophageal reflux disease (GERD) is one of the most common comorbidities in patients with IPF. In this study by Raghu et al, consecutive patients with well-defined IPF were followed with 24-h pH monitoring and esophageal manometry. The prevalence of abnormal acid GERD in IPF patients was 87%, with 76% and 63% demonstrating abnormal distal and proximal esophageal acid, respectively. 78% exhibited any GERD symptom, but only 47% of IPF patients experienced the classic GERD symptoms of heartburn and regurgitation. Patients with intractable asthma and symptoms of GERD were used as controls, though they were not age- or sex-matched. The prevalence of GERD in this group was 68%, lower than in the IPF patients (P = 0.014).
As shown in the graphs, there was no correlation between DLCO or FVC and GERD severity. Though lung injury by aspirated acid is a plausible pathologic mechanism in IPF, causality has not been shown. Though it is also not known whether management of GERD has a positive effect on the course of IPF or on acute exacerbations, management of GERD as well as other comorbidities is strongly encouraged.
Raghu G, Freudenberger TD, Yang S, et al. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J. 2006;27:
% Predicted
% Predicted
Raghu G, et al. Eur Respir J. 2006;27:

9. GERD Treatment and Survival
Taking GERD medications
Survival
Not taking GERD medications
Am J Respir Crit Care Med Dec 15;184(12): doi: /rccm OC. Epub 2011 Jun 23.
Gastroesophageal reflux therapy is associated with longer survival in patients with idiopathic pulmonary fibrosis.
Lee JS1, Ryu JH, Elicker BM, Lydell CP, Jones KD, Wolters PJ, King TE Jr, Collard HR.
Author information
Abstract
RATIONALE:
Gastroesophageal reflux (GER) is highly prevalent in patients with idiopathic pulmonary fibrosis (IPF). Chronic microaspiration secondary to GER may play a role in the pathogenesis and natural history of IPF.
OBJECTIVES:
To investigate the relationship between GER-related variables and survival time in patients with IPF.
METHODS:
Regression analysis was used to investigate the relationship between GER-related variables and survival time in a retrospectively identified cohort of patients with well-characterized IPF from two academic medical centers.
MEASUREMENTS AND MAIN RESULTS:
Two hundred four patients were identified for inclusion. GER-related variables were common in this cohort: reported symptoms of GER (34%), a history of GER disease (45%), reported use of GER medications (47%), and Nissen fundoplication (5%). These GER-related variables were significantly associated with longer survival time on unadjusted analysis. After adjustment, the use of GER medications was an independent predictor of longer survival time. In addition, the use of gastroesophageal reflux medications was associated with a lower radiologic fibrosis score. These findings were present regardless of center.
CONCLUSIONS:
The reported use of GER medications is associated with decreased radiologic fibrosis and is an independent predictor of longer survival time in patients with IPF. These findings further support the hypothesis that GER and chronic microaspiration may play important roles in the pathobiology of IPF.
Time to Event (days)
Lee JS, et al. Am J Respir Crit Care Med. 2011;184(12):

10. ATS/ERS Recommendation
The recommendation for the treatment of asymptomatic GER in patients with IPF is weak
Asymptomatic GER should be treated in the majority of patients with IPF, but not treating asymptomatic GER may be a reasonable choice in a minority ()*.
* () = GRADE quality of evidence very low
Raghu G, et al. Am J Respir Crit Care Med. 2011;183(6):

11. IPF With Severe PH
mPAP = 61 mmHg

12. Prevalence of PH in IPF RHC Echo
Hamada (2007) Raghu (2010) Patel (2007) Song (2009) Nathan (2007) Zisman (2007) Shorr (2007) Minai (2009) Nadrous (2005) Nathan (2008)
Pulmonary hypertension in patients with idiopathic pulmonary fibrosis
Steven D. Nathan and Vincent Cottin. Eur Respir Monogr 2012; 57: 148–160.
SUMMARY: There is a growing body of evidence that
pulmonary hypertension (PH) is relatively common in patients
with idiopathic pulmonary fibrosis (IPF). PH in IPF is
associated with increased dyspnoea, decreased exercise capacity,
greater oxygen requirements, lower diffusing capacity of the
lung for carbon monoxide (DL,CO) and reduced survival.
Pulmonary haemodynamics do not correlate with pulmonary
function testing. The pathogenesis is complex and multifactorial,
and includes lung destruction, intrinsic vascular
abnormalities, hypoxia, alterations in mediators, dysregulation
of neovascularisation and microvascular injuries. Additionally,
comorbidities, particularly concomitant emphysema, thromboembolic
events, cardiac diastolic dysfunction and obstructive
sleep apnoea (OSA) may increase the risk of PH in IPF. No
screening recommendations are available but right heart
catheterisation (RHC) is the diagnostic procedure of choice.
As yet, no studies of pulmonary vasoactive agents have
demonstrated clinical efficacy; however, further trials are sorely
needed. If PH therapy is considered on a case-by-case basis,
particular attention must be paid to the potential benefits and
possible risks, particularly worsening of gas exchange.
at evaluation
at transplantation
Estimate of PH Prevalence, %
Nathan SD, Cottin V. Eur Respir Monogr. 2012;57:148–160.

13. Distribution of mPAPs in IPF Patients25 20 15
Frequency 10 5
10.00
20.00
30.00
40.00
50.00
mPAP
PAH: mPAP > 25 mm Hg
Lettieri et al. Chest :

14. Mean Pulmonary Artery Pressure: Prognostic Value in IPF
1.0
n = 54
No (mPap ≤ 25 mm Hg)
0.8
n = 25
0.6
Cumulative Probability to Survival
Yes (mPap > 25 mm Hg)
0.4
0.2
P < 0.001
0.0 1 2 3 4 5 6 7
Years to Event
Lettieri CJ, et al. Chest. 2006;129: 14

15. PH in IPF: Impact on 6MWT < 0.001 0.002 mPAP < 25 mm Hg
mPAP > 25 mm Hg (N=10)
P value
6MWD (m)
366 ± 82
144 ± 66
< 0.001
SpO2 nadir (%)
88 ± 4
80 ± 4
Lettieri CJ, et al. Chest. 2006;129:
mPAP ≤ 25 mm Hg
(N=27)
mPAP > 25 mm Hg
with normal PCWP
(N=7)
P value
6MWD (m, adjusted for FVC%)*
402 ± 25
210 ± 50
0.002
Chest Sep;132(3):
Pulmonary hypertension in idiopathic pulmonary fibrosis.
Patel NM1, Lederer DJ, Borczuk AC, Kawut SM.
Author information
Abstract
Idiopathic pulmonary fibrosis (IPF) is an untreatable diffuse parenchymal lung disease with a median survival of < 3 years. Pulmonary hypertension (PH) is frequently seen in patients with IPF and is commonly attributed to hypoxic vasoconstriction and capillary destruction. Pathology findings include endothelial proliferation and medial hypertrophy that exceed those expected in the setting of hypoxia. Noninvasive evaluation has limited sensitivity and specificity for the diagnosis of PH in IPF; therefore, right-heart catheterization remains the "gold standard" diagnostic test. PH in patients with IPF is associated with decreased exercise capacity and worse survival. Given the grave consequences of this condition, treatment of PH could improve functional outcomes and survival. However, possible treatments such as long-term supplemental oxygen and targeted vascular therapy are either unstudied or remain unproven.
Certain studies have suggested harm associated with targeted vascular therapy.
Patel NM, et al. Chest. 2007;132(3):

16. When to Suspect PH in IPF
PFTs
DLCO <40%
6MWT
SpO2 ≤ 88%
Heart rate recovery at 1 minute < 13 bpm
BNP
Echocardiography

17. Echocardiography Does Not Accurately Predict PH in Patients With IPF
48%
40%
Patients (%)
12%
The utility of echocardiography as a diagnostic tool to discover PH in patients with IPF was studied in this series of 110 patients who had undergone both RHC and echo at two large tertiary care centers. Echocardiography was an insensitive test for PH, demonstrating accuracy in predicting PH in only 40% of patients.
Reference:
Nathan SD, Shlobin OA, Barnett SD, et al. Right ventricular systolic pressure by echocardiography as a predictor of pulmonary hypertension in idiopathic pulmonary fibrosis. Respir Med. 2008;102:1305–1310.
Under
Estimation
Accurate
Over
Estimation
N=110, idiopathic pulmonary fibrosis patients with both echo and RHC
Comparison of RVSP by echo to PASP by RHC
Nathan SD, et al. Respir Med. 2008;102:1305–1310. 17

18. Treatment With an Endothelin-1 Antagonist
ARTEMIS study
Patients
IPF aged 40 to 80 years
Minimal or no honeycombing on HRCT
Not selected for PH
Treatment
Ambrisentan, 10 mg/d or
Placebo
Terminated for lack of efficacy at interim analysis
P = 0.010
Ann Intern Med May 7;158(9): doi: /
Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial.
Raghu G1, Behr J, Brown KK, Egan JJ, Kawut SM, Flaherty KR, Martinez FJ, Nathan SD, Wells AU, Collard HR, Costabel U, Richeldi L, de Andrade J, Khalil N, Morrison LD, Lederer DJ, Shao L, Li X, Pedersen PS, Montgomery AB, Chien JW, O'Riordan TG; ARTEMIS-IPF Investigators*.
Don’t routinely offer pharmacologic treatment with advanced vasoactive agents approved only for the management of pulmonary arterial hypertension to patients with pulmonary hypertension resulting from left heart disease or hypoxemic lung diseases (Groups II or III pulmonary hypertension).
Evidence and clinical practice guidelines have not established benefits of vasoactive agents (e.g., prostanoids, phosphodiesterase inhibitors, endothelin antagonists) for patients with pulmonary hypertension resulting from left heart disease or hypoxemic lung diseases. Moreover, the use of these agents may cause harm in certain situations and incurs substantial cost and resource utilization. Patients should be carefully assessed (including at a minimum right heart catheterization, echocardiography, chest CT, six minute walk test and pulmonary function testing) to confirm that they have symptomatic pulmonary arterial hypertension prior to having approved agents initiated.
Raghu G, et al. Ann Intern Med. 2013;158(9):

19. Treat IPF Patients for PH?
Ambrisentan, bosentan, and macitentan have been found non-efficacious or harmful
IPF patients should NOT be routinely treated for PH 
ABIM's Choosing Wisely:
"Don’t routinely offer pharmacologic treatment with advanced vasoactive agents approved only for the management of pulmonary arterial hypertension to patients with pulmonary hypertension resulting from left-sided heart disease or hypoxemic lung diseases (groups II or III pulmonary hypertension)."
Accessed August 2014.

20. STEP-IPF Sildenafil (PDE-5 inhibitor) acts as pulmonary vasodilator
20 mg three times daily vs placebo
12 weeks + 12 week extension
N = 180 patients with IPF
Endpoint
Sildenafil
(N = 89)
Placebo
(N = 91)
P-value
6MWD improvement ≥ 20% (Primary)
9/89 (10%)
6/91 (7%)
0.39
ΔDLCO (%)
−0.33
−1.87
0.04
ΔPPO2 (mm Hg)
−0.63
−3.64
0.02
ΔSOB Questionairre
0.22
6.81
0.006
ΔSGRQ (QOL)
−1.64
2.45
0.01
N Engl J Med Aug 12;363(7): doi: /NEJMoa Epub 2010 May 18.
A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis.
Idiopathic Pulmonary Fibrosis Clinical Research Network, Zisman DA, Schwarz M, Anstrom KJ, Collard HR, Flaherty KR, Hunninghake GW.
Collaborators (122)
Abstract
BACKGROUND:
Sildenafil, a phosphodiesterase-5 inhibitor, may preferentially improve blood flow to well-ventilated regions of the lung in patients with advanced idiopathic pulmonary fibrosis, which could result in improvements in gas exchange. We tested the hypothesis that treatment with sildenafil would improve walk distance, dyspnea, and quality of life in patients with advanced idiopathic pulmonary fibrosis, defined as a carbon monoxide diffusion capacity of less than 35% of the predicted value.
METHODS:
We conducted a double-blind, randomized, placebo-controlled trial of sildenafil in two periods. The first period consisted of 12 weeks of a double-blind comparison between sildenafil and a placebo control. The primary outcome was the proportion of patients with an increase in the 6-minute walk distance of 20% or more. Key secondary outcomes included changes in oxygenation, degree of dyspnea, and quality of life. The second period was a 12-week open-label evaluation involving all patients receiving sildenafil.
RESULTS:
A total of 180 patients were enrolled in the study. The difference in the primary outcome was not significant, with 9 of 89 patients (10%) in the sildenafil group and 6 of 91 (7%) in the placebo group having an improvement of 20% or more in the 6-minute walk distance (P=0.39). There were small but significant differences in arterial oxygenation, carbon monoxide diffusion capacity, degree of dyspnea, and quality of life favoring the sildenafil group. Serious adverse events were similar in the two study groups.
CONCLUSIONS:
This study did not show a benefit for sildenafil for the primary outcome. The presence of some positive secondary outcomes creates clinical equipoise for further research. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT )
Zisman DA, et al. N Engl J Med. 2010;363(7):

21. STEP-IPF Subgroup Analysis
19% of subjects had RVSD
Subjects with RVSD treated with sildenafil (vs placebo)
Less decrement in 6MWD (P = 0.01)
Greater improvement in SGRQ (P = 0.005) and
Greater improvement in EuroQol visual analog scores (P = 0.04)
Chest Jun;143(6): doi: /chest
Sildenafil preserves exercise capacity in patients with idiopathic pulmonary fibrosis and right-sided ventricular dysfunction.
Han MK1, Bach DS, Hagan PG, Yow E, Flaherty KR, Toews GB, Anstrom KJ, Martinez FJ; IPFnet Investigators.
Author information
Abstract
BACKGROUND:
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with pulmonary vasculopathy.
OBJECTIVE:
The purpose of this study was to determine whether sildenafil improves 6-min walk distance (6MWD) in subjects with IPF and right ventricular dysfunction.
METHODS:
The IPFnet, a network of IPF research centers in the United States, conducted a randomized trial examining the effect of sildenafil on 6MWD in patients with advanced IPF, defined by carbon monoxide diffusing capacity < 35% predicted. A substudy examined 119 of 180 randomized subjects where echocardiograms were available for independent review by two cardiologists. Right ventricular (RV) hypertrophy (RVH), right ventricular systolic dysfunction (RVSD), and right ventricular systolic pressure (RVSP) were assessed. Multivariable linear regression models estimated the relationship between RV abnormality, sildenafil treatment, and changes in 6MWD, St. George's Respiratory Questionnaire (SGRQ), the EuroQol instrument, and SF-36 Health Survey (SF-36) from enrollment to 12 weeks.
RESULTS:
The prevalence of RVH and RVSD were 12.8% and 18.6%, respectively. RVSP was measurable in 71 of 119 (60%) subjects; mean RVSP was 42.5 mm Hg. In the subgroup of subjects with RVSD, subjects treated with sildenafil experienced less decrement in 6MWD (99.3 m; P = .01) and greater improvement in SGRQ (13.4 points; P = .005) and EuroQol visual analog scores (17.9 points; P = .04) than subjects receiving placebo. In the subgroup with RVH, sildenafil was not associated with change in 6MWD (P = .13), but was associated with greater relative improvement in SGRQ (14.8 points; P = .02) vs subjects receiving placebo. Sildenafil treatment in those with RVSD and RVH was not associated with change in SF-36.
CONCLUSIONS:
Sildenafil treatment in IPF with RVSD results in better preservation of exercise capacity as compared with placebo. Sildenafil also improves quality of life in subjects with RVH and RVSD.
Han MK, et al. Chest. 2013;143(6):

22. ATS/ERS Recommendation
PH should not be treated in the majority of patients with IPF, but treatment may be a reasonable choice in a minority (weak recommendation, very low-quality evidence). ()*
In patients with moderate to severe PH (mPAP > 35 mm Hg) documented by right heart catheterization, a trial of vasomodulatory therapy may be indicated
It is not clear if IPF with PH represents a distinct clinical phenotype (IPF–PH)
* () = GRADE quality of evidence very low
Raghu G, et al. Am J Respir Crit Care Med. 2011;183(6):

23. Combined Pulmonary Fibrosis and Emphysema Syndrome (CPFE)

24. CPFE Upper lobe emphysema and lower lobe fibrosis
Most often observed in males
Mean age 65 years
Tobacco smokers or ex-smokers of > 40 pack-years
May comprise up to 35% of patients with IPF
Symptoms and morbidity largely attributable to severe precapillary PH
Risk of PH ~50%
Eur Respir Rev Jun 1;22(128): doi: /
The impact of emphysema in pulmonary fibrosis.
Cottin V.
Author information
Abstract
Several groups have described a syndrome in which idiopathic pulmonary fibrosis (IPF) coexists with pulmonary emphysema. This comes as no surprise since both diseases are associated with a history of exposure to cigarette smoke. The syndrome of combined pulmonary fibrosis and emphysema (CPFE) is characterised by upper lobe emphysema and lower lobe fibrosis. Physiological testing of these patients reveals preserved lung volume indices contrasted by markedly impaired diffusion capacity. The incidence of CPFE remains unknown but several case series suggest that this subgroup may comprise up to 35% of patients with IPF. CPFE is a strong determinant of associated pulmonary hypertension (PH). In addition, CPFE has major effects on measures of physiological function, exercise capacity and prognosis, and may affect the results of pulmonary fibrosis trials. Further studies are needed to ascertain the aetiology, morbidity, mortality and management of the CPFE syndrome, with or without PH, and to evaluate novel therapeutic options in CPFE.
Cottin V. Eur Respir Rev. 2013;22(128):

25. Features of CPFE Severe dyspnea
Unexpected subnormal spirometry findings
Severely impaired DLCO
Hypoxemia with exercise
Characteristic imaging features
High HRCT fibrotic score
Basal crackles
Eur Respir Rev Jun 1;22(128): doi: /
The impact of emphysema in pulmonary fibrosis.
Cottin V.
Author information
Abstract
Several groups have described a syndrome in which idiopathic pulmonary fibrosis (IPF) coexists with pulmonary emphysema. This comes as no surprise since both diseases are associated with a history of exposure to cigarette smoke. The syndrome of combined pulmonary fibrosis and emphysema (CPFE) is characterised by upper lobe emphysema and lower lobe fibrosis. Physiological testing of these patients reveals preserved lung volume indices contrasted by markedly impaired diffusion capacity. The incidence of CPFE remains unknown but several case series suggest that this subgroup may comprise up to 35% of patients with IPF. CPFE is a strong determinant of associated pulmonary hypertension (PH). In addition, CPFE has major effects on measures of physiological function, exercise capacity and prognosis, and may affect the results of pulmonary fibrosis trials. Further studies are needed to ascertain the aetiology, morbidity, mortality and management of the CPFE syndrome, with or without PH, and to evaluate novel therapeutic options in CPFE.
Cottin V. Eur Respir Rev. 2013;22(128):

26. CPFE Outcomes in 2 IPF Cohorts
365 patients with IPF
29 (8%) had CPFE
Patients with CPFE had
Less fibrosis on HRCT scans
Higher FVC
Greater oxygen requirements
No difference in mortality with IPF +/- emphysema (HR, 1.14; 95% CI, ; P = 0.69)
Chest Jul;144(1): doi: /chest
Clinical features and outcomes in combined pulmonary fibrosis and emphysema in idiopathic pulmonary fibrosis.
Ryerson CJ1, Hartman T, Elicker BM, Ley B, Lee JS, Abbritti M, Jones KD, King TE Jr, Ryu J, Collard HR.
Author information
Abstract
BACKGROUND:
Combined pulmonary fibrosis and emphysema (CPFE) is increasingly recognized, but its prevalence and prognosis remain unclear. We sought to determine the prevalence, clinical features, and prognosis of CPFE in idiopathic pulmonary fibrosis (IPF), using a standardized and reproducible definition.
METHODS:
Patients with IPF were identified from two ongoing cohorts. Two radiologists scored emphysema and fibrosis severity on high-resolution CT (HRCT) scans. CPFE was defined as ≥10% emphysema on HRCT scan. Clinical characteristics and outcomes of patients with CPFE and IPF and those with non-CPFE IPF were compared with unadjusted analysis and then analysis after adjustment for HRCT fibrosis score. Mortality was compared using competing risks regression to handle lung transplantation. Sensitivity analyses were performed using Cox proportional hazards, including time to death (transplantation censored) and time to death or transplant.
RESULTS:
CPFE criteria were met in 29 of 365 patients with IPF (8%), with high agreement between radiologists (κ=0.74). Patients with CPFE had less fibrosis on HRCT scans and higher FVC, but greater oxygen requirements (P≤.01 for all comparisons). Findings were maintained with adjustment for fibrosis severity. Inhaled therapies for COPD were used by 53% of patients with CPFE. There was no significant difference in mortality comparing patients with CPFE and IPF to those with non-CPFE IPF (hazard ratio, 1.14; 95% CI, ; P=.69).
CONCLUSIONS:
CPFE was identified in 8% of patients with IPF and is a distinct, clinical phenotype with potential therapies that remain underutilized. Patients with CPFE and IPF and those with non-CPFE IPF have similar mortality.
Ryerson CJ, et al. Chest. 2013;144(1):

27. Management of Patients With Combined Pulmonary Fibrosis and Emphysema (CPFE)
No specific treatment for CPFE
Absence of specific trials or prospective data
IPF trials not adequate
Smoking cessation; bronchodilators; supportive care; oxygen supplementation; lung transplant
Discuss corticosteroids +/- azathioprine if NSIP considered /
Adapted from ERS/ESC guidelines, Galiè N et al. Eur Respir J. 2009;34:1219.

28. Acute Exacerbations Punctuate Slow Decline
(5-10% of patients per year)
King TE Jr, et al. Lancet. 2011;378(9807):

29. Acute Exacerbations of IPF
Incidence 5-10% per year
Diagnostic criteria
Diagnosis of IPF
Unexplained worsening or development of dyspnea within 30 days
HRCT with new bilateral ground-glass abnormality and/or consolidation superimposed on a background reticular or honeycomb pattern consistent with UIP
No evidence of pulmonary infection by endotracheal aspirate or bronchoalveolar lavage
Exclusion of alternative causes, including
Left heart failure
Pulmonary embolism
Identifiable cause of acute lung injury
Raghu G, et al. Am J Respir Crit Care Med. 2011;183(6):
Collard HR, et al. Am J Respir Crit Care Med 2007;176:636–643.

30. Management of Patients With Acute Exacerbations
Exclude other causes
Infection
CHF
Pulmonary embolism
Ischemic heart disease
HRCT
Bronchoscopy (if permitted by medical status)
Patients usually treated with broad-spectrum antibiotics and corticosteroids (unproven efficacy)
Management of Patients With Acute Exacerbations
After excluding other causes such as infection, congestive heart failure, pulmonary embolism, and ischemic heart disease, a diagnosis of acute exacerbation can be confirmed by HRCT and histology. Patients are usually treated with broad-spectrum antibiotics and corticosteroids, with unproven success. Often, mechanical ventilation is performed but is most often not successful (see Ancillary Management section in this compendium).
In patients who survive, a recurrence of acute exacerbation is common and frequently results in death. Better understanding and management of these episodes seem to be critical to reducing the death rate in IPF.
Walter N, et al. Proc Am Thorac Soc. 2006;3:
Walter N, Collard HR, King TE Jr. Current perspectives in the treatment of idiopathic pulmonary fibrosis. Proc Am Thorac Soc. 2006;3:

31. ATS/ERS Recommendation
The majority of patients with acute exacerbation of IPF should be treated with corticosteroids, but corticosteroids may not be reasonable in a minority (weak recommendation, very low-quality evidence).
Am J Respir Crit Care Med Oct 1;176(7): Epub 2007 Jun 21.
Acute exacerbations of idiopathic pulmonary fibrosis.
Collard HR1, Moore BB, Flaherty KR, Brown KK, Kaner RJ, King TE Jr, Lasky JA, Loyd JE, Noth I, Olman MA, Raghu G, Roman J, Ryu JH, Zisman DA, Hunninghake GW, Colby TV, Egan JJ, Hansell DM, Johkoh T, Kaminski N, Kim DS, Kondoh Y, Lynch DA, Müller-Quernheim J, Myers JL, Nicholson AG, Selman M, Toews GB, Wells AU, Martinez FJ; Idiopathic Pulmonary Fibrosis Clinical Research Network Investigators.
Author information
Abstract
The natural history of idiopathic pulmonary fibrosis (IPF) has been characterized as a steady, predictable decline in lung function over time. Recent evidence suggests that some patients may experience a more precipitous course, with periods of relative stability followed by acute deteriorations in respiratory status. Many of these acute deteriorations are of unknown etiology and have been termed acute exacerbations of IPF. This perspective is the result of an international effort to summarize the current state of knowledge regarding acute exacerbations of IPF. Acute exacerbations of IPF are defined as acute, clinically significant deteriorations of unidentifiable cause in patients with underlying IPF. Proposed diagnostic criteria include subjective worsening over 30 days or less, new bilateral radiographic opacities, and the absence of infection or another identifiable etiology. The potential pathobiological roles of infection, disordered cell biology, coagulation, and genetics are discussed, and future research directions are proposed.
Raghu G, et al. Am J Respir Crit Care Med. 2011;183(6):

32. Sleep Disruption is Common in IPF
Impaired physical and social functioning1
Sleep quality should be a primary therapeutic goal
Nocturnal hypoxemia is common
Associated with
significant sleep disruption,1
decreased energy levels
impaired physical functioning2
Daytime SpO2 is a strong predictor of nocturnal SpO23,4
Daytime spirometric measures are poor predictors of nocturnal hypoxia
Clinical trial of supplemental oxygen is recruiting (clinicaltrials.gov NCT )
Managing Sleep in IPF Patients
Few studies have examined effective treatments for the management of sleep in IPF patients. Mermigkis et al used questionnaires and polysomnography (PSG) to evaluate the quality of sleep and its effect on daytime quality of life in 15 IPF patients. The most common disabling symptom in these patients was daytime fatigue. PSG revealed significant impairment of sleep efficiency, extension of stage 1 sleep, reduction of slow wave and REM sleep, and decreased oxygen saturation.
Although reduced sleep quality and nocturnal hypoxia are associated with daytime fatigue, the potential benefit of nocturnal oxygen therapy in IPF patients has not been studied. The benefit of nocturnal oxygen therapy in patients with COPD is also uncertain. Clinical trials are currently underway to examine the role of oxygen therapy in COPD, but no trials are currently scheduled for studying its role in managing IPF.
there is an ongoing study regarding oxygen therapy in patients with pulmonary fibrosis. On the clinical trials site: NCT
1. Mermigkis C, et al. Med Princ Pract. 2009;18:10-15.
2. Clark M, et al. Thorax. 2001;56:
3. Douglas NJ, et al. Am Rev Respir Dis. 1990;141:
4. Cormick W, et al. Thorax. 1986;41:
Mermigkis C, Stagaki E, Amfilochiou A, et al. Sleep quality and associated daytime consequences in patients with idiopathic pulmonary fibrosis. Med Princ Pract. 2009;18:10-15.
Clark M, Cooper B, Singh S, Cooper M, Carr A, Hubbard R. A survey of nocturnal hypoxaemia and health related quality of life in patients with cryptogenic fibrosing alveolitis. Thorax. 2001;56:
Douglas NJ, Flenley DC. Breathing during sleep in patients with obstructive lung disease. Am Rev Respir Dis. 1990;141:
Cormick W, Olson LG, Hensley MJ, Saunders NA. Nocturnal hypoxaemia and quality of sleep in patients with chronic obstructive lung diseases. Thorax. 1986;41:

33. Is OSA Common in IPF? 55 subjects with IPF Sleep apnea evaluation
Epworth Sleepiness Scale (ESS)
Sleep Apnea Scale of Sleep Disorders (SA-SDQ)
Nocturnal polysomnography (NPSG)
Other measures
Spirometry (FEV1, FVC)
Total lung capacity
DLCO
BMI
Is OSA Common in IPF?
Patients who had been diagnosed with IPF according to the 2000 American Thoracic Society consensus statement criteria were studied to determine the extent of OSA as well as the clinical correlates of the condition. OSA was defined as an apnea-hypopnea index (AHI) of > 5 events per hour.
Subjects completed an Epworth Sleepiness Scale (ESS) questionnaire and a Sleep Apnea Scale of Sleep Disorders Questionnaire (SA-SDQ) and underwent nocturnal polysomnography (NPSG). Pulmonary function tests (PFTs) were administered as well. Measurements included spirometry (FEV1 and FVC), total lung capacity by body box plethysmography, and diffusing capacity of the lung for carbon monoxide (DLCO).
Lancaster LH, Mason WR, Parnell JA, et al. Obstructive sleep apnea is common in idiopathic pulmonary fibrosis. Chest. 2009;136:
Lancaster LH, et al. Chest. 2009;136:

34. OSA Is Common in IPF Findings that did not correlate with OSA
Spirometry
Lung volume
DLCO
ESS
Findings that did correlate
with OSA
SA-SDQ: r = 0.45, P = 0.01
BMI: r = 0.30, P = 0.05
No OSA
AHI  5/h
12%
20%
68%
Mild
AHI 5–15/h
OSA Is Common in IPF
According to the threshold for apnea-hypopnea index (AHI) of > 5 events per hour, 44 of 50 subjects (88%) in this study had OSA. 10 subjects (20%) had mild OSA (AHI, 5 to 15 events per hour), and 34 subjects (68%) had moderate-to-severe OSA (AHI > 15 events per hour). In contrast, OSA is estimated to occur in approximately 20% of older adults.
In this study by Lancaster et al,1 no correlation was observed between PFTs or ESS and OSA. BMI showed a weak correlation (r = 0.30, P = 0.05), but the SA-SDQ showed a positive correlation (r = 0.45, P = 0.01). However, the specificity of this test was only 50%, limiting its usefulness as a screening tool.
Mermigkis et al2 found that rapid eye movement sleep AHI was correlated with total lung capacity (r = -0.38, P = 0.03). DLCO was correlated with mean oxygen saturation during sleep (r = 0.39, P = 0.02).
OSA is prevalent in patients with IPF and is underdiagnosed; formal sleep evaluation and polysomnography should be considered as part of the management strategy.
Lancaster LH, Mason WR, Parnell JA, et al. Obstructive sleep apnea is common in idiopathic pulmonary fibrosis. Chest. 2009;136:
Mermigkis C, Stagaki E, Tryfon S, et al. How common is sleep-disordered breathing in patients with idiopathic pulmonary fibrosis? Sleep Breath Mar 16. [Epub ahead of print]
Moderate/Severe
AHI > 15 events/h
AHI: apnea-hypopnea index
Lancaster LH, et al. Chest. 2009;136:

35. Sleep in IPF Patients OSA-hypopnea syndrome (OSAHS)
34 newly diagnosed IPF patients, therapy naive
Overnight polysomnography
An abnormal total AHI (> 5) in 59% of the included subjects
TLC might predispose IPF patients in sleep disordered breathing
P = 0.03, r = -0.38
Sleep in IPF Patients
This study assessed the frequency of obstructive sleep apnea–hypopnea syndrome (OSAHS) in newly diagnosed IPF patients and looked for possible correlations with BMI and PFTs. All 34 participants underwent overnight PSG. None of the included subjects were receiving IPF treatments or nocturnal supplemental oxygen therapy.
Most participants had normal or moderately impaired apnea–hypopnea index (AHI). REM AHI was correlated with total lung capacity (r = −0.38, P = 0.03). DLCO was correlated with mean oxygen saturation during sleep (r = 0.39,P = 0.02, data not shown).
Sleep-disordered breathing is common and underdiagnosed in IPF patients. A decrease in TLC, reflecting the severity of pulmonary restriction, might predispose IPF patients to sleep-disordered breathing, especially during the vulnerable REM period.
Sleep Breath Dec;14(4): doi: /s Epub 2010 Mar 16.
How common is sleep-disordered breathing in patients with idiopathic pulmonary fibrosis?
Mermigkis C1, Stagaki E, Tryfon S, Schiza S, Amfilochiou A, Polychronopoulos V, Panagou P, Galanis N, Kallianos A, Mermigkis D, Kopanakis A, Varouchakis G, Kapsimalis F, Bouros D.
Author information
Abstract
BACKGROUND AND AIM:
The frequency of obstructive sleep apnea-hypopnea syndrome (OSAHS) in patients with idiopathic pulmonary fibrosis (IPF) remains controversial. The aim of this study was to assess the frequency of OSAHS in newly diagnosed IPF patients and to identify possible correlations with body mass index and pulmonary function testing parameters.
MATERIALS AND METHODS:
Thirty-four newly diagnosed IPF patients were included. All subjects underwent attended overnight PSG. None of the included subjects was under any of the currently available IPF treatments or nocturnal supplemental oxygen therapy.
RESULTS:
Total apnea-hypopnea index (AHI) was <5, 5-15, and ≥ 15/h of sleep in 14 (41%), 15 (44%), and five patients (15%), respectively. REM AHI was statistically significant correlated with TLC [Total lung capacity] (p=0.03, r= -0.38). Diffusing capacity of the lung for carbon monoxide was correlated with mean oxygen saturation during sleep (p=0.02, r=0.39).
CONCLUSIONS:
Sleep-disordered breathing seems frequent, although remains usually under diagnosed in IPF patients. A decrease in TLC, reflecting the severity of pulmonary restriction, might predispose IPF patients in SDB, especially during the vulnerable REM sleep period.
Mermigkis C, Stagaki E, Tryfon S, et al. How common is sleep-disordered breathing in patients with idiopathic pulmonary fibrosis? Sleep Breath Mar 16. [Epub ahead of print].
TLC, % Predicted
REM AHI
Mermigkis C, et al. Sleep Breath. 2010;14(4):

36. Managing Sleep Caregiver should observe patient
Oxygen desaturation common with ILD, independent of OSA
Frequent awakening
Arrhythmia
MI more common during sleep
GERD: don’t eat just before sleep
ATS/ERS
There are no data on which to make recommendations for treatment of OSA in the setting of IPF.
Sleep
Sleep disturbances such as desaturation, obstructive sleep apnea (OSA), frequent awakening, and arrhythmia are common problems in patients with ILD, and sometimes can be recognized by a caregiver. Signs that should trigger further investigation include snoring, increased neck circumference, witnessed apneas, morning headaches, and daytime hypersomnolence. In a recent study, only 12% patients with IPF were free of OSA (apnea-hypopnea index  5 events/hour).1
A questionnaire can be a useful screening tool for discovering sleep disturbances. Examples are the Epworth Sleepiness Scale (ESS) or the Sleep Apnea scale of Sleep Disorders Questionnaire (SA-SDQ). If warranted, a sleep study may be useful in diagnosing the sleep problem.
Acid reflux can be exaggerated by prone or supine positions; avoiding food before sleep may be helpful.
Lancaster LH, Mason WR, Parnell JA, et al. Obstructive sleep apnea is common in idiopathic pulmonary fibrosis. Chest. 2009;136:

37. Cardiovascular Disease in IPF
Prevalence: 20% of IPF patients have comorbid CVD
CVD diagnosed during follow-up significantly increased mortality (HR 4.7)
Increased incidence of
ACS
Angina
DVT
CAD
CHF and CAD account for 1/3 deaths in IPF
Zisman et al. Am J Respir Crit Care Med. 2001;163:A713.
Hypothesis: Do fibrotic lung d/o predispose to CAD?
Cross-sectional study of patients referred for lung transplantation (630 patients)
Compared the prevalence of CAD between fibrotic and nonfibrotic d/o
Hyldgaard C, et al. Respir Med. 2014;108(4):
Hubbard RB, et al. Am J Respir Crit Care Med 2008; 178:
Izbicki G, et al. Respir Med. 2009; 103(9):

38. Odds Ratios for Risk Factors of CVD for Incident Cases of IPF
UK database: The Health Improvement Network (THIN)
Risk factor
Cases
(n=3211) (%)
Controls
(n=12,307)
(%)
Odds Ratio
(95% CI) P-
value*
Hypertension
25.6
21.3
1.31 ( )
<0.001
Diabetes
14.0
12.0
1.20 ( )
0.003
Ex-smoker
38.7
26.3
2.20 ( )
Current smoker
13.54
13.45
1.44 ( )
BMI > 31
15.1
13.3
1.16 ( )
Risk factors for cardiovascular disease in people with idiopathic pulmonary fibrosis: a
population based study
William Dalleywater (BMBS), 1 Helen A Powell (PhD),1,2 Richard B Hubbard (MD) ,1,2 Vidya
Navaratnam (PhD).1
Chest
Abstract
Rationale & Objective
People with idiopathic pulmonary fibrosis (IPF) have been shown to be at an increased risk
of cardiovascular disease but reasons for this are unknown. The aim of this study was to
compare the prevalence of common cardiovascular risk factors in people with IPF and the
general population and establish the incidence of ischaemic heart disease (IHD) and stroke
after the diagnosis of IPF, controlling for these risk factors.
Methods
We used data from a large United Kingdom primary care database to identify incident cases
of IPF and matched general population controls. We compared the prevalence of risk factors
for cardiovascular disease and prescription of cardiovascular medications in people with IPF
(before diagnosis) with general population controls, and assessed the incidence of IHD and
stroke in people with IPF (after diagnosis) compared to controls.
Results
We identified 3,211 cases of IPF and 12,307 controls. Cases with IPF were more likely to
have a record of hypertension (odds ratio [OR] 1.31, 95% confidence interval [CI]
1.44), and diabetes (OR 1.20, 95% CI ) compared with controls; they were also
more likely to have been prescribed several cardiovascular drugs. The rate of first time IHD
events was more than twice as high in cases compared to controls (rate ratio [RR] 2.32, 95%
CI ; p<0.001) but the incidence of stroke was only marginally higher (p=0.09). Rate
ratios for IHD and stroke were not altered substantially after adjusting for cardiovascular
risk factors.
Conclusion
Several cardiovascular risk factors were more prevalent in people with IPF; however this did
not account for the increased rate of IHD in this group of patients.
* Likelihood ratio test
Accessed August 2014.

39. Rate Ratios for Ischemic Heart Disease and Stroke IPF vs Control Subjects
Outcome #
events
in cases
Crude
rate in
cases
(per 1000
pyrs) in
controls
Rate Ratio P-
value*
IHD
135
17.6
474
9.9
2.32
< 0.001
Stroke 87
11.3
523
10.3
1.25
0.09
Risk factors for cardiovascular disease in people with idiopathic pulmonary fibrosis: a
population based study
William Dalleywater (BMBS), 1 Helen A Powell (PhD),1,2 Richard B Hubbard (MD) ,1,2 Vidya
Navaratnam (PhD).1
Chest
Abstract
Rationale & Objective
People with idiopathic pulmonary fibrosis (IPF) have been shown to be at an increased risk
of cardiovascular disease but reasons for this are unknown. The aim of this study was to
compare the prevalence of common cardiovascular risk factors in people with IPF and the
general population and establish the incidence of ischaemic heart disease (IHD) and stroke
after the diagnosis of IPF, controlling for these risk factors.
Methods
We used data from a large United Kingdom primary care database to identify incident cases
of IPF and matched general population controls. We compared the prevalence of risk factors
for cardiovascular disease and prescription of cardiovascular medications in people with IPF
(before diagnosis) with general population controls, and assessed the incidence of IHD and
stroke in people with IPF (after diagnosis) compared to controls.
Results
We identified 3,211 cases of IPF and 12,307 controls. Cases with IPF were more likely to
have a record of hypertension (odds ratio [OR] 1.31, 95% confidence interval [CI]
1.44), and diabetes (OR 1.20, 95% CI ) compared with controls; they were also
more likely to have been prescribed several cardiovascular drugs. The rate of first time IHD
events was more than twice as high in cases compared to controls (rate ratio [RR] 2.32, 95%
CI ; p<0.001) but the incidence of stroke was only marginally higher (p=0.09). Rate
ratios for IHD and stroke were not altered substantially after adjusting for cardiovascular
risk factors.
Conclusion
Several cardiovascular risk factors were more prevalent in people with IPF; however this did
not account for the increased rate of IHD in this group of patients.
* Likelihood ratio test
Accessed August 2014.

40. Cumulative Incidence of IHD is Higher With IPF
Risk factors for cardiovascular disease in people with idiopathic pulmonary fibrosis: a
population based study
William Dalleywater (BMBS), 1 Helen A Powell (PhD),1,2 Richard B Hubbard (MD) ,1,2 Vidya
Navaratnam (PhD).1
Chest
Abstract
Rationale & Objective
People with idiopathic pulmonary fibrosis (IPF) have been shown to be at an increased risk
of cardiovascular disease but reasons for this are unknown. The aim of this study was to
compare the prevalence of common cardiovascular risk factors in people with IPF and the
general population and establish the incidence of ischaemic heart disease (IHD) and stroke
after the diagnosis of IPF, controlling for these risk factors.
Methods
We used data from a large United Kingdom primary care database to identify incident cases
of IPF and matched general population controls. We compared the prevalence of risk factors
for cardiovascular disease and prescription of cardiovascular medications in people with IPF
(before diagnosis) with general population controls, and assessed the incidence of IHD and
stroke in people with IPF (after diagnosis) compared to controls.
Results
We identified 3,211 cases of IPF and 12,307 controls. Cases with IPF were more likely to
have a record of hypertension (odds ratio [OR] 1.31, 95% confidence interval [CI]
1.44), and diabetes (OR 1.20, 95% CI ) compared with controls; they were also
more likely to have been prescribed several cardiovascular drugs. The rate of first time IHD
events was more than twice as high in cases compared to controls (rate ratio [RR] 2.32, 95%
CI ; p<0.001) but the incidence of stroke was only marginally higher (p=0.09). Rate
ratios for IHD and stroke were not altered substantially after adjusting for cardiovascular
risk factors.
Conclusion
Several cardiovascular risk factors were more prevalent in people with IPF; however this did
not account for the increased rate of IHD in this group of patients.
Accessed August 2014.

41. Influence of CAD on IPF Mortality
Prevalence and impact of coronary artery disease in idiopathic pulmonary fibrosis.
Nathan SD1, Basavaraj A, Reichner C, Shlobin OA, Ahmad S, Kiernan J, Burton N, Barnett SD.
Respir Med Jul;104(7): doi: /j.rmed Epub 2010 Mar 2.
Abstract
INTRODUCTION:
Idiopathic Pulmonary Fibrosis (IPF) is a progressive disease with a poor prognosis for which there is no effective medical therapy. An awareness of comorbidities that are treatable and might impact outcomes in these patients is therefore very important. We sought to determine the prevalence of coronary artery disease (CAD) in IPF patients in comparison to a control group of patients with chronic obstructive pulmonary disease (COPD). We also sought to assess the impact of CAD on IPF patient outcomes.
PATIENTS AND METHODS:
IPF and COPD transplant candidates whose work-up included left heart catheterization were categorized as having significant CAD, non-significant CAD or no disease. The risk factor profile and prevalence of CAD in both groups was compared.
RESULTS:
There were 73 IPF and 56 COPD patients. The prevalence of CAD was 65.8% in the IPF group compared to 46.1% in the COPD patients (p<0.028). Significant disease was present in 28.8% of IPF patients vs.16.1% of the COPD patients (p<0.081). Unsuspected significant CAD was found in 18% of IPF patients versus 10.9% of COPD patients (p<0.004). Outcomes of IPF patients with significant CAD was worse than those with no or non-significant disease (p<0.003) with a median survival of 572 days from the time of left heart catheterization.
CONCLUSION:
There is a higher prevalence of CAD in IPF patients compared to a similarly matched COPD group. This increased association appeared to be independent of common coronary artery risk factors. IPF patients with significant CAD appear to have worse outcomes
Nathan SN, et al. Respir Med. 2010:104:

42. VTE is Elevated in Patients With IPF
National Center for Health Statistics, 1988–2007
46,450,489 total records
218,991 patients with IPF
3815 (1.74%) also diagnosed with VTE
Increased risk of IPF 
VTE decreased life span of patients with IPF
Data suggest a link between a pro-fibrotic and a pro-coagulant state
Eur Respir J Jan;39(1): doi: / Epub 2011 Jul 7.
Pulmonary fibrosis is associated with an elevated risk of thromboembolic disease.
Sprunger DB1, Olson AL, Huie TJ, Fernandez-Perez ER, Fischer A, Solomon JJ, Brown KK, Swigris JJ.
Author information
Abstract
Recent epidemiological studies have suggested an increased risk of venous thromboembolism (VTE) in lung fibrosis. Large-scale epidemiological data regarding the risk of VTE in pulmonary fibrosis-associated mortality have not been published. Using data from the National Center for Health Statistics from , we determined the risk of VTE in decedents with pulmonary fibrosis in the USA. We analysed 46,450,489 records, of which 218,991 met our criteria for idiopathic pulmonary fibrosis. Among these, 3,815 (1.74%) records also contained a diagnostic code for VTE. The risk of VTE in pulmonary fibrosis decedents was 34% higher than in the background population, and 44% and 54% greater than among decedents with chronic obstructive pulmonary disease and lung cancer, respectively. Those with VTE and pulmonary fibrosis died at a younger age than those with pulmonary fibrosis alone (females: 74.3 versus 77.4 yrs (p<0.0001); males: 72.0 versus 74.4 yrs (p<0.0001)). Decedents with pulmonary fibrosis had a significantly greater risk of VTE. Those with VTE and pulmonary fibrosis died at a younger age than those with pulmonary fibrosis alone. These data suggest a link between a pro-fibrotic and a pro-coagulant state.
Sprunger DB, et al. Eur Respir J. 2012;39(1):

43. VTE is Associated with ILD
Danish registry study, records
7.4 million individuals
Conclusion: In the general population, ever-diagnosed VTE was associated with ILD, particularly among those never treated with anticoagulants
Am J Respir Crit Care Med May 15;181(10): doi: /rccm OC. Epub 2010 Feb 18.
Venous thromboembolism and risk of idiopathic interstitial pneumonia: a nationwide study.
Sode BF1, Dahl M, Nielsen SF, Nordestgaard BG.
Author information
Abstract
RATIONALE:
Idiopathic interstitial pneumonia is characterized by pulmonary fibrosis and high mortality.
OBJECTIVES:
We examined the association between ever-diagnosed venous thromboembolism and risk of incident idiopathic interstitial pneumonia. Venous thromboembolism was taken as a proxy for a procoagulant state in an individual.
METHODS:
We conducted a study of the entire Danish population from 1980 through 2007, comprising 7.4 million individuals. Incident idiopathic interstitial pneumonia, ever-diagnosed venous thromboembolism, and use of prescription anticoagulants were drawn from national Danish registries.
MEASUREMENTS AND MAIN RESULTS:
Age-standardized incidence rates per 10,000 person-years for idiopathic interstitial pneumonia were higher among those ever diagnosed with venous thromboembolism (1.8; n = 158,676), pulmonary embolism (2.8; n = 70,586), and deep venous thrombosis only (1.2; n = 88,090), than among control subjects (0.8; n = 7,260,278). Multivariate-adjusted hazard ratios for idiopathic interstitial pneumonia were 1.8 (95% confidence interval [CI], ) in those ever diagnosed with venous thromboembolism, 2.4 (95% CI, ) in those ever diagnosed with pulmonary embolism, and 1.3 (95% CI, ) in those ever diagnosed with deep venous thrombosis only, compared with control subjects. Corresponding hazard ratios in those ever diagnosed with venous thromboembolism stratified in those ever and never treated with anticoagulants were 1.4 (95% CI, ) and 2.8 (95% CI, ) (venous thromboembolism x anticoagulation use interaction on idiopathic interstitial pneumonia outcome: P = 1.5 x 10(-10)).
CONCLUSIONS:
In the general population, ever-diagnosed venous thromboembolism was associated with idiopathic interstitial pneumonia, particularly among those never treated with anticoagulants.
Sode BF, et al. Am J Respir Crit Care Med. 2010;181(10):

44. Depression in IPF Observed in ~25% of patients with IPF
9.8% in a general population of elderly subjects
26% in patients with COPD
Correlated strongly and independently with
dyspnea
pain
sleep quality
FVC
Baseline depression score was the strongest predictor of depression score at 6 months (r = 0.59, P < )
Respirology Apr;17(3): doi: /j x.
Depression is a common and chronic comorbidity in patients with interstitial lung disease.
Ryerson CJ1, Arean PA, Berkeley J, Carrieri-Kohlman VL, Pantilat SZ, Landefeld CS, Collard HR.
Author information
Abstract
BACKGROUND AND OBJECTIVE:
Little is known about depression in interstitial lung disease (ILD). The aim of this study was to determine the prevalence of depression, characterize the association of depression with clinical variables and describe the natural history of depression in patients with ILD.
METHODS:
In this prospective cohort study, clinical variables were recorded at baseline and 6 months. Depression was measured with the Centre for Epidemiologic Studies Depression scale. Depression prevalence was determined using the established threshold of >15 points. Multivariate linear regression was used to determine the baseline features that independently correlated with baseline depression score and that predicted depression severity at follow-up.
RESULTS:
Fifty-two subjects were enrolled, and 45 returned for follow-up (three deaths, one lung transplant). Prevalence of depression was 21% at baseline. Independent predictors of depressive symptoms at baseline included dyspnoea severity, pain severity, sleep quality and forced vital capacity (R(2) 0.67). The odds of clinically meaningful depression at follow-up were 34-fold higher for subjects who had clinically meaningful depression at baseline compared with those who were not (95% confidence interval , P < ). Baseline depression score was the strongest predictor of depression score at follow-up (r 0.59, P < ).
CONCLUSIONS:
Depressive symptoms in ILD are common, persistent, and strongly and independently correlated with dyspnoea, pain, sleep quality and forced vital capacity. Clinically meaningful depression at baseline is the most important predictor of depressive symptoms at follow-up. Patients with ILD should routinely be screened for depression
Ryerson CJ, et al. Respirology ;17(3):

45. Correlation of Dyspnea with Depression
All patients (N = 52, r = 0.50; P = )
Patients with IPF (n = 20, r = 0.57; P = 0.009)
UCSD SOBQ Score (increasing dyspnea)
Chest Mar;139(3): doi: /chest Epub 2010 Aug 5.
Depression and functional status are strongly associated with dyspnea in interstitial lung disease.
Ryerson CJ1, Berkeley J, Carrieri-Kohlman VL, Pantilat SZ, Landefeld CS, Collard HR.
Author information
Abstract
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.
● Non-IPF
o IPF
Depression Score
Ryerson CJ, et al. Chest. 2011;139(3):

46. Proposed Study: CaNoPy
UK mixed-methods cross-sectional study of care
Interviews
Interpretative Phenomenological Analysis
Validated patient questionnaires
Quality of life (EQ-5D)
Depression (Hospital Anxiety and Depression Scale)
Breathlessness (Borg dyspnea scale)
Cough (Leicester Cough Questionnaire, Cough Symptom Score)
BMJ Open Aug 7;3(8). pii: e doi: /bmjopen
A mixed-methods study of the Care Needs of individuals with idiopathic Pulmonary fibrosis and their carers--CaNoPy: a study protocol.
Byrne A1, Sampson C, Baillie J, Harrison K, Hope-Gill B, Hubbard R, Griffiths G, Nelson A.
Author information
Abstract
INTRODUCTION:
Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening illness of unknown aetiology, with no proven pharmacological treatments. There is a limited evidence base indicating that the disease negatively affects quality of life, leading to increased dependence, restrictions on daily activities and fatigue. However, there is a paucity of in-depth information on disease impact across its trajectory, particularly in relation to unmet needs, outcomes of importance to patients and the experiences of carers. Furthermore, little is known about the support and information needs of individuals and their carers, or at what point individual need should trigger a referral to palliative care services.
METHODS AND ANALYSIS:
A mixed-methods study is proposed recruiting individuals with IPF at different stages of the disease and their carers from three respiratory centres in England and Wales. In-depth interviews will be undertaken with participants, adopting an Interpretative Phenomenological Analysis approach. The study will also use validated questionnaires to explore quality of life (EQ-5D), depression (Hospital Anxiety and Depression Scale), breathlessness (Borg dyspnoea scale) and cough (Leicester Cough Questionnaire, Cough Symptom Score).
ETHICS AND DISSEMINATION:
Ethical approvals were gained in April Palliative care research is a developing field, but there has been limited focus on IPF. We anticipate that the results of the study will enable healthcare professionals to provide appropriate palliative care across the trajectory for individuals with the disease, and their carers, and we therefore aim to disseminate via relevant respiratory and palliative care journals and conferences. We will also support the lay representative involved in the project to disseminate the findings to patient groups.
Byrne A, et al.BMJ Open Aug 7;3(8). pii: e

47. Conclusions
Comorbidities associated with IPF such as GERD, CPFE, CVD, sleep apnea, and depression should be treated
Clinical trials testing drugs approved for pulmonary hypertension in patients with IPF and PH have been negative on IPF endpoints
Other endpoints have been positive
Guidelines recommend against treating IPF patients for PH
Acute exacerbation is a serious complication of IPF
Take Home Messages
No pharmacologic therapy for IPF has been shown to be effective, but several phase 3 trials are under way. No drug has been approved by the FDA for the treatment of patients with IPF, so clinical trials are critical both for patients and for advancing the state of knowledge.
Disease management is crucial for patients with IPF, and it encompasses many approaches such as pulmonary rehabilitation, managing comorbidities, supplemental oxygen, and social/psychological support.
Lung transplantation can prolong survival; early evaluation and listing as a candidate are important. Controversy still exists regarding single vs bilateral transplantation, age limitations for transplant candidacy, and the advisability of esophageal wraps in conjunction with transplantation surgery.