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Recent Advances in Chest Medicine |

Management of Idiopathic Pulmonary Fibrosis in the Elderly PatientIdiopathic Pulmonary Fibrosis in the Elderly: Addressing Key Questions FREE TO VIEW

Keith C. Meyer, MD, FCCP; Sonye K. Danoff, MD, FCCP; Lisa H. Lancaster, MD; Steven D. Nathan, MD, FCCP
Author and Funding Information

From the Department of Medicine (Dr Meyer), Division of Allergy, Pulmonary, and Critical Care Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI; Division of Allergy, Pulmonary, and Critical Care Medicine (Dr Danoff), the Johns Hopkins University School of Medicine, Baltimore, MD; Division of Allergy, Pulmonary, and Critical Care Medicine (Dr Lancaster), the Vanderbilt University Medical Center, Nashville, TN; and Advanced Lung Disease and Transplant Program (Dr Nathan), Department of Medicine, Inova Health Systems, Falls Church, VA.

CORRESPONDENCE TO: Keith C. Meyer, MD, FCCP, University of Wisconsin School of Medicine and Public Health, K4/910 Clinical Science Center, 600 Highland Ave, Madison, WI 53792-9988; e-mail: kcm@medicine.wisc.edu


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;148(1):242-252. doi:10.1378/chest.14-2475
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Idiopathic pulmonary fibrosis (IPF) is strongly associated with advanced age. Making an accurate diagnosis of IPF is critical, as it remains only one of many potential diagnoses for an elderly patient with newly recognized interstitial lung disease. Optimal management of IPF, especially in older-aged patients, hinges on such factors as balancing the application of standard-of-care measures with the patient’s overall health status (robustness vs frailty) and considering the patient’s wishes, desires, and expectations. IPF is known to be associated with certain comorbidities that tend to be more prevalent in the elderly population. Until recently, options for the pharmacologic management of IPF were limited and included therapies such as immunosuppressive agents, which may pose substantial risk to the elderly patient. However, the antifibrotic agents pirfenidone and nintedanib have now become commercially available in the United States for the treatment of IPF. The monitoring and treatment of patients with IPF, especially elderly patients with comorbid medical conditions, require consideration of adverse side effects, the avoidance of potential drug-drug interactions, treatment of comorbidities, and the timely implementation of supportive and palliative measures. Individualized counseling to guide decision-making and enhance quality of life is also integral to optimal management of the elderly patient with IPF.

Achieving age 65 years or older is generally defined as elderly in developed countries and in the medical literature. Because of the aging process, elderly individuals display gradual organ system functional decline that is likely linked to cumulative damage to molecules, cells, and tissues that occurs over a lifetime.1 However, there are considerable interindividual differences in the rate of decline. Some people maintain robust physiologic function well beyond their sixth decade of life, whereas others may be seriously challenged by progressive organ system dysfunction and frailty as they age (Table 1).2,3

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TABLE 1 ]  Characteristics of Fit vs Frail Elderly Individuals

Various types of interstitial lung disease (ILD) can affect individuals of any age, but idiopathic pulmonary fibrosis (IPF) stands out as a form of ILD strongly associated with advanced age, with resultant high prevalence in the elderly.4,5 The clinical evaluation of an elderly individual with possible IPF should seek to balance attaining a confident diagnosis while also minimizing risk of harm to the patient. Subsequent management of elderly patients with IPF should include personalized, targeted therapy that optimizes quality of life and survival but limits the risk of significant adverse events associated with any recommended treatment. This article reviews and examines key issues faced by clinicians evaluating and managing IPF in elderly patients.

IPF is one of many potential diagnoses for a patient with newly recognized ILD. Therefore, accurately diagnosing IPF remains one of the most basic, yet critical steps in providing optimal care for the elderly patient with ILD.6,7 The American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association consensus statement on the diagnosis and management of IPF provides a useful diagnostic algorithm for evaluating a patient with possible IPF.8

Most elderly patients with new-onset ILD present with symptoms including dyspnea with exertion, cough, or fatigue. Less commonly, patients are identified when interstitial abnormalities are incidentally detected on radiographs obtained for other purposes. With increasing acceptance of screening CT scan of the chest, it is likely that more cases of ILD in the elderly will emerge. The initial evaluation of a patient with suspected ILD should include careful physical examination that may identify basilar crackles on lung auscultation and the variable presence of digital clubbing. Pulmonary function testing usually shows a reduced FVC and total lung capacity as well as a reduced single breath diffusing capacity of lung for carbon monoxide (Dlco). If symptoms, signs, and physiology are consistent with a restrictive lung disease, then the diagnosis of IPF should be explicitly considered.

The best test for radiographic diagnostic assessment is a noncontrast, thoracic high-resolution CT (HRCT) scan (1-2 mm cuts) performed at full inspiration with supine, prone, and expiratory imaging. Findings consistent with a definite usual interstitial pneumonia (UIP) pattern on HRCT scanning allow clinicians to make a confident diagnosis of IPF. These HRCT scan features include changes that are subpleural, predominantly affecting the lung bases, reticular changes, honeycombing with or without traction bronchiectasis, and the absence of features inconsistent with a UIP pattern. Advanced age combined with extensive interstitial fibrosis on HRCT scanning is highly predictive of a diagnosis of IPF.9

The next (and most important) step is the exclusion of alternative causes that include pneumotoxic drug reactions caused by commonly used medications (eg, amiodarone, methotrexate, nitrofurantoin), ILD associated with the presence of connective tissue disease (CTD), and ILD caused by occupational or environmental exposures. Other prominent mimics of IPF include fibrotic nonspecific interstitial pneumonia and chronic hypersensitivity pneumonitis. The clinical evaluation of a patient with suspected IPF should include serologic testing to exclude common autoimmune processes that may manifest primarily as ILD, since subsequent management options are strongly influenced by this distinction. However, it should be recognized that the prevalence of positive autoantibodies increases with advancing age.10 Therefore, positive serologic testing for rheumatoid factor or low-level antinuclear antibodies is not by itself diagnostic of the presence of CTD, and if other CTD diagnostic criteria are absent, a diagnosis of IPF is not ruled out.

For older patients whose HRCT scan findings are not definitive or probable for UIP, a surgical lung biopsy (SLB) can be considered. The decision to perform a biopsy should be weighed with the recognized potential for complications,11,12 especially in the frail elderly patient. Potential risks and benefits should be carefully discussed with the patient, particularly emphasizing how the SLB findings will affect subsequent management decisions. Additionally, the age of the patient does factor into the pretest likelihood of the patient having IPF and, therefore, the need for a biopsy in any given clinical situation decreases with age.9 If a biopsy is obtained, a UIP histopathologic pattern can provide a diagnosis of IPF if other causes have been excluded. Ideally, the SLB should be reviewed and discussed by a multidisciplinary group (pulmonologists, radiologists, and pathologists) that evaluates the clinical presentation, imaging results, and pathology findings to achieve a consensus diagnosis.13

It is well established that the prognosis of IPF is significantly worse in elderly patients than in younger patients.14,15 There are a number of potential explanations, including a more aggressive disease course in the elderly, lead-time bias with or without a delay in diagnosis, and a more significant impact of IPF-associated comorbidities on outcomes in elderly patients. A variety of comorbidities and complications16 (Table 2) can have a profound impact on quality of life and outcomes, especially in the elderly patient. Indeed, some patients may succumb with their IPF rather than from their IPF.

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TABLE 2 ]  Comorbid Disorders and Complications Associated with IPF in Elderly Patients

IPF = idiopathic pulmonary fibrosis.

a 

May have preserved ejection fraction.

Coexistent pulmonary fibrosis with emphysema (CPFE) has been described in approximately one-third of patients with IPF.17 An important clue suggesting the presence of CPFE is a significantly reduced Dlco in the context of normal or mildly reduced lung volume measurements, which is due to the counterbalancing effects of the restrictive and obstructive processes on lung mechanics. Whether elderly patients have a greater propensity for CPFE than younger patients with IPF is unknown; it is conceivable, however, that a history of COPD might result in the underdiagnosis of CPFE in the elderly, since its detection is invariably contingent on chest CT scanning, which may be less likely to be performed in patients with a known diagnosis of COPD. CPFE is more likely to be complicated by pulmonary hypertension (PH) and may be associated with a worse prognosis than IPF. However, in patients with a prior diagnosis of COPD and progressive dyspnea with basilar crackles, it certainly warrants consideration, since such patients may be candidates for antifibrotic or other therapies.

PH is another common complication and may portend worse outcomes in IPF.18 However, there are no data suggesting a higher incidence of PH in elderly vs younger patients with IPF. It is conceivable that elderly patients might be more predisposed to comorbidities that could contribute to the development of PH, including heart failure, coronary artery disease (CAD), thromboembolic disease, and OSA.1921

The presence of CAD, in particular, is an independent risk factor for mortality in IPF.19 Most of the studies attesting to this association have been in younger patients with IPF being evaluated for lung transplantation, but the association between CAD and IPF is likely to be stronger in the elderly owing to an increased prevalence of CAD in this age group. OSA is highly prevalent in patients with IPF and more common in the elderly; moreover, OSA is associated with the presence of other IPF comorbidities, such as gastroesophageal reflux disease (GERD), PH, and CAD.21 It is possible that sleep-disordered breathing could have a cascade effect on these other comorbidities, such as the development or worsening of CAD, PH, and GERD.21,22

GERD is not only associated with advanced age but also highly prevalent in the IPF population. Gastroesophageal reflux (GER) with microaspiration may play a significant role in IPF pathogenesis and episodes of acute disease exacerbation.2225 However, GER is often silent in IPF, with only 47% of patients in one study experiencing GER symptoms when a significant degree of reflux was detected by pH monitoring.22 The role of GER in the initiation and perpetuation of lung disease in IPF remains unknown, but studies suggest that it may have an impact on lung function and survival.26,27

Once a confident diagnosis of IPF has been attained, optimal management must balance standard-of-care measures with the patient’s overall health status as well as the patient’s wishes, desires, and expectations. For serial monitoring of health status, it is usual practice to see patients with IPF every 3 to 6 months. At each visit, consideration should be given to pulmonary function testing, a 6-min walk test (6MWT), and oxygen titration walk study.2832 However, clinical testing should be adjusted according to the usefulness of the information obtained and whether management will be influenced by the results. Ongoing management should also include counseling about prognosis; consequently, the results of serial physiologic testing may provide a platform for a transition from a disease-oriented to a more palliative approach including end-of-life discussions. Additionally, interpretation of lung function testing (especially the 6MWT) needs to be placed in the context of other comorbidities. For example, if an elderly patient has walk-limiting musculoskeletal disease or significant frailty with sarcopenia, the usefulness of the 6MWT may be largely negated.

The role and usefulness of supportive measures should not be neglected in the elderly patient with IPF. The threshold at which supplemental oxygen therapy is prescribed for an elderly patient should be the same as that for any other patient with IPF, but selection of the delivery system should be balanced by the ability of the elderly patient to manage and ambulate with the recommended devices.33 Pulmonary rehabilitation is an important management resource for all patients with IPF irrespective of age and may improve long-term outcomes.34 Although an elderly patient’s ability to participate in and complete usual pulmonary rehabilitation activities may be limited by various comorbidities, any exercise and all activities performed on a regular basis are key to maintaining functional status. In addition, instructions provided during rehabilitation sessions for managing day-to-day activity and performing breathing exercises may be invaluable.35 Assessment of comorbidities that contribute to shortness of breath should also be a point of focus. Careful management of these comorbidities, such as CAD and congestive heart failure, may lessen shortness of breath and improve of quality of life.

Finding effective pharmacologic treatment of IPF has mostly proven elusive despite the completion of many clinical trials.7,36 Medical therapies prescribed for patients with IPF have ranged from corticosteroids to cytotoxic drugs or various combinations, but these were previously adopted in the absence of robust clinical trial results.36,37 Indeed, immunosuppressive therapies that were suggested and commonly administered prior to publication of the current American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guideline were undoubtedly more harmful than beneficial in patients with IPF.8,38 Indeed, when an adequately powered, prospective, randomized clinical trial (Prednisone, Azathioprine, and N-Acetylcysteine: a Study That Evaluates Response in Idiopathic Pulmonary Fibrosis [PANTHER-IPF]) of an azathioprine-based regimen (azathioprine, prednisone, and N-acetylcysteine [NAC]) with a true placebo arm was finally performed, there was a significant increase in mortality with triple therapy.39 Anticoagulation as a primary form of therapy for IPF (given to prevent thrombosis-related clinical events and to potentially antagonize the role of procoagulant enzymes in the fibrotic process) has also been shown to be associated with increased hospitalization and mortality.40 However, it should be stressed that anticoagulant therapy should not be withheld if patients require it for other indications, such as atrial fibrillation or thromboembolic events. Although observational studies have suggested that antireflux medications may have a significant beneficial impact on FVC decline, risk of acute exacerbation, and survival,26,27 additional research is needed to determine the efficacy of antireflux measures as therapy for IPF. Finally, although NAC has been suggested as providing benefit in IPF through its antioxidant properties,41 a recently completed trial of NAC vs placebo demonstrated no benefit.42

Clinical trials of novel antifibrotic agents have shown some success in the treatment of IPF.4346 The recently completed phase 3 Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) clinical trial showed a significant impact of pirfenidone on FVC and progression-free survival compared with placebo.45 In addition, a significant survival benefit was observed when outcome data from the replicate, similarly performed phase 3 Clinical Studies Assessing Pirfenidone in Idiopathic Pulmonary Fibrosis: Research of Efficacy and Safety Outcomes (CAPACITY) trials were combined with the ASCEND data in a prespecified, pooled analysis.44,45 Results from the replicate Safety and Efficacy of BIBF 1120 at High Dose in Idiopathic Pulmonary Fibrosis Patients (INPULSIS) trials of nintedanib also demonstrated a significant impact on FVC decline, and the risk of acute exacerbation of IPF was significantly reduced in the INPULSIS-2 trial (hazard ratio, 0.38), although this was not observed for INPULSIS-1.46 The positive results from the ASCEND and INPULSIS trials led to the licensing of both pirfenidone and nintedanib by the US Food and Drug Administration on October 15, 2014, for treatment of patients with IPF.

Data from trials with pirfenidone and nintedanib have shown these drugs to be generally well tolerated and reasonably safe, but significant side effects can occur (Table 3).47,48 Therefore, several precautions are recommended when these drugs are prescribed. For example, elderly patients are frequently taking multiple medications that may be significant inhibitors or inducers of the hepatic enzyme systems (CYP1A2, CYP3A4, P-glycoprotein) that metabolize these drugs. Since most IPF studies have typically excluded patients beyond 80 years of age, the efficacy and tolerability of new therapies in the oldest of the elderly population remain mostly unknown. However, a subgroup analysis of patients older than 65 years in the CAPACITY studies of pirfenidone did not show an increased incidence of adverse side effects or reduced efficacy,44 and a similar benefit of pirfenidone over placebo on FVC decline was observed for age subgroups < 65, 65 to 74, or ≥ 74 years when pooled data from the ASCEND and CAPACITY trials were recently analyzed.49 This raises the notion that elderly patients should not be excluded from future clinical trials, especially when recruitment remains an ongoing issue.

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TABLE 3 ]  Antifibrotic Agents for IPF: Properties, Side Effects, and Precautions

ALT = alanine aminotransferase; AST = aspartate aminotransferase; FGFR = fibroblast growth factor receptor; GERD = gastroesophageal reflux disease; PDGFR = platelet-derived growth factor receptor; VEGFR = vascular endothelial growth factor receptor.

a 

Occurred in ≥ 10% of treated patients and more commonly than placebo in clinical trials. Clinical trials conducted under varying conditions and in varied patient populations. Not intended for head-to-head comparison.

b 

Frequency not available.

Although immunosuppressive therapies may provide significant benefit to patients with non-IPF inflammatory or autoimmune lung diseases,50 such therapies appear to provide little benefit and may pose substantial risk for the elderly patient with IPF. Antifibrotic therapies (eg, pirfenidone, nintedanib) have the potential to provide significant benefit, but the elderly patient must be able to comply with a treatment regimen and should have adequate monitoring for adverse side effects such as GI intolerance, liver enzyme elevation (both pirfenidone and nintedanib), and skin reactions (pirfenidone).45,46 In addition, because many elderly patients receive multiple medications for other medical conditions, clinicians must monitor carefully for possible drug-drug interactions.

Historically, lung transplantation was reserved for patients < 65 years of age, but the 2006 International Society for Heart and Lung Transplantation guidelines recommended an upper age limit of 70 years, and the most recent (2014) guidelines suggest a limit of 75 years.51 These guidelines reflect the evolution of clinical practice, with the relative number of patients ≥ 65 years of age undergoing lung transplantation progressively increasing, whereas an examination of the United Network for Organ Sharing registry data did not detect a significant disparity in outcomes for patients ≥ 70 years old vs patients aged 60 to 69 years.52 Age itself needs to be viewed in the context of the patient’s overall condition, including the degree of frailty, which may play a decisive role in posttransplant survival.53 Although lung transplantation can be considered as a treatment option for select elderly patients with IPF, potential candidates must understand the substantial risks involved if a lung transplant is performed. Whether a patient with IPF is a potential transplant candidate should not influence the decision for an early referral to a subspecialty care center. Indeed, Lamas and colleagues54 have found that early referral may have a significant beneficial impact on survival for patients with IPF that is independent of disease severity with or without lung transplantation.

IPF is a heterogeneous disorder with a clinical course that varies from prolonged periods of stability to episodes of rapid progression8,14; therefore, clinicians must carefully consider many factors when providing patients with a prognosis. Patients with a lesser degree of fibrotic change on HRCT scan are likely to have a better survival with relatively stable lung function when compared with those with HRCT scan changes that indicate “definite” UIP, a greater degree of fibrotic change, or both.5558 Changes in FVC, Dlco, and 6MWT distance, as well as the need for supplemental oxygen, have also been correlated with the risk of disease progression.29,30,32,5963 An FVC decline of ≥ 10%, a Dlco decline of ≥ 15%, declining 6MWT distance, and oxyhemoglobin desaturation during a 6MWT to < 88% have all been correlated with decreased survival. Additionally, both all-cause and respiratory hospitalizations have implications for a greater risk of subsequent mortality.64 Although elderly patients with IPF might be more apt to be hospitalized owing to their greater propensity for comorbidities, differences in hospitalization rate based on age were not borne out in a recent large retrospective analysis of 592 patients.65 Finally, frailty has been shown to correlate with diminished survival for patients with COPD,66 but this outcome measure has not yet been studied in an IPF population.

Other factors may affect disease progression, including the presence or absence of specific gene polymorphisms,67,68 use of supplemental oxygen, and administration of statins or proton pump inhibitors that may affect fibrogenesis.26,27,69 A number of biomarkers have been identified (eg, matrix metalloproteinase-7, Krebs von den Lungen-6, surfactant proteins) that appear to correlate with disease progression and mortality.62,70 These biomarkers are being validated in clinical trial settings but are not as yet routinely available or currently recommended for clinical use. In addition, scoring systems such as the GAP (gender, age, lung physiology) index have been correlated with disease outcome and may prove useful in clinical trial design and clinical prognostication.15

Traditionally, the care of patients with IPF has largely been driven by a disease-centered model, which assumes that treating the disease treats the patient and, thus, leads to improved quality and quantity of life. However, adopting a patient-centered care model may be far more effective, especially for managing older patients with IPF.71 In the elderly patient population, IPF occurs in the context of accumulating age-related comorbidities. Therefore, evaluating elderly patients for treatable disorders, such as cardiac disease and OSA, can have a significant beneficial impact on patients’ symptoms and quality of life. Furthermore, addressing issues such as deconditioning through pulmonary rehabilitation may have a positive effect on both physiologic and psychologic measures. Patients in whom oxygen desaturation occurs with activity are likely to experience an exercise-tolerance benefit if prescribed oxygen supplementation. Teaching patients how to use a home pulse oximeter and providing guidelines on how oxygen flow rates can be raised and lowered in particular situations can also contribute a measure of patient control. Additionally, nocturnal oxyhemoglobin desaturation can be detected by means of screening with overnight oximetry. The degree of intermittent oxyhemoglobin desaturation during sleep may exceed that associated with maximal exercise and has been associated with survival in IPF.72 Therefore, providing supplemental oxygen to patients with significant nocturnal desaturation may decrease the risk of developing PH and improve survival. However, a significant benefit for oxygen supplementation during sleep in patients with IPF with nocturnal desaturation has not as yet been reported.

Significant emotional burdens invariably accompany IPF, and elderly patients face the loss of autonomy as dyspnea becomes increasingly limiting. Although supplemental oxygen can improve endurance, it also renders the disease visible, and patients may have to struggle to explain the presence of oxygen cannulas to young grandchildren and peers. Patients with cough are often frustrated by the disruption of their social lives, and they may be hesitant to go outside their homes for fear others will think they are “contagious.” Addressing these concerns on an individual basis can provide the necessary starting point to help patients find suitable coping strategies while encouraging patients to identify activities that are meaningful to them, and developing plans for continuation of these activities can foster a sense of control.

Symptom management and palliation should be a component of patient care from the time that the initial diagnosis is established.73 When patients have progressive lung function loss and worsening quality of life despite a disease-centered approach with antifibrotic therapies and other interventions, management should increasingly focus on patient support and symptom control, which are integral aspects of palliative care. Pulmonary rehabilitation, supplemental oxygen use, cough suppression, counseling, and psychosocial support, as well as the identification and treatment of comorbidities, can provide significant benefit, improve quality of life, and help patients cope with key symptoms (shortness of breath, cough, depression, anxiety, insomnia, deconditioning, and fatigue) of their disease.71,74 Unfortunately, effective treatment of cough, a debilitating symptom that affects up to 80% of patients with IPF and has been correlated with survival,75 remains elusive, although a clinical trial with thalidomide showed significant improvement in cough and respiratory-related quality of life.76

Because respiratory failure is ultimately the major cause of death in patients with IPF,5,62 acknowledging this reality in a sensitive manner is critical in creating an effective doctor-patient relationship. Providing an opportunity for patients and their family members to ask uncomfortable questions is one of the most important steps on the path to caring for the elderly patient with IPF. Discussing end-of-life care is another critical aspect of the ongoing conversation with elderly patients who have IPF. This subject is best broached early, before there is a need for an immediate answer. Coupling this conversation with discussion of the availability of palliative care to minimize symptoms as the disease progresses is often an effective strategy. Preferably, advance care planning should be initiated by health-care providers before a crisis occurs and death appears imminent. Patients should be made aware that regaining a reasonably good quality of life following deterioration in respiratory function that requires mechanical ventilation is relatively unlikely,65,77 as this may help them in their decision-making.

The prevalence of IPF is highest in the population of affected patients who are elderly, making optimal IPF management in this group an important priority for their health-care providers. IPF can be effectively managed even in the “oldest old” (Table 4). Critical steps include an accurate and timely diagnosis that minimizes risk of harm; careful assessment of disease status; provision of disease-specific, supportive, and palliative care as needs evolve; and appropriate monitoring. Additionally, clinicians should have a high index of suspicion for the presence of common comorbidities, since successful management of these conditions can have a meaningful impact on patient outcomes. Potential adverse side effects of emerging medical therapies and drug-drug interactions require special attention in elderly patients. Like their younger counterparts, older patients also benefit from individually tailored counseling focused on the emotional and psychosocial burdens of IPF, techniques for improving health-related quality of life, and, at the appropriate time, end-of-life issues.

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TABLE 4 ]  Key Aspects of Disease Management in the Elderly Patient With IPF

See Table 2 and 4 legends for expansion of abbreviations.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Meyer is a consultant for InterMune and Medimmune in the field of IPF, and he has received research funding from Actelion Pharmaceuticals Ltd; Boehringer Ingelheim GmbH; Bristol-Myers Squibb; FibroGen, Inc; InterMune; and the National Institutes of Health in the field of IPF. Dr Danoff participates in an industry advisory committee for Boehringer Ingelheim GmbH and the ASCEND Mortality Assessment Committee for InterMune. Dr Lancaster participates in industry advisory committees for Boehringer Ingelheim GmbH and InterMune. Dr Nathan participates in Speaker Bureau activities for Bayer AG, Gilead, and United Therapeutics Corporation. He also participates in industry advisory committees for Actelion Pharmaceuticals Ltd, Bayer, Gilead, InterMune, Roche Diagnostics, and United Therapeutics Corporation.

Other contributions: This publication originated from an Expert Roundtable discussion, “Management of IPF in the Elderly Patient,” which took place on October 26, 2013, in Chicago, Illinois, and was supported by InterMune. Editorial assistance in the preparation of the manuscript was provided by BioScience Communications, New York, NY, supported by InterMune.

6MWT

6-min walk test

ASCEND

Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis

CAD

coronary artery disease

CAPACITY

Clinical Studies Assessing Pirfenidone in Idiopathic Pulmonary Fibrosis: Research of Efficacy and Safety Outcomes

CPFE

coexistent pulmonary fibrosis with emphysema

CTD

connective tissue disease

Dlco

diffusing capacity of lung for carbon monoxide

GER

gastroesophageal reflux

GERD

gastroesophageal reflux disease

HRCT

high-resolution CT

ILD

interstitial lung disease

INPULSIS

Safety and Efficacy of BIBF 1120 at High Dose in Idiopathic Pulmonary Fibrosis Patients

IPF

idiopathic pulmonary fibrosis

NAC

N-acetylcysteine

PH

pulmonary hypertension

SLB

surgical lung biopsy

UIP

usual interstitial pneumonia

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Raghu G, Meyer KC. Silent gastro-oesophageal reflux and microaspiration in IPF: mounting evidence for anti-reflux therapy? Eur Respir J. 2012;39(2):242-245. [CrossRef] [PubMed]
 
Lee JS, Ryu JH, Elicker BM, et al. Gastroesophageal reflux therapy is associated with longer survival in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;184(12):1390-1394. [CrossRef] [PubMed]
 
Lee JS, Collard HR, Anstrom KJ, et al. IPFnet Investigators. Anti-acid therapy and disease progression in idiopathic pulmonary fibrosis: an analysis of data from three randomized controlled trials. Lancet Respir Med. 2013;1(5):369-376. [CrossRef] [PubMed]
 
Zappala CJ, Latsi PI, Nicholson AG, et al. Marginal decline in forced vital capacity is associated with a poor outcome in idiopathic pulmonary fibrosis. Eur Respir J. 2010;35(4):830-836. [CrossRef] [PubMed]
 
du Bois RM, Weycker D, Albera C, et al. Forced vital capacity in patients with idiopathic pulmonary fibrosis: test properties and minimal clinically important difference. Am J Respir Crit Care Med. 2011;184(12):1382-1389. [CrossRef] [PubMed]
 
Lama VN, Flaherty KR, Toews GB, et al. Prognostic value of desaturation during a 6-minute walk test in idiopathic interstitial pneumonia. Am J Respir Crit Care Med. 2003;168(9):1084-1090. [CrossRef] [PubMed]
 
Caminati A, Bianchi A, Cassandro R, Mirenda MR, Harari S. Walking distance on 6-MWT is a prognostic factor in idiopathic pulmonary fibrosis. Respir Med. 2009;103(1):117-123. [CrossRef] [PubMed]
 
du Bois RM, Weycker D, Albera C, et al. Six-minute-walk test in idiopathic pulmonary fibrosis: test validation and minimal clinically important difference. Am J Respir Crit Care Med. 2011;183(9):1231-1237. [CrossRef] [PubMed]
 
Crockett AJ, Cranston JM, Antic N. Domiciliary oxygen for interstitial lung disease. Cochrane Database Syst Rev. 2001;;(3):CD002883.
 
Ryerson CJ, Cayou C, Topp F, et al. Pulmonary rehabilitation improves long-term outcomes in interstitial lung disease: a prospective cohort study. Respir Med. 2014;108(1):203-210. [CrossRef] [PubMed]
 
Ferreira A, Garvey C, Connors GL, et al. Pulmonary rehabilitation in interstitial lung disease: benefits and predictors of response. Chest. 2009;135(2):442-447. [CrossRef] [PubMed]
 
Kim R, Meyer KC. Therapies for interstitial lung disease: past, present and future. Ther Adv Respir Dis. 2008;2(5):319-338. [CrossRef] [PubMed]
 
Peikert T, Daniels CE, Beebe TJ, Meyer KC, Ryu JH; Interstitial Lung Diseases Network of the American College of Chest Physicians. Assessment of current practice in the diagnosis and therapy of idiopathic pulmonary fibrosis. Respir Med. 2008;102(9):1342-1348. [CrossRef] [PubMed]
 
American Thoracic Society. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med. 2000;161(2 pt 1):646-664. [PubMed]
 
Raghu G, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ; Idiopathic Pulmonary Fibrosis Clinical Research Network. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012;366(21):1968-1977. [CrossRef] [PubMed]
 
Noth I, Anstrom KJ, Calvert SB, et al; Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFnet). A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2012;186(1):88-95. [CrossRef] [PubMed]
 
Demedts M, Behr J, Buhl R, et al; IFIGENIA Study Group. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. 2005;353(21):2229-2242. [CrossRef] [PubMed]
 
Martinez FJ, de Andrade JA, Anstrom KJ, King TE Jr, Raghu G; Idiopathic Pulmonary Fibrosis Clinical Research Network. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2093-2101. [CrossRef] [PubMed]
 
Taniguchi H, Ebina M, Kondoh Y, et al; Pirfenidone Clinical Study Group in Japan. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J. 2010;35(4):821-829. [CrossRef] [PubMed]
 
Noble PW, Albera C, Bradford WZ, et al; CAPACITY Study Group. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. 2011;377(9779):1760-1769. [CrossRef] [PubMed]
 
King TE Jr, Bradford WZ, Castro-Bernardini S, et al; ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2083-2092. [CrossRef] [PubMed]
 
Richeldi L, du Bois RM, Raghu G, et al; INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071-2082. [CrossRef] [PubMed]
 
Esbriet [package insert]. Brisbane, CA: InterMune, Inc; 2014.
 
Ofev [package insert]. Ridgefield, CT: Boehringer-Ingelheim Pharmaceuticals, Inc; 2014.
 
Noble PW, Albera C, Bradford WZ, et al. Analysis of pooled data from 3 phase 3, multinational, randomized, double-blind, placebo controlled trials evaluating pirfendione in patients with idiopathic pulmonary fibrosis (IPF) [abstract]. Am J Respir Crit Care Med. 2014;189:A1423.
 
Meyer KC, Bierach J. Immunosuppressive therapy for autoimmune lung diseases. Immunol Allergy Clin North Am. 2012;32(4):633-669. [CrossRef] [PubMed]
 
Weill D, Benden C, Corris PA, et al. A consensus document for the selection of lung transplant candidates: 2014-An update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2015;34(1):1-15. [CrossRef] [PubMed]
 
Kilic A, Merlo CA, Conte JV, Shah AS. Lung transplantation in patients 70 years old or older: have outcomes changed after implementation of the lung allocation score? J Thorac Cardiovasc Surg. 2012;144(5):1133-1138. [CrossRef] [PubMed]
 
Hook JL, Lederer DJ. Selecting lung transplant candidates: where do current guidelines fall short? Expert Rev Respir Med. 2012;6(1):51-61. [CrossRef] [PubMed]
 
Lamas DJ, Kawut SM, Bagiella E, Philip N, Arcasoy SM, Lederer DJ. Delayed access and survival in idiopathic pulmonary fibrosis: a cohort study. Am J Respir Crit Care Med. 2011;184(7):842-847. [CrossRef] [PubMed]
 
Flaherty KR, Thwaite EL, Kazerooni EA, et al. Radiological versus histological diagnosis in UIP and NSIP: survival implications. Thorax. 2003;58(2):143-148. [CrossRef] [PubMed]
 
Lynch DA, Godwin JD, Safrin S, et al; Idiopathic Pulmonary Fibrosis Study Group. High-resolution computed tomography in idiopathic pulmonary fibrosis: diagnosis and prognosis. Am J Respir Crit Care Med. 2005;172(4):488-493. [CrossRef] [PubMed]
 
Oda K, Ishimoto H, Yatera K, et al. High-resolution CT scoring system-based grading scale predicts the clinical outcomes in patients with idiopathic pulmonary fibrosis. Respir Res. 2014;15:10. [CrossRef] [PubMed]
 
Ley B, Elicker BM, Hartman TE, et al. Idiopathic pulmonary fibrosis: CT and risk of death. Radiology. 2014;273(2):570-579. [CrossRef] [PubMed]
 
Flaherty KR, Andrei AC, Murray S, et al. Idiopathic pulmonary fibrosis: prognostic value of changes in physiology and six-minute-walk test. Am J Respir Crit Care Med. 2006;174(7):803-809. [CrossRef] [PubMed]
 
Nathan SD, Shlobin OA, Weir N, et al. Long-term course and prognosis of idiopathic pulmonary fibrosis in the new millennium. Chest. 2011;140(1):221-229. [CrossRef] [PubMed]
 
Hook JL, Arcasoy SM, Zemmel D, Bartels MN, Kawut SM, Lederer DJ. Titrated oxygen requirement and prognostication in idiopathic pulmonary fibrosis. Eur Respir J. 2012;39(2):359-365. [CrossRef] [PubMed]
 
Ley B, Collard HR, King TE Jr. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;183(4):431-440. [CrossRef] [PubMed]
 
Lettieri CJ, Nathan SD, Browning RF, Barnett SD, Ahmad S, Shorr AF. The distance-saturation product predicts mortality in idiopathic pulmonary fibrosis. Respir Med. 2006;100(10):1734-1741. [CrossRef] [PubMed]
 
Nathan SD, Meyer KC. IPF clinical trial design and endpoints. Curr Opin Pulm Med. 2014;20(5):463-471. [CrossRef] [PubMed]
 
Brown AW, Fischer CP, Shlobin OA, et al. Outcomes after hospitalization in idiopathic pulmonary fibrosis: a cohort study. Chest. 2015;147(1):173-179. [CrossRef] [PubMed]
 
Galizia G, Cacciatore F, Testa G, et al. Role of clinical frailty on long-term mortality of elderly subjects with and without chronic obstructive pulmonary disease. Aging Clin Exp Res. 2011;23(2):118-125. [CrossRef] [PubMed]
 
Peljto AL, Zhang Y, Fingerlin TE, et al. Association between the MUC5B promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis. JAMA. 2013;309(21):2232-2239. [CrossRef] [PubMed]
 
Noth I, Zhang Y, Ma SF, et al. Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study. Lancet Respir Med. 2013;1(4):309-317. [CrossRef] [PubMed]
 
Watts KL, Sampson EM, Schultz GS, Spiteri MA. Simvastatin inhibits growth factor expression and modulates profibrogenic markers in lung fibroblasts. Am J Respir Cell Mol Biol. 2005;32(4):290-300. [CrossRef] [PubMed]
 
Zhang Y, Kaminski N. Biomarkers in idiopathic pulmonary fibrosis. Curr Opin Pulm Med. 2012;18(5):441-446. [CrossRef] [PubMed]
 
Lee JS, McLaughlin S, Collard HR. Comprehensive care of the patient with idiopathic pulmonary fibrosis. Curr Opin Pulm Med. 2011;17(5):348-354. [CrossRef] [PubMed]
 
Kolilekas L, Manali E, Vlami KA, et al. Sleep oxygen desaturation predicts survival in idiopathic pulmonary fibrosis. J Clin Sleep Med. 2013;9(6):593-601. [PubMed]
 
Lanken PN, Terry PB, Delisser HM, et al; ATS End-of-Life Care Task Force. An official American Thoracic Society clinical policy statement: palliative care for patients with respiratory diseases and critical illnesses. Am J Respir Crit Care Med. 2008;177(8):912-927. [CrossRef] [PubMed]
 
Bajwah S, Higginson IJ, Ross JR, et al. The palliative care needs for fibrotic interstitial lung disease: a qualitative study of patients, informal caregivers and health professionals. Palliat Med. 2013;27(9):869-876. [CrossRef] [PubMed]
 
Ryerson CJ, Abbritti M, Ley B, Elicker BM, Jones KD, Collard HR. Cough predicts prognosis in idiopathic pulmonary fibrosis. Respirology. 2011;16(6):969-975. [CrossRef] [PubMed]
 
Horton MR, Santopietro V, Mathew L, et al. Thalidomide for the treatment of cough in idiopathic pulmonary fibrosis: a randomized trial. Ann Intern Med. 2012;157(6):398-406. [CrossRef] [PubMed]
 
Stern JB, Mal H, Groussard O, et al. Prognosis of patients with advanced idiopathic pulmonary fibrosis requiring mechanical ventilation for acute respiratory failure. Chest. 2001;120(1):213-219. [CrossRef] [PubMed]
 

Figures

Tables

Table Graphic Jump Location
TABLE 1 ]  Characteristics of Fit vs Frail Elderly Individuals
Table Graphic Jump Location
TABLE 2 ]  Comorbid Disorders and Complications Associated with IPF in Elderly Patients

IPF = idiopathic pulmonary fibrosis.

a 

May have preserved ejection fraction.

Table Graphic Jump Location
TABLE 3 ]  Antifibrotic Agents for IPF: Properties, Side Effects, and Precautions

ALT = alanine aminotransferase; AST = aspartate aminotransferase; FGFR = fibroblast growth factor receptor; GERD = gastroesophageal reflux disease; PDGFR = platelet-derived growth factor receptor; VEGFR = vascular endothelial growth factor receptor.

a 

Occurred in ≥ 10% of treated patients and more commonly than placebo in clinical trials. Clinical trials conducted under varying conditions and in varied patient populations. Not intended for head-to-head comparison.

b 

Frequency not available.

Table Graphic Jump Location
TABLE 4 ]  Key Aspects of Disease Management in the Elderly Patient With IPF

See Table 2 and 4 legends for expansion of abbreviations.

References

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Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2006;174(7):810-816. [CrossRef] [PubMed]
 
Fernández Pérez ER, Daniels CE, Schroeder DR, et al. Incidence, prevalence, and clinical course of idiopathic pulmonary fibrosis: a population-based study. Chest. 2010;137(1):129-137. [CrossRef] [PubMed]
 
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Meyer KC. Diagnosis and management of interstitial lung disease. Transl Respir Med. 2014;2:4. [CrossRef] [PubMed]
 
Raghu G, Collard HR, Egan JJ, et al; ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788-824. [CrossRef] [PubMed]
 
Fell CD, Martinez FJ, Liu LX, et al. Clinical predictors of a diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2010;181(8):832-837. [CrossRef] [PubMed]
 
Ramos-Casals M, García-Carrasco M, Brito MP, López-Soto A, Font J. Autoimmunity and geriatrics: clinical significance of autoimmune manifestations in the elderly. Lupus. 2003;12(5):341-355. [CrossRef] [PubMed]
 
Nguyen W, Meyer KC. Surgical lung biopsy for the diagnosis of interstitial lung disease: a review of the literature and recommendations for optimizing safety and efficacy. Sarcoidosis Vasc Diffuse Lung Dis. 2013;30(1):3-16. [PubMed]
 
van Stijn MFM, Korkic-Halilovic I, Bakker MS, van der Ploeg T, van Leeuwen PA, Houdijk AP. Preoperative nutrition status and postoperative outcome in elderly general surgery patients: a systematic review. JPEN J Parenter Enteral Nutr. 2013;37(1):37-43. [CrossRef] [PubMed]
 
Galvin JR, Frazier AA, Franks TJ. Collaborative radiologic and histopathologic assessment of fibrotic lung disease. Radiology. 2010;255(3):692-706. [CrossRef] [PubMed]
 
King TE Jr, Tooze JA, Schwarz MI, Brown KR, Cherniack RM. Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model. Am J Respir Crit Care Med. 2001;164(7):1171-1181. [CrossRef] [PubMed]
 
Ley B, Ryerson CJ, Vittinghoff E, et al. A multidimensional index and staging system for idiopathic pulmonary fibrosis. Ann Intern Med. 2012;156(10):684-691. [CrossRef] [PubMed]
 
King C, Nathan SD. Identification and treatment of comorbidities in idiopathic pulmonary fibrosis and other fibrotic lung diseases. Curr Opin Pulm Med. 2013;19(5):466-473. [CrossRef] [PubMed]
 
Jankowich MD, Rounds SIS. Combined pulmonary fibrosis and emphysema syndrome: a review. Chest. 2012;141(1):222-231. [CrossRef] [PubMed]
 
Lettieri CJ, Nathan SD, Barnett SD, Ahmad S, Shorr AF. Prevalence and outcomes of pulmonary arterial hypertension in advanced idiopathic pulmonary fibrosis. Chest. 2006;129(3):746-752. [CrossRef] [PubMed]
 
Nathan SD, Basavaraj A, Reichner C, et al. Prevalence and impact of coronary artery disease in idiopathic pulmonary fibrosis. Respir Med. 2010;104(7):1035-1041. [CrossRef] [PubMed]
 
Sprunger DB, Olson AL, Huie TJ, et al. Pulmonary fibrosis is associated with an elevated risk of thromboembolic disease. Eur Respir J. 2012;39(1):125-132. [CrossRef] [PubMed]
 
Lancaster LH, Mason WR, Parnell JA, et al. Obstructive sleep apnea is common in idiopathic pulmonary fibrosis. Chest. 2009;136(3):772-778. [CrossRef] [PubMed]
 
Raghu G, Freudenberger TD, Yang S, et al. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J. 2006;27(1):136-142. [CrossRef] [PubMed]
 
Savarino E, Carbone R, Marabotto E, et al. Gastro-oesophageal reflux and gastric aspiration in idiopathic pulmonary fibrosis patients. Eur Respir J. 2013;42(5):1322-1331. [CrossRef] [PubMed]
 
Lee JS, Song JW, Wolters PJ, et al. Bronchoalveolar lavage pepsin in acute exacerbation of idiopathic pulmonary fibrosis. Eur Respir J. 2012;39(2):352-358. [CrossRef] [PubMed]
 
Raghu G, Meyer KC. Silent gastro-oesophageal reflux and microaspiration in IPF: mounting evidence for anti-reflux therapy? Eur Respir J. 2012;39(2):242-245. [CrossRef] [PubMed]
 
Lee JS, Ryu JH, Elicker BM, et al. Gastroesophageal reflux therapy is associated with longer survival in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;184(12):1390-1394. [CrossRef] [PubMed]
 
Lee JS, Collard HR, Anstrom KJ, et al. IPFnet Investigators. Anti-acid therapy and disease progression in idiopathic pulmonary fibrosis: an analysis of data from three randomized controlled trials. Lancet Respir Med. 2013;1(5):369-376. [CrossRef] [PubMed]
 
Zappala CJ, Latsi PI, Nicholson AG, et al. Marginal decline in forced vital capacity is associated with a poor outcome in idiopathic pulmonary fibrosis. Eur Respir J. 2010;35(4):830-836. [CrossRef] [PubMed]
 
du Bois RM, Weycker D, Albera C, et al. Forced vital capacity in patients with idiopathic pulmonary fibrosis: test properties and minimal clinically important difference. Am J Respir Crit Care Med. 2011;184(12):1382-1389. [CrossRef] [PubMed]
 
Lama VN, Flaherty KR, Toews GB, et al. Prognostic value of desaturation during a 6-minute walk test in idiopathic interstitial pneumonia. Am J Respir Crit Care Med. 2003;168(9):1084-1090. [CrossRef] [PubMed]
 
Caminati A, Bianchi A, Cassandro R, Mirenda MR, Harari S. Walking distance on 6-MWT is a prognostic factor in idiopathic pulmonary fibrosis. Respir Med. 2009;103(1):117-123. [CrossRef] [PubMed]
 
du Bois RM, Weycker D, Albera C, et al. Six-minute-walk test in idiopathic pulmonary fibrosis: test validation and minimal clinically important difference. Am J Respir Crit Care Med. 2011;183(9):1231-1237. [CrossRef] [PubMed]
 
Crockett AJ, Cranston JM, Antic N. Domiciliary oxygen for interstitial lung disease. Cochrane Database Syst Rev. 2001;;(3):CD002883.
 
Ryerson CJ, Cayou C, Topp F, et al. Pulmonary rehabilitation improves long-term outcomes in interstitial lung disease: a prospective cohort study. Respir Med. 2014;108(1):203-210. [CrossRef] [PubMed]
 
Ferreira A, Garvey C, Connors GL, et al. Pulmonary rehabilitation in interstitial lung disease: benefits and predictors of response. Chest. 2009;135(2):442-447. [CrossRef] [PubMed]
 
Kim R, Meyer KC. Therapies for interstitial lung disease: past, present and future. Ther Adv Respir Dis. 2008;2(5):319-338. [CrossRef] [PubMed]
 
Peikert T, Daniels CE, Beebe TJ, Meyer KC, Ryu JH; Interstitial Lung Diseases Network of the American College of Chest Physicians. Assessment of current practice in the diagnosis and therapy of idiopathic pulmonary fibrosis. Respir Med. 2008;102(9):1342-1348. [CrossRef] [PubMed]
 
American Thoracic Society. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med. 2000;161(2 pt 1):646-664. [PubMed]
 
Raghu G, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ; Idiopathic Pulmonary Fibrosis Clinical Research Network. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012;366(21):1968-1977. [CrossRef] [PubMed]
 
Noth I, Anstrom KJ, Calvert SB, et al; Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFnet). A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2012;186(1):88-95. [CrossRef] [PubMed]
 
Demedts M, Behr J, Buhl R, et al; IFIGENIA Study Group. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. 2005;353(21):2229-2242. [CrossRef] [PubMed]
 
Martinez FJ, de Andrade JA, Anstrom KJ, King TE Jr, Raghu G; Idiopathic Pulmonary Fibrosis Clinical Research Network. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2093-2101. [CrossRef] [PubMed]
 
Taniguchi H, Ebina M, Kondoh Y, et al; Pirfenidone Clinical Study Group in Japan. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J. 2010;35(4):821-829. [CrossRef] [PubMed]
 
Noble PW, Albera C, Bradford WZ, et al; CAPACITY Study Group. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. 2011;377(9779):1760-1769. [CrossRef] [PubMed]
 
King TE Jr, Bradford WZ, Castro-Bernardini S, et al; ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2083-2092. [CrossRef] [PubMed]
 
Richeldi L, du Bois RM, Raghu G, et al; INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071-2082. [CrossRef] [PubMed]
 
Esbriet [package insert]. Brisbane, CA: InterMune, Inc; 2014.
 
Ofev [package insert]. Ridgefield, CT: Boehringer-Ingelheim Pharmaceuticals, Inc; 2014.
 
Noble PW, Albera C, Bradford WZ, et al. Analysis of pooled data from 3 phase 3, multinational, randomized, double-blind, placebo controlled trials evaluating pirfendione in patients with idiopathic pulmonary fibrosis (IPF) [abstract]. Am J Respir Crit Care Med. 2014;189:A1423.
 
Meyer KC, Bierach J. Immunosuppressive therapy for autoimmune lung diseases. Immunol Allergy Clin North Am. 2012;32(4):633-669. [CrossRef] [PubMed]
 
Weill D, Benden C, Corris PA, et al. A consensus document for the selection of lung transplant candidates: 2014-An update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2015;34(1):1-15. [CrossRef] [PubMed]
 
Kilic A, Merlo CA, Conte JV, Shah AS. Lung transplantation in patients 70 years old or older: have outcomes changed after implementation of the lung allocation score? J Thorac Cardiovasc Surg. 2012;144(5):1133-1138. [CrossRef] [PubMed]
 
Hook JL, Lederer DJ. Selecting lung transplant candidates: where do current guidelines fall short? Expert Rev Respir Med. 2012;6(1):51-61. [CrossRef] [PubMed]
 
Lamas DJ, Kawut SM, Bagiella E, Philip N, Arcasoy SM, Lederer DJ. Delayed access and survival in idiopathic pulmonary fibrosis: a cohort study. Am J Respir Crit Care Med. 2011;184(7):842-847. [CrossRef] [PubMed]
 
Flaherty KR, Thwaite EL, Kazerooni EA, et al. Radiological versus histological diagnosis in UIP and NSIP: survival implications. Thorax. 2003;58(2):143-148. [CrossRef] [PubMed]
 
Lynch DA, Godwin JD, Safrin S, et al; Idiopathic Pulmonary Fibrosis Study Group. High-resolution computed tomography in idiopathic pulmonary fibrosis: diagnosis and prognosis. Am J Respir Crit Care Med. 2005;172(4):488-493. [CrossRef] [PubMed]
 
Oda K, Ishimoto H, Yatera K, et al. High-resolution CT scoring system-based grading scale predicts the clinical outcomes in patients with idiopathic pulmonary fibrosis. Respir Res. 2014;15:10. [CrossRef] [PubMed]
 
Ley B, Elicker BM, Hartman TE, et al. Idiopathic pulmonary fibrosis: CT and risk of death. Radiology. 2014;273(2):570-579. [CrossRef] [PubMed]
 
Flaherty KR, Andrei AC, Murray S, et al. Idiopathic pulmonary fibrosis: prognostic value of changes in physiology and six-minute-walk test. Am J Respir Crit Care Med. 2006;174(7):803-809. [CrossRef] [PubMed]
 
Nathan SD, Shlobin OA, Weir N, et al. Long-term course and prognosis of idiopathic pulmonary fibrosis in the new millennium. Chest. 2011;140(1):221-229. [CrossRef] [PubMed]
 
Hook JL, Arcasoy SM, Zemmel D, Bartels MN, Kawut SM, Lederer DJ. Titrated oxygen requirement and prognostication in idiopathic pulmonary fibrosis. Eur Respir J. 2012;39(2):359-365. [CrossRef] [PubMed]
 
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