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Expert Review of Respiratory Medicine

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A comprehensive and practical approach to themanagement of idiopathic pulmonary fibrosis

Onofre Moran-Mendoza, Rebecca Colman, Meena Kalluri, Czerysh Cabalteja& Ingrid Harle

To cite this article: Onofre Moran-Mendoza, Rebecca Colman, Meena Kalluri, CzeryshCabalteja & Ingrid Harle (2019) A comprehensive and practical approach to the managementof idiopathic pulmonary fibrosis, Expert Review of Respiratory Medicine, 13:7, 601-614, DOI:10.1080/17476348.2019.1627204

To link to this article: https://doi.org/10.1080/17476348.2019.1627204

Published online: 08 Jun 2019.

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A comprehensive and practical approach to the management of idiopathicpulmonary fibrosisOnofre Moran-Mendozaa, Rebecca Colmanb, Meena Kalluric, Czerysh Cabaltejad and Ingrid Harlee

aDivision of Respiratory Medicine, Department of Medicine, Queen’s University, Kingston, ON, Canada; bDivision of Respirology, Department ofMedicine, University Health Network, Toronto, ON, Canada; cDivision of Pulmonary Medicine, Department of Medicine, University of Alberta,Edmonton, AB, Canada; dHoffmann-La Roche Ltd, Mississauga, ON, Canada; eDivision of Palliative Medicine, Department of Medicine andDepartment of Oncology, Queen’s University, Kingston, ON, Canada

ABSTRACTIntroduction: Idiopathic pulmonary fibrosis (IPF) is a debilitating, progressive, and fatal fibrotic pul-monary disease with a prognosis comparable to that of lung cancer. IPF management is a complexprocess that involves pharmacological and nonpharmacological interventions, extensive patient educa-tion, and addressing patient needs that change through the course of the illness.Areas covered: This review summarizes the key aspects of a multifaceted, multidisciplinary, individua-lized approach to IPF care that incorporates available treatment options, strategies to improve com-pliance with antifibrotic therapies, pulmonary rehabilitation, and the integration of palliative care forsymptom management. Aspects of care discussed include the use of antifibrotic therapy and non-pharmacological treatments, targeted education and psychosocial support, evaluation and manage-ment of comorbidities, and early integration of palliative care.Expert opinion: By incorporating this comprehensive approach to disease management, physicians canaddress most aspects of care for a patient with IPF to optimize survival and quality of life.

ARTICLE HISTORYReceived 11 February 2019Accepted 31 May 2019

KEYWORDSIdiopathic pulmonaryfibrosis; interstitial lungdisease; diseasemanagement; diseaseprogression; pirfenidone;nintedanib

1. Introduction

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible,and fatal fibrosing lung disease with a median survival of2–5 years from diagnosis [1–3]. The 5-year survival rate of20–40% associated with IPF is worse than that of many can-cers [4]. IPF is the most common idiopathic interstitial lungdisease (ILD), affecting ≈5 million persons worldwide, particu-larly males; the mean age at presentation is 66 years [5,6].Smoking, environmental exposures, gastroesophageal refluxdisease (GERD), infections, and genetic predisposition arepotential risk factors for the development of IPF [1,7].

The clinical course of IPF is progressive, highly variable andunpredictable in individual patients and is frequently asso-ciated with a significant symptom burden [4]. Disease progres-sion can be accelerated by an acute exacerbation, a clinicallysignificant, rapid decline in lung function [8,9]. Risk factors forshort-term mortality include acute exacerbations, absoluteand relative decline of ≥10% in % predicted forced vital capa-city (FVC) over 52 weeks, high supplemental oxygen flow-rates, and respiratory-related hospitalizations [10–14].Whether disease progression is rapid or slow, managementof IPF is challenging because the needs of individual patientsare variable and change throughout the course of the disease.

Current models of IPF care emphasize multidisciplinaryteams, early diagnosis, the use of antifibrotic therapy, andmonitoring of disease progression [15–17]. The 2011American Thoracic Society/European Respiratory Society/

Japanese Respiratory Society/Latin American ThoracicAssociation (ATS/ERS/JRS/ALAT) consensus guidelines recom-mend clinical follow-up every 4–6 months, long-term oxygentherapy if hypoxemia is present, pulmonary rehabilitation (PR),and treatment of comorbidities such as GERD for the majorityof patients with IPF, as well as lung transplant for selectpatients [1]. In 2015, the conditional use of approved antifi-brotic therapies, which slow disease progression, was addedto the ATS/ERS/JRS/ALAT guidelines for IPF treatment [18].

The management of dyspnea, cough, and psychological suf-fering, which nearly all patients with IPF develop as the diseaseprogresses, are important aspects of care [1,4,15,19,20].A comprehensive care approach that includes pharmacologicaland nonpharmacological treatment, palliative care, patient edu-cation, and increased support throughout the course of illness isneeded. Disease-centric caremodels focus on specific treatmentsfor IPF but do not adequately meet all patient and caregiverneeds. In addition to controlling disease, the goals for deliveringcare should include improving quality of life (QoL), decreasingsymptom burden, providing caregiver support, and reducing theeconomic burden of IPF.

A single-center, retrospective cohort study (conducted beforethe approval of antifibrotics) in 284 patients with IPF showed thata bundled care approach for IPF based on the 2011 ATS/ERS/JRS/ALAT guidelines improved transplant-free survival [21]. Thisapproach included semiannual visits to an ILD clinic, PR, anannual 6-minute walk distance (6MWD) test, an annual

CONTACT Onofre Moran-Mendoza morano@queensu.ca Interstitial Lung Disease Clinic, Division of Respiratory and Sleep Medicine, Queen’s University,102 Stuart Street, Kingston, Ontario K7L 2V6, Canada

EXPERT REVIEW OF RESPIRATORY MEDICINE2019, VOL. 13, NO. 7, 601–614https://doi.org/10.1080/17476348.2019.1627204

© 2019 Informa UK Limited, trading as Taylor & Francis Group

echocardiogram, and GERD therapy [21]. In a recent exploratoryanalysis of experience at a single center in Canada,a multidisciplinary collaborative care model was associatedwith a reduction in healthcare utilization and more at-homedeaths compared with care received at the same center priorto the implementation of the collaborative care model [22]. Thecollaborative care team included a pulmonologist with expertisein ILD, a pulmonologist with expertise in palliative care, a nurse,a respiratory therapist, a physiotherapist, and a dietitian [22].A single-center survey of bereaved caregivers of patients withIPF indicated that targeted education, advance care planning,and improved communication can positively impact symptomcontrol, QoL, and caregiver burden in IPF [23]. These 3 studieshighlight the benefit of a holistic approach to IPF managementthat encompasses all aspects of care.

In this review, we provide evidence-based recommenda-tions when available and, in cases when no evidence-basedrecommendations are available, the consensus approach usedby experts in the management of patients with IPF from 3 ILDcenters in Canada. These recommendations based on expert

opinion should be applied as appropriate, given availabletreatment options wherever the treating physician practices.The available evidence is derived from randomized controlledtrials (RCTs)and cohort studies or extrapolated from studies ofother chronic pulmonary conditions. Our goal is to providea thorough overview of all care components that we considerimportant and necessary in a comprehensive approach to IPFmanagement (Figure 1). We describe treatment options andstrategies to mitigate antifibrotic-related adverse events (AEs)and explain the benefits of PR and the need for managementplans that are tailored to meet the needs of the specificpatient. We review the value of a multifaceted, multidisciplin-ary, individualized approach to treatment with early integra-tion of palliative care to optimize symptom control, improveQoL, and ease transitions throughout the illness journey.

2. Multifaceted IPF management approach

2.1. Education

Education for patients with IPF needs to be specific to theirdisease and to the treatments the individual patient receives.Disease education should address patient concerns about dis-ease progression and health deterioration and help them toprepare for the future [24]. Important components of educationinclude patient empowerment that prepares patients to copeand to live well with IPF [25,26]. Internet resources alone areinadequate, and clinicians should consider the informationalneeds of both patients and caregivers throughout the course ofthe illness [27–30]. Specialist ILD nurses and nurse practitionersare well positioned to support education, AE management, andadherence [31–33]. Several specific aspects of patient educationare noted in the relevant sections throughout this review.

2.2. Antifibrotic therapy

The two currently available antifibrotic therapies, pirfenidone(ideal dose, 801 mg 3 times daily [TID]) and nintedanib (ideal

Article Highlights

● The management of IPF is complex due to the unpredictable rate ofdisease progression, adverse events associated with antifibrotic thera-pies, the burden of comorbidities, the significant symptom burden,and the changing care and education needs of patients throughoutthe course of the disease

● A multifaceted, multidisciplinary approach to IPF management, tai-lored to each patient’s individual needs is recommended to optimallymanage a patient’s overall health and expectations

● Key aspects of a multifaceted approach to IPF management includeextensive patient education; early initiation of antifibrotic therapy,supplemental oxygen therapy, and pulmonary rehabilitation; moni-toring and management of IPF-associated comorbidities; early inte-gration of palliative care for managing IPF symptoms, especiallycough and dyspnea; psychosocial support and nutritional counseling;and dynamic conversations on advance care planning and to estab-lish goals of care throughout the illness journey

Figure 1. Overview of a multifaceted IPF management approach. COPD, chronic obstructive pulmonary disease; GERD, gastroesophageal reflux disease; IPF,idiopathic pulmonary fibrosis; O2, oxygen; OSA, obstructive sleep apnea.

602 O. MORAN-MENDOZA ET AL.

dose 150 mg twice daily [BID]), were approved for the treat-ment of IPF in Canada in 2012 and 2014, in Europe in 2011and 2015, and in the United States in 2014 and 2014, respec-tively, and received a conditional recommendation in the 2015ATS/ERS/JRS/ALAT treatment guidelines in 2015 [18]. Bothantifibrotics can slow disease progression as measured bythe rate of decline in % predicted FVC [34–37].

A meta-analysis of the phase 3 ASCEND (Study 016,NCT01366209) and CAPACITY (Studies 004 and 006;NCT00287716 and NCT00287729, respectively) trials and 2Japanese trials (Shionogi) of pirfenidone vs. placebo showedthat pirfenidone reduced the risk of all-cause mortality (HR,0.52; P = 0.01) and IPF-related mortality (HR, 0.35; P = 0.003)[38]. Post hoc analyses also found that pirfenidone reduced therisk of respiratory-related hospitalizations (HR, 0.52; P = 0.001)[39]. The INPULSIS-1 and -2 trials (NCT01335464 andNCT01335477) showed that nintedanib had a nonsignificanttrend toward reducing all-cause mortality (HR, 0.70; P = 0.14)[40]. The reasons for differences between nintedanib and pirfe-nidone regarding mortality and acute exacerbations are notwell understood, but the magnitude of the reduction in FVC(mL) decline was very similar in the phase 3 trials [34–37].Open-label long-term extension studies of pirfenidone (RECAP[NCT00662038] and INPULSIS-ON [NCT01619085]) supportedthe safety findings of the phase 3 trials [41,42].

A treatment benefit for either pirfenidone or nintedanibhas been shown in patients with less-advanced vs. more-advanced disease across a range of lung function criteria (%baseline FVC ≤50%–90%) in post hoc analyses of clinical trialdata and in real-world studies [43–48]. A post hoc analysis ofdata from ASCEND and CAPACITY showed that patients whoexperienced ≥10% absolute decline in % predicted FVC duringthe first 6 months of treatment and continued treatment withpirfenidone had lower risk of further decline in % predictedFVC or death during the subsequent 6 months compared withplacebo [49]. In a post hoc analysis of patients with IPF whohad ≥10% absolute decline in FVC in the first 24 weeks oftreatment with nintedanib in the INPULSIS trials, continuedtreatment was not associated with further FVC decline in thefollowing 24 weeks compared with placebo [50].

Important factors to consider when selecting antifibrotictherapy include a patient’s preferences, individual burden ofcomorbidities, and potential risks. The selection between pir-fenidone and nintedanib may be influenced by the patient’slifestyle and clinical conditions. Pirfenidone requires avoidanceof direct sun exposure (due to treatment-associated photo-sensitivity); nintedanib should be used with caution in patientswith a risk of bleeding or gastrointestinal (GI) perforation,including those receiving concomitant anticoagulants, corti-costeroids, or nonsteroidal anti-inflammatory drugs (due totreatment-associated increased bleeding risk) [51–56]. It isimportant to note that patients with recent history of myocar-dial infarction or stroke were excluded from the antifibroticclinical trials; however, an increased risk of these AEs has notbeen observed in post hoc analyses [34–37,57,58]. Pirfenidoneis metabolized by cytochrome P450 1A2 (CYP1A2) and shouldnot be used in combination with CYP1A2 inhibitors (e.g. flu-voxamine [absolute contraindication] and ciprofloxacin [per-mitted at 750 mg BID with a reduced dose of pirfenidone

534 mg TID], amiodarone, omeprazole, esomeprazole) due toincreased exposure and thus increased risk of AEs.Consumption of grapefruit juice is associated with CYP1A2inhibition and should be avoided during pirfenidone treat-ment. Pirfenidone should be avoided in combination withCYP1A2 inducers (e.g. rifampin, phenytoin, carbamazepine)due to reduced exposure [51]. Nintedanib is contraindicatedin patients with peanut or soy allergies and during pregnancy;nintedanib should be used cautiously (possibly at reduceddose) in combination with P-glycoprotein (P-gp) and cyto-chrome P450 3A4 (CYP3A4) inhibitors (e.g. ketoconazole, ery-thromycin) due to increased exposure and should be carefullyconsidered in combination with P-gp and CYP3A4 inducers(e.g. rifampicin, carbamazepine, phenytoin, St. John’s Wort)due to decreased exposure [54–56].

A new formulation of pirfenidone was approved in Canada,the United States, and Europe in 2017: 801-mg tablets TIDwith meals for patients maintaining full dose; this new formu-lation reduces the pill burden associated with the 267-mgcapsules, which are used for initial pirfenidone titration [59].However, the approval of the new 801-mg tablets was basedon a single-dose pharmacokinetics study performed in healthyvolunteers; fewer AEs were reported in patients who receivedpirfenidone after a meal than after an overnight fast [59].Therefore, it is important to monitor patients who switch to801-mg tablets; patients who experience significant AEs maybe switched back to the 267-mg capsules to accommodatedose reductions instead of discontinuing treatment.

2.2.1. Consideration of early initiation of antifibrotictherapyPatients may benefit from early initiation of antifibrotics forseveral reasons. Lung function decline is irreversible; therefore,the goal of antifibrotic treatment is to slow disease progression[15,16,60]. Baseline % predicted FVC itself does not predictdisease progression [43,44]. Patients with less-advanced disease(i.e. baseline % predicted FVC ≥50%) experience benefit fromantifibrotics similar to that in patients with more-advanceddisease [43–48]. Finally, disease progression, as measured byeither absolute or relative decline in % predicted FVC, andlower % predicted FVC are associated with an increased riskof IPF exacerbations and mortality [10–13,61,62]. Despite thesefindings, some countries do not provide reimbursement forpatients with less-advanced disease. Patients in these countriesshould be monitored frequently, so antifibrotics can be initiatedas early as possible in the course of the disease.

2.2.2. Antifibrotic-related adverse eventsIn the clinical trials, the most commonly reported treatment-emergent AEs (TEAEs) associated with antifibrotic therapieswere GI TEAEs (Figure 2) [63–65]. In the pooled phase 3pirfenidone clinical trials, the most common TEAEs were nau-sea (pirfenidone vs. placebo, 35.5% vs. 15.1% of patients),cough (23.1% vs. 24.0%), diarrhea (24.6% vs. 18.8%) upperrespiratory tract infection (22.6% vs. 20.2%), fatigue (23.0%vs. 16.8%), headache (20.5% vs. 18.1%), and rash (29.2% vs.9.0%) [66]. Other GI TEAEs reported in ≥10% of pirfenidone-treated patients were dyspepsia, GERD, and vomiting [66]. GITEAEs were most likely to occur within the first 3–6 months of

EXPERT REVIEW OF RESPIRATORY MEDICINE 603

pirfenidone treatment [67]. In the pooled phase 2 TOMORROW(NCT00514683) and phase 3 INPULSIS-1 and −2 nintedanibclinical trials, the most frequent TEAEs were diarrhea (ninteda-nib vs. placebo, 61.5% vs. 17.9%) and nausea (24.3% vs. 7.1%)[40]. Other GI TEAEs occurring in ≥10% of nintedanib-treatedpatients were vomiting and decreased appetite [40].

In the clinical trials, pirfenidone-specific TEAEs includedskin-related TEAEs, such as photosensitivity (pirfenidone vs.placebo, 9.3% vs. 1.1%) and rash (30.2% vs. 10.3%), whereasnintedanib-specific TEAEs included cardiovascular (nintedanibvs. placebo, 2.5% vs. 0.8%) and bleeding events (10% vs. 7%)[35,36,51,54,63,64,66]. Results from INPULSIS-ON, the open-label extension study of the INPULSIS trials, showed rates ofcardiovascular and bleeding events that were similar to thoseobserved in the placebo groups of INPULSIS and were notsignificantly different between previous nintedanib and pre-vious placebo groups [42].

The safety and tolerability profiles of antifibrotics observedin these large, RCTs have been supported by real-world dataand postmarketing experiences, in which patients typicallyhave more-advanced disease and significantly more comor-bidities than those in the clinical trials. In a single-center retro-spective study of 351 patients who received pirfenidone over4.5 years, TEAEs were mostly GI-related and similar to thoseobserved in the clinical trials; 61% of pirfenidone-treatedpatients experienced >2 AEs [68]. The majority of pirfenidone-associated TEAEs were tolerable or manageable by dosereduction and slower dose titrations, and approximately 1 in5 (20%) TEAEs resulted in treatment discontinuation [68]. Over4.5 years, 29% of patients discontinued pirfenidone comparedwith 12% of patients who discontinued over 1 year in thephase 3 trials [66,68]. The same study also reviewed TEAEs in124 patients receiving nintedanib over 1.5 years [68]. Mostnintedanib-associated TEAEs were GI-related, similar to theclinical trial findings [40,68]. Most patients (82%) experienced≥2 TEAEs, and 26% of patients discontinued nintedanib over1.5 years compared with 20.6% who discontinued over 1 yearin the clinical trials [40,68]. Consistent with these findings,

a separate, single-center, retrospective chart review study of129 pirfenidone-treated patients and 57 nintedanib-treatedpatients with IPF reported discontinuation rates of 21% and26% over a mean observation period of 1 year for pirfenidoneand nintedanib, respectively [69].

2.2.3. Prevention and management of antifibrotic-relatedadverse eventsA stepwise approach can be adopted to help patients preventand manage AEs associated with antifibrotics and continuetreatment (Table 1). Real-world studies indicate that access toan ILD nurse can play a critical role in AE management andadherence to antifibrotics through continued patient educa-tion [32,33]. The goal is to provide patients with informationand resources to help prevent the onset of AEs and, if AEs doarise, to implement effective strategies to mitigate the dura-tion and severity of symptoms. It is important for patients tounderstand the progressive and fatal nature of the disease andthe benefits of current treatment options. Education shouldbegin early, ideally at the time of diagnosis, and continuealong the illness trajectory as each patient’s experience willbe different. Whenever feasible, patients should be enrolled inpatient support groups.

If AE symptoms occur, dose reduction or temporary doseinterruptions should be considered to maintain ongoing treat-ment with either pirfenidone or nintedanib [64,70,71]. InPASSPORT, a safety study of pirfenidone in European patients,dose modifications were frequent (39% of patients who hadan AE associated with treatment), and patients who under-went dose modifications were less likely to discontinue treat-ment due to AEs (20% vs. 31%) [72,73]. Similarly, in anExpanded Access Program with pirfenidone in US patients,almost half of patients who had dose modifications wereable to return to the full dose [74]. Furthermore, analyses ofthe pirfenidone and nintedanib clinical trials indicate thatefficacy is maintained at doses below the full recommendeddose [36,37,42,75,76]. If AE symptoms persist or are severe,temporary treatment interruption can be used as a mitigating

Figure 2. Shared and drug-specific treatment-emergent adverse events with antifibrotic therapies [51,54]. ALT, alanine aminotransferase; AST, aspartate amino-transferase; CV, cardiovascular; GI, gastrointestinal.a Although both pirfenidone and nintedanib are associated with gastrointestinal adverse events, the frequency of individual adverse events is different with each drug.

604 O. MORAN-MENDOZA ET AL.

Table1.

Summaryof

strategies

topreventandmanageadverseevents

associated

with

antifibrotic

therapies[51,54,64,70,71].

Pirfenidon

eNintedanib

AEtype

GI

Skin

Liver

GI

Liver

AEpreventio

n●Take

pirfenidon

ewith

asubstantialm

eal,

specifically

thefull

dose

attheendof

ameal,or

spread

out

durin

gameal

●Titrateover

aperio

dof

4weeks

insteadof

2weeks

●Avoidor

minimizedirect

and

indirect

expo

sure

tosunlight

orintenseartificiallight

●Ap

plysunscreen(≥SPF-50,

activeagainstUVA

/UVB

)every2ho

ursas

needed

●Wearprotectiveclothing

(e.g.

hat,sung

lasses,and

gloves)

even

whendrivingor

expo

sedto

sunthroug

hwindo

ws

●Avoiduseof

other

medications

associated

with

phototoxicity

●Mon

itorliver

chem

istry(ALT,A

ST,b

ilirubin)

before

treatm

entandmon

thlydu

ringthe

first6of

mon

thstreatm

entandthen

every

3mon

thsthereafter

●Take

nintedanib

with

orat

theendof

ameal

●Mon

itorliver

chem

istry(ALT,A

ST,

bilirub

in)before

treatm

entandmon

thly

durin

gthefirst

3mon

thsof

treatm

ent

andperio

dically

thereafter

(i.e.at

each

patient

visit)

AEtreatm

ent

●ProkineticsandPPIs

may

help

mitigate

GI

AEs

●Treatsevere

phototoxicity

with

steroids

orsilver

sulfadiazine

●An

tidiarrheal(loperamide,≤8tablets

perdayor

≤16

mg/day)a

●An

tiemetictherapy

●Ad

equate

hydration

Doseredu

ction

●Redu

cedo

seto

1–2

capsules

2–3tim

esperdayor

astolerated

●Focusredu

ctions

attim

eof

daywhenAE

saremostprom

inent

(e.g.n

auseain

the

morning

)

●Formild

tomod

erate

photosensitivity

orrash,

redu

cedo

seto

1capsuleTID

for7days

andre-escalateto

thefulldo

se

●IfAS

TandALTelevations

(>3to

≤5×ULN

)occurwith

outsymptom

sor

hyperbilirubinemia,the

dose

may

beredu

cedor

interrup

tedun

tilvalues

return

tono

rmal.O

nceresolved,treatmentmay

bere-escalated

totherecommendeddo

seas

tolerated

●Fordiarrhea

of4–6extrastoolsperday

orIV

fluids<24

hoursthat

continues

≥8days,reducedo

seto

100mgBID

●Ifsymptom

spersistdespite

supp

ortive

care,doseredu

ctionor

interrup

tionmay

berequ

ired.Treatm

entmay

beresumed

ataredu

ceddo

seof

100mgBIDor

atthefullrecommendeddo

se

●IfAS

TandALTelevations

(>3×ULN

)occur,thedo

semay

beredu

cedor

interrup

tedun

tilvalues

return

tono

rmal.

Oncelevelshave

returned

tobaseline

values,re-introd

ucetreatm

entat

100mg

BIDandincrease

torecommendeddo

seas

tolerated

Doseinterrup

tion

●IfAE

spersist,

tempo

rarily

discon

tinue

treatm

ent

until

symptom

sresolveor

become

tolerable

●Forrash

persistin

g>7days

despite

dose

redu

ction,

discon

tinue

treatm

entfor

15days

followed

byaslow

re-escalationback

tofull

dose

astolerated.

●Forsevere

rash,d

iscontinue

until

resolved

andslow

lyre-

escalate

tothe

recommendeddo

seas

tolerated

●IfAS

TandALTelevations

(>3to

≤5×ULN

)areaccompanied

byhyperbilirubinemia,

perm

anently

discon

tinue

●Ifpatientsexhibit>5×ULN

,permanently

discon

tinue

●Fordiarrhea

of>6extrastoolsperday

orIV

fluids≥24

hoursor

hospitalization,

interrup

ttherapyplus

administeran

antid

iarrhealun

til<4extrastools

perday;discon

tinue

ifdiarrhea

recurs

for≥8days

●Ifsevere

symptom

spersistdespite

symptom

atictreatm

ent,discon

tinue

treatm

ent

●Ifliver

elevations

areaccompanied

byclinicalsign

sor

symptom

sof

liver

injury

(i.e.jaun

dice),perm

anently

discon

tinue

treatm

ent

AE,adverse

event;ALT,alanineam

inotransferase;A

ST,aspartate

aminotransferase;BID,twicedaily;G

I,gastrointestinal;IV,intravenou

s;PPI,proton

pumpinhibitor;SPF,sunprotectio

nfactor;TID,3

times

daily;U

LN,upp

erlim

itof

norm

al;U

VA/UVB

,ultravioletA/B.

aIn

patientswho

experienceAE

sassociated

with

loperamide,naturala

ntidiarrheals(e.g.d

iosm

ectite,gelatin

tann

ate)

couldbe

considered.

EXPERT REVIEW OF RESPIRATORY MEDICINE 605

strategy. Once symptoms have resolved, the patient’s doseshould be slowly titrated back to the full dose or to themaximum tolerated dose. Slow dose titration at treatmentinitiation can be considered with either pirfenidone or ninte-danib, particularly in patients with history of GI conditions.

2.3. Smoking cessation

Resources to assist in the cessation of smoking should beprovided to patients who are smokers. These may includediscussions, websites (American Lung Association [www.lung.org/stop-smoking/] and National Cancer Institute [www.smokefree.gov]), and referral for PR or counseling. At many trans-plant centers, in accordance with the 2014 InternationalSociety for Heart and Lung Transplantation (ISHLT) guidelines,tobacco addiction within the past 6 months is an absolutecontraindication to lung transplant [77]. Finally, pharmacoki-netics studies have revealed that both antifibrotics clear morerapidly in smokers vs. nonsmokers, resulting in lower exposureto the medications [51,54]. Thus, cigarette smoking should beavoided to prevent reduced exposure to antifibrotics.

2.4. Management of gastroesophageal reflux diseaseand other comorbidities

GERD is highly prevalent in patients with IPF, but only 25–50%of patients are symptomatic [78,79]. Chronic microaspirationsecondary to GERD may play a role in IPF pathogenesis andprogression and may trigger acute exacerbations [80–82].Antacid treatment has received a conditional recommendationin the 2015 update to the ATS/ERS/JRS/ALAT treatment guide-lines, but with very low confidence in estimates of effect [18].

A post hoc analysis of data from ASCEND and CAPACITYfound that patients receiving antacid therapy (histamine H2

blockers and/or proton pump inhibitors [PPIs]) and pirfeni-done had similar disease progression (absolute decline in %predicted FVC ≥10%, decline in 6MWD ≥50 m, or death) andall-cause mortality compared with those receiving pirfenidonewithout antacids; a similar analysis of the INPULSIS trials foundno additional benefit of antacids in combination with ninte-danib [83,84]. An analysis of the placebo groups of 3 IPFClinical Research Network clinical trials showed that patientsreceiving antacids had less decline in FVC (mL) and feweracute exacerbations at 30 weeks than those without antacids[85]. A study in patients with IPF from 2 US academic centersfound that antacids (88% of patients received PPIs) wereassociated with longer survival and decreased radiologic pul-monary fibrosis [80].

A recent meta-analysis reported that pharmacologic treat-ment of GERD is associated with a reduction in IPF-relatedmortality but not overall mortality [86]. However, the benefi-cial effects of antacids on mortality observed in patients withIPF in observational studies may be due to immortal time biasbecause in several studies, ≥12 months’ exposure to antacidswas required for inclusion in survival analysis; thus, patientshad a 12-month ‘immortal’ time period [86]. A separate meta-analysis found beneficial effects for antacids in 4 studies thatwere affected by immortal time bias but no beneficial effectsin 5 studies that avoided immortal time bias [87].

In summary, data suggest a beneficial role for antacids, PPIsin particular, in slowing disease progression and reducingmortality in patients with IPF, but the findings are inconsistent,highlighting a need for RCTs to clarify the role of antacids inIPF [85]. A recently published phase 2 trial of omeprazole in 45patients with IPF, which included patients who were receivingstable antifibrotics (≥4 weeks before enrollment), showeda reduction in cough in omeprazole-treated patients com-pared with placebo, but larger studies are needed to deter-mine the role of PPIs in other clinically relevant outcomes [88].The phase 2 WRAP-IPF trial of laparoscopic antireflux surgeryin patients with IPF demonstrated the safety of the procedure,but additional data are needed to determine if a clear benefitexists [89]. In addition to antacids, dietary changes, includingthe avoidance of heavy or fatty foods and the avoidance ofcaffeine and alcohol ≤3 hours before bedtime, and elevatingthe head of the bed 4–6 inches may be useful GERD manage-ment strategies in patients with IPF [85].

Several other key comorbidities require monitoring andmanagement in patients with IPF. Patients with IPF shouldbe evaluated for obstructive sleep apnea (OSA) because OSAis highly prevalent in the IPF population [90]. If OSA is present,continuous positive airway pressure therapy may improvenight-time oxygenation [91]. Coexisting chronic obstructivepulmonary disease (COPD) and emphysema in patients withIPF should be evaluated with pulmonary function tests andhigh-resolution computed tomography (HRCT), respectively;;although evidence for treatments is lacking, inhaled broncho-dilators could be considered if any of these conditions ispresent [92]. Pulmonary hypertension (PH) is common inpatients with more-advanced IPF and increases mortality risk;however, to date no therapies have been approved to treat PHin the IPF population [1,18,93,94]. A recent trial of nintedanibwith concomitant sildenafil in patients with advanced IPF(diffusing capacity for carbon monoxide [DLCO] ≤35%) didnot meet the primary endpoint of change in St. George’sRespiratory Questionnaire over 12 weeks, and a trial isongoing to evaluate pirfenidone with concomitant sildenafilin patients with advanced IPF (DLCO ≤40%) and risk of PH[95,96]. Lung cancer is more prevalent in patients with IPFthan in the general population, but treatment options arelacking [97,98]. Whether antifibrotics can be combined withchemotherapy or radiation therapy remains an open question,and patients with more-advanced IPF may not be eligible forsurgical resection, radiation therapy, or other treatments thatcan impair lung function [99,100].

2.5. Transplant referral

The 2011 ATS/ERS/JRS/ALAT and 2014 ISHLT treatment guidelinesstrongly recommend early lung transplant referral for patientswith IPF, so modifiable contraindications (e.g. obesity and decon-ditioning) can bemanaged accordingly despite the unpredictabil-ity of disease progression [1,77]. Patients must be appropriatelyeducated, with discussions starting at the time of diagnosis, aboutappropriate expectations, the realities of life posttransplant, andmanaging contraindications. Palliative care and opioids are nota barrier for transplant in most centers and should not be delayedif needed [101]. Similarly, prior use of antifibrotics has not been

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observed to compromise wound healing in patients undergoinglung transplant; therefore, patients who are listed for transplantcan receive antifibrotics [102]. Finally, when referred for transplant,patients should also be referred for PR and encouraged to exerciseregularly while awaiting a transplant evaluation to maintain asmuch physical function as possible.

The estimated 5-year survival rates after lung transplant forIPF are 50–56% [103]. One single-center study identified a 75%reduced risk of death at 5 years in 46 patients with IPF whohad lung transplants [104]. Many patients with IPF (14–67%)die after listing and before receiving a lung transplant due toshortage of donor organs [103].

2.6. Psychosocial support

Patients with IPF should be assessed for the presence ofanxiety and depression, as these conditions frequently occurduring IPF progression [19,20]. Offering counseling for bothpatients and caregivers, providing connections to individual orgroup support networks, and promoting overall well-being areall important when addressing a patient’s psychological dis-tress throughout their illness. These means of support areoptimally addressed by a multidisciplinary team. Medicationscan be prescribed as necessary, although RCTs in this patientpopulation are lacking: such as methylphenidate (to improveenergy and reduce fatigue); serotonin and norepinephrinereuptake inhibitors (for anxiety and depression); serotoninselective reuptake inhibitors (for depression); less commonlyused tricyclic antidepressants (for depression and sleep dis-turbances); bupropion (for depression); mirtazapine (fordepression, to improve appetite, sleep, and potentiallycough), which should be avoided in combination withCYP1A2 inhibitors and pirfenidone; benzodiazepines (use cau-tiously for anxiety or sleep); and buspirone (for sleep) [51,105].In addition to reducing the psychological burden of IPF, parti-cipation in patient support groups may improve adherence toantifibrotic therapy and other treatments [32]. Online supportgroups, such as the Pulmonary Fibrosis Foundation website(www.pulmonaryfibrosis.org), may benefit patients who havelimited mobility or live in rural areas. Patients and caregivershave also expressed the need for more community-basedmedical support, including at-home disease monitoring withmechanisms to identify decline and to respond appropriatelybefore the next clinic visit [28]. This can be facilitated throughcommunity support systems and working collaboratively tomonitor and support patients at home [106,107].

2.7. Updated vaccinations

Respiratory infections may trigger acute exacerbations of IPF[108]. Therefore, the vaccination status of patients should beassessed. No specific studies regarding vaccinations in patientswith IPF have been performed. The specific vaccination poli-cies and recommendations vary from country to countryregarding schedules for the annual influenza vaccination, 23-valent pneumococcal polysaccharide vaccine, and 13-valentpneumococcal vaccine based on a patient’s age and medicalhistory [109,110]. Clinicians should consult local guidelines.

2.8. Regular exercise/pulmonary rehabilitation

Per the 2011 ATS/ERS/JRS/ALAT treatment guidelines, PR shouldbe used in the majority of patients with IPF and encouragedimmediately after diagnosis before disease progression reducestheir functional status [1]. The goals of PR are to reduce dyspnea,depression, anxiety, and fatigue, leading to the benefits ofincreased exercise capacity, QoL, and cognitive function [111].

Several RCTs in patients with IPF or ILD have assessed thebenefits of PR. One study showed that 6MWD was significantlyimproved immediately following PR (+36 m, P = 0.0004) [112].Increased endurance and improved dyspnea during exertionwere reported when supplementary oxygen was provided topatients with IPF without resting hypoxemia [113]. A meta-analysis in patients with IPF found that PR had short-termbenefits in exercise capacity and health-related QoL but nodetectable effects at long-term follow-up (6–12 months) [114].In contrast, a recent RCT in 60 patients with ILD showedexercise and health benefits of a 6-month PR program per-sisted for an additional 6 months after completion [115].Continued PR is important for improving exercise capacity,particularly in patients waiting to receive a lung transplant.

Prior to initiating PR, the patient’s safety should be ensured[116]. An evaluation of baseline lung function and comorbiditiesshould be conducted, and before exercise initiation, a patient’ssupplemental oxygen supply should be assessed to confirm thatit is adequate. No specific guidelines for PR exist for IPF. Existingeducation and exercise programs for patients with COPD maynot be optimal for those with IPF [24]. Patients must be wellrested prior to exercise. Desaturation should be expected, soa supply of supplemental oxygen sufficient to maintain periph-eral capillary oxygen saturation (SaO2) ≥88% should be ensured.Before and after enrollment of patients in a PR program, encoura-ging patients to remain active by performing an aerobic exercisematching their interest and capability (e.g. walking, swimming,and cycling) is advised; however, it is important to assess theneed for supplemental oxygen during exertion.

2.9. Supplemental oxygen therapy

The 2011 ATS/ERS/JRS/ALAT treatment guidelines stronglyrecommend that patients with IPF with clinically significantresting hypoxemia should be treated with long-term oxygentherapy [1]. However, no data on long-term oxygen therapyare available in IPF; indirect evidence from COPD has demon-strated a survival benefit, and limited evidence has shown thatoxygen therapy improves exercise capacity in patients withresting hypoxemia and walk distance in patients with exer-tional hypoxemia [1]. Recently, the prospective, open-label,crossover-controlled AmbOx trial showed a benefit with sup-plemental oxygen in health-related QoL measures in patientswith ILD [117]. Therefore, prescribing supplemental oxygenand titrating to maintain SaO2 at ≥92–95% at rest and ≥88%during exertion is recommended. This value should berechecked every 60–90 days (or more frequently via self-monitoring), adjusting the supplemental oxygen as required.

Patients prescribed supplemental oxygen frequently lackadequate education about the effective use and availabilityof appropriate, ambulatory equipment [118]. The involvement

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of multiple stakeholders, including patient organizations, pro-fessional organizations, and industry partners, is needed toimprove oxygen access and use in the IPF population.Heterogeneity exists in supplemental oxygen use in clinicalpractice due to differences in policies around the world.Clinicians and ILD nurses should engage in patient educationto ensure both frequent monitoring of SaO2 and the availabil-ity of sufficient supply to meet the oxygen needs of eachindividual patient.

Patient-reported experiences of air travel with supplementaloxygen indicate that the experience can be challenging butmanageable with preparation [119]. In preparation for travel,a high-altitude simulation test should be performed to assessthe need for in-flight oxygen in patients who may not be fit tofly and in those with severe restrictive disease (vital capacity<1 L), advanced COPD (forced expiratory volume in 1 second<30%) especially with resting hypoxemia or hypercapnia, orpulmonary hypertension (New York Heart Association func-tional class III or IV) [120]. Patients deemed to require oxygenshould be instructed how to monitor and adjust the oxygenflow-rate to ensure that SaO2 is ≥90%% while in-flight [120,121].The patient should be advised to arrange oxygen supply logis-tics well in advance of the specific flight, inquiring about spe-cific supplemental oxygen policies with the airline andarranging for local oxygen supply at their destinations [120].

2.10. Symptom management and palliative care

An important component of symptom management is educat-ing patients about common symptoms that arise if diseaseprogression occurs and how they can best monitor theirsymptoms. Patients are more likely to engage in self-monitoring if they understand both why symptoms occurand what their role is managing them. Key symptoms todiscuss include breathlessness, fatigue, cough, anxiety, anddepression, plus it is important to ensure that patients under-stand their oxygen needs.

The goals of early integration of palliative care for patientswith IPF are to (1) establish regular monitoring and optimizesymptom management; (2) introduce appropriate medica-tions, such as opioids, with close monitoring and titration ofdose; (3) assist patients in understanding the trajectory of theillness; (4) engage in discussions about goals of care, includinglong-term goals and advance care planning; (5) facilitate tran-sitions from ambulatory and/or hospital-based care to home-based or hospice care as appropriate; (6) discuss end-of-lifecare expectations with the patient and family members and tomobilize resources close to home to support end-of-life care;(7) arrange transfer to alternate locations if optimal care provi-sion is not possible in the patient’s home; and (8) ultimatelyoptimize QoL as much as possible [22].

Physicians should consider implementing a palliative careapproach at the onset of symptoms of progressive respiratorydisease, concurrentl with curative or restorative care in anindividualized manner [105–107]. Preliminary evidence sug-gests a benefit of initiating palliative care early after an IPFdiagnosis because the disease is a progressive, life-limitingillness. Suggested criteria for referral to palliative care includea score of 4 or 5 on the Medical Research Council dyspnea

scale, the need for supplemental oxygen at rest or with exer-tion, increasing supportive care needs, and/or declining func-tional status (Palliative Performance Scale ≤50%) [105,122].

To provide effective palliative care, symptom managementneeds to be patient-centered and individualized [123].A systematic assessment of symptoms and patient needsmust lead to the prioritization of integrated symptom manage-ment and an understanding of the pathophysiology causingthe symptoms. Specific instructions for each medication pre-scription – dosing, timing, and route of administration, as wellas education about monitoring and managing medication AEs –should be provided to the patient according to the patient’sage and other comorbidities. Drugs that are ineffective orunnecessary for an individual patient should be discontinuedto limit polypharmacy. Changes in medications or doses shouldbe implemented one at a time, with frequent reassessments tomonitor the effect. Encouraging patients to keep a diary ofsymptoms, medication effectiveness, and AEs is also important.

For worsening dyspnea, there is no satisfactory treatment,but several options can be explored [105]. PR can instructpatients in techniques that may help manage dyspnea, andsupplemental oxygen use should be evaluated. Medicationssuch as low-dose opioids, methotrimeprazine, anxiolytics,mucolytics, and occasionally antibiotics can help somepatients, but direct evidence of efficacy in patients with IPFis lacking. For initial dyspnea management, we suggestimmediate-release morphine 2.5 mg (or 5 mg in patientswith high body mass index [BMI]) orally (PO) every 4 hours(q4h) while awake. Hydromorphone 0.5 mg (or 1 mg inpatients with high BMI) q4h while awake may be consideredif morphine should be avoided [106,107]. The opioid doseshould be titrated to the lowest effective dose that decreasesthe sensation of dyspnea and minimizes AEs. After the appro-priate dose has been determined, initiation of a controlled-released opioid could be considered for ease of administra-tion. If a patient is nearing the end of life, then immediate-release formulations are recommended to allow more rapiddose titration depending on the patient’s needs (titration after≥24 hours at a specific dose). In addition, it may becomenecessary to replace orally administered opioids with equipo-tent parenteral opioids (subcutaneous/intravenous) whenrapid symptom relief is needed or if patients can no longertake medications orally. Alternative therapies (e.g. relaxationtherapy, acupuncture, imagery) and a fan blowing cool airacross the face may help some patients control dyspnea [124].

For worsening cough, opioids are commonly prescribed[125]. Hydrocodone cough syrup is not more effective thanother opioids, so it should not be added to other opioid pre-scriptions. Systematic assessments should be performed toidentify and treat other etiologies of cough, such as sinusitis,GERD, and respiratory infections. Treatment could be initiatedwith a low dose of opioid with regular reassessment and titra-tion as needed. Inhaled corticosteroids or long-acting beta-agonists can be tried if concomitant asthma or COPD is present.

Common side effects from opioids include drowsiness andnausea, both of which are transient, typically resolving in4–6 days; constipation, which typically worsens with doseescalation; confusion and urinary retention, which are morefrequent in the elderly with comorbidities and polypharmacy.

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For opioid-induced nausea, metoclopramide 5 or 10 mg PO orhaloperidol 0.5 or 1 mg PO q4h as needed can be considered.Patients should be monitored for the development of opioid-induced constipation. A bowel routine should be initiatedconcurrently with the initiation and titration of opioids. Thefollowing regimens are suggested: senna glycoside 8.6 mg (2tablets) PO at bedtime, increased as needed (maximum 8tablets/day), or the total dose may be divided into BID dosing.Alternatively, polyethylene glycol 3350 at 8.5 g/day (one-halfcapful or one-half packet) or 17 g/day (1 capful, 1 packet, or≈1 heaping tablespoon) dissolved in 250 mL of liquid may beused and increased to BID if needed to ensure soft, easy-to-pass stool every 1–2 days.

2.11. IPF exacerbations

Acute worsening or the development of dyspnea, typicallyoccurring over the course of <30 days, may be an acuteexacerbation. IPF exacerbations are also characterized bynew bilateral ground glass opacities on HRCT, not fullyexplained by hydrostatic pulmonary edema (heart failure andfluid overload) [9]. Alternative diagnoses should be consideredin a patient with acute worsening dyspnea. In a patient witha history of smoking, emphysema, or chronic bronchitis,a COPD exacerbation should be considered if imaging studiesdo not show evidence of IPF exacerbation, because IPF canmask COPD in pulmonary function tests, due to the increasedelastic recoil of the lungs secondary to fibrosis, resulting inincreased airflows [9,126].

A chest x-ray can be used as an initial diagnostic test toeliminate differential diagnoses, such as atelectasis, pneumonia,pneumothorax, or congestive heart failure. If a patient’s chestx-ray is unchanged, a computed tomography pulmonary angio-gram (CTPA) should be considered to determine whether pul-monary embolism is present, provided renal function allowsadministration of the intravenous contrast required for CTPA[9]. The presence of ground glass opacities on CTPA or on chestHRCT would support the diagnosis of an IPF exacerbation.

IPF exacerbations are relatively uncommon (annual risk of5–15%), but have a very high short-term mortality (≈50%);therefore, the prevention, prompt diagnosis, and managementof IPF exacerbations are all very important [127]. Commonlyreported risk factors or triggers of IPF exacerbations includemore-advanced disease (low FVC or low DLCO), infections,GERD with microaspiration, air pollution, bronchoscopy, andsurgical procedures [9,108,128]. High pressures duringmechanical ventilation and high oxygen use during anesthesiahave been proposed as possible causes of alveolar injuryleading to an IPF exacerbation [9]. Therefore, if mechanicalventilation or anesthesia is required, judicious use of oxygenand low pressures is recommended. Other proposed preven-tive measures for IPF exacerbations are antacids, antifibrotics(to slow the IPF progression to advanced stages), and vaccina-tions against influenza and pneumococcus [127].

The management of IPF exacerbations typically includessupportive treatment, supplemental oxygen, and, despitevery limited evidence, systemic corticosteroids [1,94]. ThePANTHER-IPF trial found increased risk of mortality in patientsreceiving prednisone, azathioprine, and N-acetylcysteine, and

a single-center nonrandomized study of 24 patients with IPFwho experienced acute exacerbations found lower survival inthose who had previously received immunosuppressive ther-apy compared with those who had not [129,130]. Additionaldata are needed to evaluate the safety and efficacy of corti-costeroids and immunosuppressive therapy in patients whoexperience an IPF exacerbation [131].

We cautiously suggest initiating intravenous high-dose corti-costeroids (intravenous methylprednisolone 125–500 mg every12 hours) for 3 days followed by oral prednisone (50–100 mg/day) with a plan of tapering to discontinuation over 2–4 weeks.Oral methylprednisolone or dexamethasone might be consid-ered instead of prednisone, due to their lack of mineralocorti-coid effect, in patients with congestive heart failure, systemichypertension, or fluid retention (e.g. leg edema).

Small nonrandomized studies have reported associationsbetween other treatments and improved survival in patientswith IPF exacerbations; these treatments include preventiveantacids, cyclophosphamide, cyclosporine, tacrolimus, andcombined rituximab with plasma exchange and intravenousimmunoglobulin [9]. Initiation of empiric broad spectrum anti-biotics during IPF exacerbations is also routinely recom-mended by experts because bacterial infections are frequenttriggers of exacerbations and they are difficult to exclude incritically ill patients [132]. Whenever possible, sputum cultureand sensitivity should be ordered to guide antimicrobial ther-apy, especially in patients with suspected bacterial lowerrespiratory tract infection. Routine bronchoscopy in the clinicalassessment of acute respiratory failure in patients with ILD isnot indicated because diagnostic yield is low (13%), the pro-cedure is high risk in these patients, and it does not changemanagement approaches or in-hospital mortality [133].Supplemental oxygen, especially high-flow oxygen by nasalcannula or noninvasive ventilation, are recommended inpatients with IPF exacerbations to manage their dyspnea andhypoxemia [134]. Intubation and mechanical ventilation arenot recommended by the 2011 ATS/ERS/JRS/ALAT treatmentguidelines, based on the high rates of in-hospital mortality(90%) in these patients [1].

Patients with IPF should self-monitor for increased breath-lessness or fatigue, new or worsening cough, anxiety ordepression, and SaO2. A home pulse oximeter is an objectivemethod that patients can use to assess whether their worsen-ing dyspnea is due to hypoxemia, to determine the properflow-rate of oxygen at rest and during exertion, and to detectany increase in oxygen requirements. If a patient notices anychanges in symptoms, they should inform their physician orhome care nurse (if applicable) because the change couldindicate an acute exacerbation of IPF. Patients should seekimmediate medical attention for any sudden worsening ofdyspnea or increase in oxygen needs.

2.12. Nutrition

Both IPF itself and GI-related AEs associated with antifibrotictherapy can affect patients’ nutritional status, and their BMIshould be considered in many management decisions [63–65,135,136]. The needs for nutritional support to optimizecalories with protein and fat content varies in individual

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patients; both patients and their caregivers should be includedin discussions related to appropriate nutrition [136]. Dietarychanges may be needed to address obesity, which isa contraindication for lung transplant, or to control GERDsymptoms. Eating full meals can also help in the managementof gastrointestinal AEs associated with antifibrotic therapy,and dose reductions or interruptions should be consideredin patients with nausea or reduced appetite, with the knowl-edge that pirfenidone and nintedanib can maintain their effi-cacy at doses less than recommended [51,54,64,71]. In patientswith progressive weight loss due to nausea and reducedappetite despite antifibrotic dose reductions and the use ofPPIs and prokinetics (e.g. domperidone or metoclopramide),consider nutritional supplements (e.g. Ensure, Boost),a possible trial of oral cannabis where medical cannabis ispermitted, and referral to a dietician.

2.13. End-of-life preparations

End-of-life care should be discussed as early as possible toensure that patients and their families have the support theyneed to help the patient live as fully and comfortably as possi-ble [23,105]. This care can be provided in multiple settings,including a hospital, hospice facility, or the patient’s home.Documentation of a patient’s goals of care should includespecific information on their values, wishes, and beliefs; theirdesired level of medical interventions; the preferred site of caredelivery; and their life-support preferences. Documentationshould provide a clear understanding of a patient’s goals ofcare and should be communicated to the patient’s family, lovedones, and physicians. These are dynamic discussions thatshould begin early in the illness and continue throughout thecourse of the disease, especially at transition points, such assignificant worsening of pulmonary status or a decline in thepatient’s functional abilities. An interdisciplinary approach topalliative and end-of-life care is paramount and should includethe physicians, nurses, and social worker and could also includea spiritual health practitioner, volunteers, and counselors.

3. Conclusion

In summary, managing the care of a patient with IPF requiresa multifaceted approach that combines disease-specific stra-tegies for slowing disease progression and extending patientsurvival, simultaneously with palliative care to improve symp-tom management and QoL. This approach includes the follow-ing components: early initiation of antifibrotic therapy,assessment of physical and psychological needs, early inte-grated symptom management as part of a palliative careapproach, patient and caregiver education and support,open and often difficult communications, shared decision-making to facilitate time-sensitive decisions and advancecare planning, and ongoing reassessment of the patient’sgoals of care as the disease progresses. A patient’s preferencesand comorbidities should be considered prior to choosingantifibrotics, and TEAEs can be mitigated through educationand dose modifications. In addition to antifibrotics and inte-grated palliative care, PR, supplemental oxygen therapy, lungtransplant evaluation and referral, and advance care planning

should be established early in the disease course. ThroughoutIPF progression, oxygen requirements and the management ofdyspnea and cough need to be continually monitored. Theuse of opioids, antifibrotics, and a palliative care approach arenot barriers for lung transplant. Frequent communicationsshould occur with the patient and family to ensure theirunderstanding of the disease, treatment goals, and specificpatient goals and plans, particularly around end-of-life care.Finally, the importance of promoting collaborative practicebetween interdisciplinary team members needs to be high-lighted. Use of a multifaceted approach that targets all aspectsof IPF management throughout the course of the illness willensure that patients receive the most appropriate, compre-hensive, and patient-centered care possible.

4. Expert opinion

IPF management is complex: a multifaceted approach to man-agement that includes antifibrotic therapy, consideration ofreferral for lung transplant, treatment of comorbidities, pallia-tive care for symptom management, nutritional assessment,psychosocial support for patients, and caregiver support mayimprove QoL in patients with IPF. As new clinical trials areconducted to improve therapeutic options for patients withIPF and IPF-associated comorbidities, there is need forresearch to identify opportunities for improving and standar-dizing comprehensive care delivery in this patient population.A key challenge to achieving the goal of improved compre-hensive care is limited resources – both time and allied health-care providers – available to physicians who manage patientswith IPF within and outside of specialized centers. Here, wehighlight the need for multidisciplinary care to effectivelymanage this complex illness and to optimize patient survivaland QoL life. We hypothesize that the emergence of newpharmacological treatments and active research across thefields of pulmonology, nursing, palliative care, and lung trans-plantation will continue to lead to robust improvements insurvival and QoL in patients with IPF over the next decade.

Acknowledgments

The authors acknowledge Benjamin L. Ricca, PhD, of Health Interactions,Inc – third-party writing assistance funded by Hoffmann-La Roche Ltd.

Funding

This paper was sponsored by Hoffmann-La Roche Ltd.

Declaration of interest

Dr. Moran-Mendoza reports research funding, honoraria, clinical trial par-ticipation fees, and funding of editorial support from Hoffmann-La RocheLtd. and consultancy fees from Boehringer Ingelheim and Hoffmann-LaRoche Ltd. Dr. Colman reports honoraria from Boehringer Ingelheim andHoffmann-La Roche Ltd. and funding of editorial support from Hoffmann-La Roche Ltd. Meena Kalluri declares research funding, honoraria, clinicaltrial participation fees, and funding of editorial support from Hoffmann-LaRoche Ltd. and consultancy fees from Boehringer Ingelheim andHoffmann-La Roche Ltd. Dr Cabalteja is an employee of Hoffmann-LaRoche Ltd. Dr Harle reports funding of editorial support from Hoffmann-La Roche Ltd. The authors have no other relevant affiliations or financial

610 O. MORAN-MENDOZA ET AL.

involvement with any organization or entity with a financial interest in orfinancial conflict with the subject matter or materials discussed in themanuscript apart from those disclosed.

Reviewers Disclosure

Peer reviewers on this manuscript have no relevant financial relationshipsor otherwise to disclose.

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