Comorbidities in Idiopathic Pulmonary Fibrosis: A Clinical Resource GuideA CME/CE-certified supplement to CHEST® Physician

2 / COMORBIDITIES IN IDIOPATHIC PULMONARY FIBROSIS: A CLINICAL RESOURCE GUIDE

Comorbidities in Idiopathic Pulmonary Fibrosis: A Clinical Resource Guide

Table of ContentsLearning Objectives ................................... 3

Introduction ............................................. 3

Pulmonary Comorbidities ............................ 3

Pulmonary hypertension ..........................................3

Sleep disorders ......................................................3

Pneumonia ............................................................4

Venous thromboembolism and pulmonary embolism ...4

Lung cancer ...........................................................4

Emphysema ...........................................................4

Extrapulmonary Comorbidities ..................... 4

GERD and hiatal hernia ........................................4

Cardiovascular disease ............................................5

Diabetes mellitus ....................................................5

Depression and anxiety ...........................................6

Short telomere syndrome ........................................6

Resources and Websites ............................. 6

Conclusion ................................................ 7

References ............................................... 7

Timothy Blackwell, MDRalph and Lulu Owen Professor of MedicineProfessor of Cell, Developmental Biology and Cancer BiologyDirector, Division of Allergy, Pulmonary and Critical Care Vanderbilt University Medical CenterNashville, Tennessee

Faculty

This activity is supported by an independent educational grant from Boehringer Ingelheim.

Jointly provided by

Neither the editors of CHEST® Physician nor the Editorial Advisory Board nor the reporting staff contributed to its content. The ideas and opinions expressed are those of the faculty and do not necessarily reflect the views of the supporters, American College of Chest Physicians (CHEST®), Global Academy for Medical Education, Postgraduate Institute for Medicine, or the Publisher.

This activity is not an official program of the American College of Chest Physicians (CHEST®), and, accordingly, is not accredited by CHEST®.

A CME/CE-certified supplement to CHEST® Physician

Original Release Date: March 15, 2019 Expiration Date: March 15, 2020 Estimated Time to Complete Activity: 45 minutes Media: PublicationTarget AudienceThis activity has been designed to meet the educational needs of pulmonologists, radiologists, pathologists, primary care physicians, PAs, nurse practitioners, nurses, and other healthcare profes-sionals who care for patients with idiopathic pulmonary fibrosis (IPF).Learning ObjectivesUpon completing this activity, the participant should be better able to: • Describe comorbidities commonly occurring in IPF patients • Apply strategies to diagnose comorbidities in IPF patients• Employ best practices for engaging other members of the healthcare team when managing

comorbidities• Review optimal treatment approaches to comorbidities in IPF patients• Apply strategies to engage patients in shared decision-making regarding the management of

their comorbidities and IPF careCredit AvailablePhysicians — maximum of 0.75 AMA PRA Category 1 Credit™ All other healthcare professionals completing this course will be issued a statement of participation.Joint Accreditation Statement

In support of improving patient care, this activity has been planned and imple-mented by the Postgraduate Institute for Medicine and Catamount Medical Education. Postgraduate Institute for Medicine is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing

Center (ANCC), to provide continuing education for the healthcare team.

The Postgraduate Institute for Medicine designates this enduring material for a maximum of 0.75 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.Disclosure of Conflicts of Interest The Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers, and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to PIM policy. PIM is committed to providing its learners with high quality activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest.Timothy Blackwell, MD: Contracted Research: Boehringer Ingelheim, CelgenePlanners and Managers: PIM planners and managers have nothing to disclose. Catamount Medical Education planners and managers have nothing to disclose. Instructions for Participation and CreditThere are no fees for participating and receiving CME/CE credit for this activity. During the period March 15, 2019 through March 15, 2020, participants must read the learning objectives and faculty disclosures and study the educational activity. If you wish to receive acknowledgment for completing this activity, please complete the post-test and evaluation on www.cmeuniversity.com. Access the site directly or scan the bar code on the back of this publication. On the navigation menu, click on “Find Post-test/Evaluation by Course” and search by course ID 13651. Upon registering and successfully completing the post-test with a score of 80% or better and the activity evaluation, your certificate will be made available immediately. DISCLOSURE OF UNLABELED USEThis educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contrain-dications, and warnings. DISCLAIMERSParticipants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clini-cians without evaluation of their patient‘s conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer‘s product information, and comparison with recom-mendations of other authorities.CHEST® Physician is pleased to distribute this informational resource for pulmonary, critical care, and sleep medicine physicians; cardiothoracic surgeons; cardiovascular surgeons; and cardiologists, but this distribution does not convey endorsement and is not intended to replace professional medical care and physician advice, which always should be sought for any specific condition. CHEST and its officers, regents, members, and employees disclaim all liability for the accuracy or completeness of the content and disclaim all warranties, express or implied.

Copyright © 2019 by Global Academy for Medical Education, LLC, Frontline Medical Communications Inc., and its Licensors. All rights reserved. No part of this publication may be reproduced or transmitted in any form, by any means, without prior written permission of the Publisher. Global Academy for Medical Education, LLC and Frontline Medical Communications will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein.

COMORBIDITIES IN IDIOPATHIC PULMONARY FIBROSIS: A CLINICAL RESOURCE GUIDE / 3

Pulmonary hypertensionPulmonary hypertension (PH) is defined as mean arterial pressures (mPAP) at rest of 25 mm Hg or more, confirmed by right heart catherization.9 An estimated 10% of patients with IPF have mPAP values above 25 mm Hg at diagnosis, and 30% to 50% of patients with advanced IPF show evidence of PH.8,10 In patients with IPF, PH is associated with reduced survival, impaired quality of life, lower exercise tolerance, and increased need for supplemental oxygen.1,10,11

Most of the symptoms of IPF overlap with those of PH, which makes it difficult to diagnose PH in patients with IPF.12 Signs of PH include accentuated pulmonary heart sound, tricuspid regurgitation murmur, and fixed splitting of the second heart sound.12 While some changes may be evident on cardiac CT, echocardiogram, or ECG, definitive diagnosis of PH requires right heart catherization.12 A study of 135 patients with IPF, 73 of whom also had PH, showed that the best noninvasive predictors of PH were ventilatory efficiency for CO2 (expressed as the relationship between minute ventilation [VE] and carbon dioxide output [VCO2]) and peak oxygen uptake during exercise.11

Practice Pearl: Although there have been several trials investigating pharmacotherapies for PH in IPF, there is not enough evidence to

recommend PH-targeted treatment at this time.8

Sleep disordersMost patients with IPF have reduced sleep quality, with up to 65% of patients with IPF having moderate to severe obstructive sleep apnea (OSA).7,13 Severity of OSA correlates with the extent of fibrosis in IPF.7 Nocturnal oxygen desaturation is also common in IPF, can occur in the absence of OSA, and negatively correlates with survival.1,14

Disordered sleep architecture is also seen in patients with IPF, including disturbances in sleep stage distribution, multiple awakenings, reduced total sleep time, and more sleep micro-arousals resulting in sleep fragmentation.15

A study of 77 patients with IPF responding to question-naires showed that 15% had measurable symptoms of sleepiness, and 45% of patients had symptoms of fatigue.16 In this cohort, increasing symptoms of dys-pnea were associated with increasing fatigue.16

Pulmonary Comorbidities

Introduction Most patients with idiopathic pulmonary fibrosis (IPF) have at least one comorbid condition involving the lungs (pulmonary comorbidities) or other organs (extrapulmonary comorbidities) that affects disease outcome and/or quality of life.1 While reported rates vary widely, important pulmonary comorbidities include pulmonary hypertension, sleep apnea, pneumonia, pulmonary embolism, and lung cancer. Extrapulmonary comorbidities include gastroesophageal reflux disease, diabetes, and anxiety/depression.1-3 In addition, growing evidence suggests that both familial and sporadic IPF can be caused by mutations in telomerase genes, and that patients with these forms of IPF may be at risk for liver disease, bone marrow failure, and cancer involving the lungs and other organs.4-6

Comorbidities in IPF can have a significant impact on patients by adding physiologic and symptomatic effects to the already challenging burden of IPF.1,7 Identifying and managing comorbidities may improve the physical condition and quality of life of patients with this chronic, progressive disease.1,8 This concise resource guide highlights some key pulmonary and extrapulmonary conditions that commonly co-occur with IPF and provides sources of additional information about these and other clinically relevant comorbidities.

Learning Objectives• Describe comorbidities commonly occurring in IPF patients • Apply strategies to diagnose comorbidities in IPF patients• Employ best practices for engaging other members of the

healthcare team when managing comorbidities

• Review optimal treatment approaches to comorbidities in IPF patients

• Apply strategies to engage patients in shared decision-making regarding the management of their comorbidities and IPF care

4 / COMORBIDITIES IN IDIOPATHIC PULMONARY FIBROSIS: A CLINICAL RESOURCE GUIDE

Practice Pearl: It is reasonable to screen all patients with IPF for sleep disorders, including OSA, given the high prevalence in IPF and the

improvements in sleep quality and quality of life that are possible with treatment.7 The preferred method of establishing a diagnosis is through polysomnography, but a combination of overnight oximetry and a trial of continuous positive airway pressure (CPAP) therapy may be useful when polysomnography is not available.7

CPAP therapy is the mainstay of treatment for OSA and confers significant benefits to patients.7 Preferably, CPAP therapy should be introduced as early as possible in the disease course to increase acceptance of the therapy. The addition of heated humidification to standard CPAP therapy can also help increase adherence.15 Supplemental oxygen is the preferred treatment for nocturnal hypoxemia without OSA.1

PneumoniaInfection is common in patients with IPF, and the 30-day mortality rate in those hospitalized for infection was reported to be 14.5%, at least twice the rate for hospitalization associated with community-acquired pneumonia in the general population.17 In addition, it is estimated that approximately 20% to 50% of acute exacerbations of IPF result from pulmonary infection, which sometimes goes undiagnosed.18 Although infection in patients with IPF is difficult to diagnose, bronchoscopy should be considered.17,18

Practice Pearl: Measures to prevent infection are important in patients with IPF, including influenza and pneumococcal vaccinations.

Venous thromboembolism and pulmonary embolismA review of death certificates revealed that venous thromboembolism (VTE) contributed to 1.74% of all deaths in patients with IPF in the United States over a 20-year period, which is 34% higher than in the general population and approximately 50% higher than in patients with chronic obstructive pulmonary disease (COPD) or lung cancer.7

Practice Pearl: Although VTE is challenging to diagnose in patients with IPF, as it has a nonspecific presentation in this population, this

diagnosis should be considered in IPF cases with subacute worsening or acute exacerbation.7,8 Currently, CT scanning with contrast is the most common method to identify pulmonary embolism.7

Patients with IPF who have VTE are typically managed by guideline-directed therapy for VTE in the general

population.7,19 Routine use of warfarin is not currently recommended because of a lack of benefit and an increased mortality seen in a randomized controlled trial in patients with progressive IPF and no other indication for anticoagulation therapy.7

Lung cancerThe prevalence of lung cancer in patients with IPF is 5% to 10%, representing an approximately 7-fold increased risk compared with the general population.8

Pulmonary fibrosis is an independent risk factor for developing lung cancer, even after controlling for shared risk factors such as cigarette smoking.1 Lung cancer in IPF is associated with reduced survival.20

Practice Pearl: While symptoms of lung cancer in patients with IPF are often nonspecific, signs and symptoms such as hemoptysis and weight

loss suggest a need for further evaluation.7 There is some rationale for lung cancer screening in patients with IPF, especially if the presence of lung cancer would affect a treatment or management plan for IPF.7

Treating lung cancer in IPF is challenging, in part because of the increased risk of acute exacerbations associated with surgical resection, radiation therapy, or chemotherapy.8 Lung cancer in IPF should be managed on a case-by-case basis, considering the likelihood of cure or palliative effect against the possibility of complications, and taking into account the overall prognosis of IPF.7

EmphysemaAlthough emphysema and lung fibrosis are distinct pathological conditions, there is evidence that emphysema may be present in the lungs of >30% of patients with IPF.21 The co-occurrence of emphysema and IPF, which has been labeled “combined pulmonary fibrosis and emphysema (CPFE),” creates challenges in diagnosis and management.22 The presence of CPFE has been associated with poor prognosis; however, it is unclear whether any specific therapies are beneficial in this condition.22 This interesting and complex topic has been covered extensively elsewhere.1,7,8,22,23

Extrapulmonary ComorbiditiesGERD and hiatal herniaApproximately 75% of patients with IPF have evidence of gastroesophageal reflux disease (GERD), however these patients do not always report typical symptoms.8,24 GERD is a known cause of chronic cough in IPF.24 Approximately one-third of patients with IPF have a hiatal hernia, which may be a cause of GERD.7,25

COMORBIDITIES IN IDIOPATHIC PULMONARY FIBROSIS: A CLINICAL RESOURCE GUIDE / 5

The first step in evaluating a patient for GERD is a comprehensive gastrointestinal history.1 Esophageal manometry and 24-hour pH monitoring can identify GERD, though there are no clear-cut guidelines on when to use the tests.1 Barium swallow studies do not perform well in IPF to identify GERD. Additionally, 24-hour pH monitoring is not sensitive to non-acid reflux.1 Hiatal hernia can be identified on CT scans.26

Practice Pearl: Guidelines recommend the routine use of antacid therapy in most patients with IPF, and this therapy can be initiated on

the basis of the presence of GERD symptoms alone.1,27 For asymptomatic patients with GERD, clinicians and patients should discuss the potential benefits and risks of antacid therapy.1

For patients whose symptoms are refractory to antireflux therapy, surgical correction of a hiatal hernia should be considered.26 Results from a phase 2 randomized, controlled trial showed that laparoscopic antireflux surgery is safe and well tolerated in patients with IPF, with trends toward reduced respiratory-related hospitalization and death.28

Cardiovascular diseaseCongestive heart failure occurs in approximately 5% to 25% of patients with IPF.1 Patients with IPF are 1.5 to 2 times more likely to have coronary artery disease (CAD) compared with patients with nonfibrotic lung diseases.12 An estimated 30% to 65% of patients with IPF have CAD, depending on the severity of their IPF.12 CAD in IPF is associated with an almost 3-fold

increased risk of death compared with patients with IPF who do not have CAD.29

In a retrospective study of medical records, more than 3000 patients with IPF were significantly more likely to be prescribed cardiovascular drugs (eg, ACE inhibitors, angiotensin II receptor antagonists, digoxin, antiplatelet agents, lipid lowering agents) than the matched control group.30 Cardiovascular comorbidities can significantly reduce the survival and outcomes of patients with IPF who undergo lung transplantation.12

Treatment of CAD in IPF is challenging because of the morbidity and mortality of the underlying IPF, as well as higher risks of more invasive CAD therapies in IPF patients with poor functional capacity and respiratory status.7

Practice Pearl: Standard medical therapies for CAD are appropriate in IPF, but clinicians should consider the long-term implications of drug-

eluting stents on possible lung transplantation in IPF.7

Diabetes mellitusIn a retrospective study of medical records for more than 3000 patients with IPF, this group was 20% more likely than the matched control group to have diabetes mellitus before their IPF diagnosis.30 In a study of 121 patients with IPF, the presence of diabetes mellitus at IPF diagnosis was significantly associated with a decrease in survival, which persisted after adjusting for age, gender, and forced vital capacity (FVC).2 The explanation for the association between IPF and diabetes is uncertain.

As a result of the physical limitations of IPF and/or comorbid conditions such as cardiovascular diseases, many patients with IPF limit their physical activity and become deconditioned.31 Pulmonary rehabilitation aims to restore some of the lost cardiopulmonary capacity and improve the ability to perform tasks of daily living.32 Pulmonary rehabilitation in patients with IPF should use approaches tailored to the patient population, taking into consideration rapid occurrence of hypoxemia during exercise, limiting dyspnea, and skeletal muscle dysfunction as a result of tissue hypoxia and systemic oxidative stress.31

Pulmonary rehabilitation consists of a regular exercise program, patient education, and behavioral change, and is usually performed over 6 to 12 weeks on an outpatient basis.32,33 A recent systematic review examined the outcomes of pulmonary rehabilitation from randomized controlled trials in interstitial lung disease (ILD).33 The analysis favored pulmonary rehabilitation, with a mean difference in the 5-minute walk distance of 44.3 m compared with no/sham pulmonary rehabilitation.34 Pulmonary rehabilitation also resulted in superior outcomes in peak VO2, dyspnea, and quality of life in ILD patients, including the IPF subgroup.33 Though the pooled data analyzed a relatively small number of patients, pulmonary rehabilitation appears to provide benefit and should be considered as a therapeutic option for all patients with IPF, as there appear to be very few adverse effects associated with it.32 Pulmonary rehabilitation is also associated with improvements in depressive symptoms.1

Pulmonary rehabilitation

6 / COMORBIDITIES IN IDIOPATHIC PULMONARY FIBROSIS: A CLINICAL RESOURCE GUIDE

As there are no specific guidelines to treat diabetes in patients with IPF, clinicians should consult the diabetes clinical practice guidelines for the general population.35,36

Practice Pearl: Recent preclinical studies showing efficacy of metformin in reducing fibrosis in an animal model of lung fibrosis

suggest that using this drug to address diabetes in a patient with IPF could have salutary effects on progression of IPF.34,37 Despite these intriguing data, a large-scale clinical trial of metformin in IPF is required before strongly advocating this approach.

Depression and anxietyA study of 77 patients with IPF reporting their symptoms on questionnaires showed that almost 30% of patients had symptoms of anxiety on the Hospital Anxiety and Depression Scale-Anxiety (HADS-A), and 14% had symptoms of depression on the HADS-Depression.16 In another study of 118 patients with IPF, symptoms of depression were reported by 49% of patients as measured by the Wakefield Self-assessment of Depression Inventory.38

Available data suggest that depression and anxiety in IPF persist and may worsen over time. Over 12 months of follow-up, approximately 20% of patients with IPF showed persistent anxiety, and 14% of patients showed persistent depression; approximately half of these patients had wors-ening symptoms over this period.39

Approximately 75% to 85% of patients with IPF who show symptoms of anxiety or depression are undiagnosed or untreated.38,39 Across several studies, depression and anxiety were associated with increased dyspnea in IPF.7 Depression symptoms are negatively correlated with health-related quality of life in IPF.40

Practice Pearl: Because of the high prevalence, persistence of symptoms, and effect on disease severity and quality of life, patients with IPF should

be routinely screened for depression and anxiety.7

Few studies have specifically examined treatment for depression or anxiety in IPF. Cognitive behavioral therapy is effective at reducing symptoms of anxiety and depression in patients with COPD, and is therefore a reasonable therapeutic option in IPF.7 Antidepressant medications improve symptoms of depression in patients with chronic physical conditions, including COPD; however, data on treating anxiety in IPF are lacking.7

Short telomere syndromeIn adults, the short telomere syndrome (STS) can present with some combination of premature graying, IPF, liver disease (particularly cryptogenic cirrhosis), bone

marrow disease (macrocytosis, cytopenias, bone marrow hypoplasia or aplasia, myelodysplastic syndromes, acute myeloid leukemia), or cancer.4 STS typically results from a loss-of-function mutation in a gene encoding components of the telomerase pathway.5

Although the association between telomere pathway mutations and IPF was first reported in familial IPF and is currently thought to account for approximately 20% of familial IPF cases, as many as 10% of sporadic IPF patients may also harbor a telomerase pathway mutation.41,42 In addition, short telomeres (below the 10th percentile in length, adjusted for age) can be found in peripheral blood mononuclear cells from many IPF patients without detectable mutations in telomerase genes.4 Patients with IPF and telomerase pathway mutations have more rapid disease progression, reduced survival, and may have more complications after lung transplantation than those without telomerase pathway mutations.6

Practice Pearl: Clinicians should take a complete medical and family history when evaluating a patient with IPF, including evaluating for the

presence of ILD in other family members, and for a personal or family history of liver cirrhosis, bone marrow disease, premature graying, or cancer. The presence of these disease manifestations should raise suspicion for STS resulting from a telomerase mutation.

Genetic testing for telomerase pathway mutations is currently available from a number of clinical laboratories, and telomere length testing from peripheral blood is commercially available. Suspicion for the presence of STS should prompt consideration of referral to a specialized ILD center.43

Resources and WebsitesAmerican Thoracic Society – Sleep and Respiratory Neurobiology Journal Club/Webinar, https://www.thoracic.org/members/assemblies/assemblies/srn/journal-club/index.phpPulmonary Fibrosis Foundation, https://www.pulmonaryfibrosis.org/medical-community 2015 Clinical Practice Guidelines for IPF from the American Thoracic Society, the European Respiratory Society, the Japanese Respiratory Society, and the Latin American Thoracic Association; https://www.atsjournals.org/doi/10.1164/rccm.201506-1063ST(For Patients) – American Lung Association – Coping with stress and emotions from pulmonary fibrosis, http://www.lung.org/lung-health-and-diseases/lung-disease-lookup/pulmonary-fibrosis/patients/living-well-with-pulmonary-fibrosis/coping-with-stress-and-emotions.html(For Patients) Patients Like Me – Pulmonary fibrosis, https://www.patientslikeme.com/conditions/1954-pulmonary-fibrosis(For Patients) Action for Pulmonary Fibrosis – Living with pulmonary fibrosis, https://www.actionpulmonaryfibrosis.org/living-with-pulmonary-fibrosis/

1. King CS, Nathan SD. Idiopathic pulmonary fibrosis: effects and optimal management of comorbidities. Lancet Respir Med. 2017;5:72-84.

2. Hyldgaard C, Hilberg O, Bendstrup E. How does comorbidity influence survival in idiopathic pulmo-nary fibrosis? Respir Med. 2014;108:647-653.

3. Raghu G, Amatto VC, Behr J, Stowasser S. Comorbidities in idiopathic pulmonary fibrosis patients: a systematic literature review. Eur Respir J. 2015;46:1113-1130.

4. Armanios M. Telomerase and idiopathic pulmonary fibrosis. Mutat Res. 2012;730:52-58.

5. Barbaro PM, Ziegler DS, Reddel RR. The wide-ranging clinical implications of the short telo-mere syndromes. Intern Med J. 2016;46:393-403.

6. Snetselaar R, van Batenburg AA, van Oosterhout MFM, et al. Short telomere length in IPF lung asso-ciates with fibrotic lesions and predicts survival. PLoS One. 2017;12:e0189467.

7. Fulton BG, Ryerson CJ. Managing comorbidities in idiopathic pulmonary fibrosis. Int J Gen Med. 2015;8:309-318.

8. Fell CD. Idiopathic pulmonary fibrosis: phenotypes and comorbidities. Clin Chest Med. 2012;33:51-57.

9. Hoeper MM, Bogaard HJ, Condliffe R, et al. Definitions and diagnosis of pulmonary hyperten-sion. J Am Coll Cardiol. 2013;62:D42-D50.

10. Seeger W, Adir Y, Barberà JA, et al. Pulmonary hypertension in chronic lung diseases. J Am Coll Cardiol. 2013;62:D109-D116.

11. Gläser S, Obst A, Koch B, et al. Pulmonary hypertension in patients with idiopathic pulmo-nary fibrosis: the predictive value of exercise capacity and gas exchange efficiency. PLoS One. 2013;8:e65643.

12. Agrawal A, Verma I, Shah V, Agarwal A, Sikachi RR. Cardiac manifestations of idiopathic pulmonary fibrosis. Intractable Rare Dis Res. 2016;5:70-75.

13. Lee RNC, Kelly E, Nolan G, et al. Disordered breathing during sleep and exercise in idiopathic pulmonary fibrosis and the role of biomarkers. Q J Med. 2015;108:315-323.

14. Kolilekas L, Manali E, Vlami KA, et al. Sleep oxygen desaturation predicts survival in idio-pathic pulmonary fibrosis. J Clin Sleep Med. 2013;9:593-601.

15. Mermigkis C, Bouloukaki I, Schiza SE. Sleep as a new target for improving outcomes in idiopathic pulmonary fibrosis (IPF). Chest. 2017;152:1327-1338.

16. Atkins CP, Gilbert D, Brockwell C, Robinson S, Wilson AM. Fatigue in sarcoidosis and idiopathic pulmonary fibrosis: differences in character and

severity between diseases. Sarcoidosis Vasc Diffuse Lung Dis. 2016;33:130-138.

17. Yamazaki R, Nishiyama O, Sano H, et al. Clinical features and outcomes of IPF patients hospitalized for pulmonary infection: a Japanese cohort study. PLoS One. 2016;11:e0168164.

18. Azadeh N, Limper AH, Carmona EM, Ryu JH. The role of infection in interstitial lung diseases: a review. Chest. 2017;152:842-852.

19. Kearon C, Akl EA, Omelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149:315-352.

20. Tomasetti S, Gurioli C, Ryu JH, et al. The impact of lung cancer on survival of idiopathic pulmonary fibrosis. Chest. 2015;147:157-164.

21. Buendía-Roldán I, Mejía M, Navarro C, Selman M. Idiopathic pulmonary fibrosis: clinical behavior and aging associated comorbidities. Respir Med. 2017;129:46-52.

22. Jankowich MD, Rounds SIS. Combined pulmonary fibrosis and emphysema syndrome: a review. Chest. 2012;141:222-231.

23. Moua T, Ryu JH. Recognizing and treating comor-bidities of IPF. In: Meyer KC, Nathan SD, eds. Idiopathic Pulmonary Fibrosis: A Comprehensive Clinical Guide. New York: Springer Science+Business Media; 2014.

24. Gao F, Hobson AR, Shang ZM, et al. The prev-alence of gastro-esophageal reflux disease and esophageal dysmotility in Chinese patients with idiopathic pulmonary fibrosis. BMC Gastroenterol. 2015;15:26.

25. Noth I, Zangan SM, Soares RV, et al. Prevalence of hiatal hernia by blinded multidetector CT in patients with idiopathic pulmonary fibrosis. Eur Respir J. 2012;39:344-351.

26. Oldham JM, Collard HR. Comorbid conditions in idiopathic pulmonary fibrosis: recognition and management. Front Med. 2017;4:123.

27. Raghu G, Rochwerg B, Zhang Y, et al. An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. Am J Crit Care Med. 2015;192:e3-e19.

28. Raghu G, Pelligrini CA, Yow E, et al. Laparoscopic anti-reflux surgery for the treatment of idiopathic pulmonary fibrosis (WRAP-IPF): a multicentre, randomised, controlled phase 2 trial. Lancet Respir Med. 2018;6:707-714.

29. Lettieri CJ, Nathan SD, Barnett SC, Ahmad S, Shorr AF. Prevalence and outcomes of pulmonary arterial hypertension in advanced idiopathic pulmonary fibrosis. Chest. 2006;129:746-752.

30. Dalleywater W, Powell HA, Hubbard RB, Navaratnam V. Risk factors for cardiovascular

disease in people with idiopathic pulmonary fibrosis: a population based study. Chest. 2015;147:150-156.

31. Gaunaurd IA, Gómez-Marín OW, Ramos CF, et al. Physical activity and quality of life improvements of patients with idiopathic pulmonary fibrosis com-pleting a pulmonary rehabilitation program. Respir Care. 2014;59:1872-1879.

32. Kenn K, Gloeckl R, Behr J. Pulmonary rehabilitation in patients with idiopathic pulmonary fibrosis - a review. Respiration. 2013;86:89-99.

33. Dowman L, Hill C, Holland AE. Pulmonary reha-bilitation for interstitial lung disease (review). Cochrane Database Syst Rev. 2014;10:CD0066322.

34. Rangarajan S, Bone NB, Zmijewska AA, et al. Metformin reverses established lung fibrosis in a bleomycin model. Nat Med. 2018;24:1121-1127.

35. American Diabetes Association. Standards of medical care in diabetes - 2018. Diabetes Care. 2018;41:S1-S159.

36. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm – 2018 executive summary. Endocr Pract. 2018;24:91-120.

37. Sato N, Takasaka N, Yoshida M, et al. Metformin attenuates lung fibrosis development via NOX4 suppression. Respir Res. 2016;17:107.

38. Akhtar AA, Ali MA, Smith RP. Depression in patients with idiopathic pulmonary fibrosis. Chron Respir Dis. 2013;10:127-133.

39. Glaspole I. Determinants and outcomes of prolonged anxiety and depression in idiopathic pulmonary fibrosis. Eur Respir J. 2017;50:1700168.

40. Matsuda T, Taniguchi H, Ando M, et al. Depression is significantly associated with the health status in patients with idiopathic pulmonary fibrosis. Intern Med. 2017;56:1637-1644.

41. Dressen A, Abbas AR, Cabanski C, et al. Analysis of protein-altering variants in telomerase genes and their association with MUC5B common variant status in patients with idiopathic pulmonary fibro-sis: a candidate gene sequencing study. Lancet Respir Med. 2018;6:603-614.

42. Petrovski S, Todd JL, Durheim MT, et al. An exome sequencing study to assess the role of rare genetic variation in pulmonary fibrosis. Am J Respir Crit Care Med. 2017;196:82-93.

43. Kropski JA, Young LR, Cogan JD, et al. Genetic evaluation and testing of patients and families with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2017;195:1423-1428.

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REFERENCES

ConclusionDespite the availability of FDA-approved therapies, IPF is a progressive and often fatal disease whose median survival remains in the range of 3.5 to 5 years after diagnosis. The disease itself is highly morbid with symptoms that include chronic cough, dyspnea, and exercise limitations. Making matters worse, a range of comorbidities discussed here can add to the symptomatic burden of this disease, worsen quality of life, and reduce survival. A comprehensive, multidisciplinary approach to the recognition and management of comorbidities is important to optimize care for these patients. Ongoing development of new and more effective disease modifying treatments, along with increased attention to comorbid conditions, are necessary to improve outcomes for patients with this disease.

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