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Overview of Idiopathic Pulmonary Fibrosis (IPF) and Evidence-Based Guidelines
Roozbeh Sharif, MD, MEd, MSc
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Overview of Idiopathic Pulmonary Fibrosis (IPF) and Evidence-Based Guidelines

Roozbeh Sharif, MD, MEd, MSc
One of the most feared complications of IPF is an acute exacerbation. It is defined as acute decline in lung function and worsening of respiratory symptoms, with no evidence of infection and exclusion of alternative causes. It occurs in 5% to 10% of patients annually, with mortality rates as high as 85% and significant risk of recurrence.30 In addition to acute exacerbation of IPF, other causes of acute worsening of respiratory symptoms in patients with IPF, such as pneumonia, pulmonary embolism, or heart failure, have similar clinical presentation with comparable outcomes.31 Supportive care is the mainstay of therapy.7 Recently a classification of worsening of symptoms has been proposed but studies are ongoing to confirm the clinical implications and efficacy.32

Life expectancy and survival

The median survival of IPF is 2 to 3 years because diagnosis with a 5-year survival rate ranges between 20% and 40%.7,33 A recent analysis of Medicare data found that the median survival time from all-cause mortality was 3.8 years, with survival time decreasing sharply based on age at diagnosis. Patients between age 66 and 69 years had a median survival of 8 years, compared with 4.5 years in those diagnosed between age 75 and 79 years, and 2.5 years in those diagnosed at 80 years or older.13

Comorbidities in IPF

The majority of patients with IPF have multiple comorbid conditions, which, rather than fibrotic disease itself, may contribute to the high morbidity and mortality they experience.34,35 Comorbidities result in more frequent exacerbations and rapid decline in function and survival. Conversely, there is some evidence that obesity may convey a protective effect on mortality.36 Studies suggest that identifying and treating comorbidities may improve overall outcomes, including quality of life and survival.37

Table 337 summarizes some of the common comorbidities among patients with IPF: pulmonary hypertension, GERD, chronic obstructive pulmonary disease, lung cancer, pulmonary embolism, obstructive sleep apnea, ischemic heart disease, and diabetes.37

In a retrospective study of 352 patients with IPF, 79.3% of the cohort had at least 1 comorbid condition and 57.2% had 2 or more. The multivariate analysis result indicated that each additional comorbid condition increased mortality risk by nearly 10%.38 The authors suggested that the number of comorbidities relates to overall patient well-being.

The majority of patients with IPF have comorbid GERD, yet up to half may not exhibit any symptoms.8 There is some evidence that GERD may be a causative factor of IPF, with animal studies documenting worsening pulmonary parenchymal damage with exposure to decreasing pH, and damage to the lung periphery from gastric acid.39 Studies also suggest that treating GERD in IPF patients can improve survival.40,41

Guidelines for the management of IPF address the treatment of pulmonary hypertension and GERD. The updated ATS/ERS guideline on IPF treatment published in 2015 made a weak recommendation against treatment of pulmonary hypertension and weak recommendation in favor of GERD treatment.1 These are suggested due to conflicting data in this field.

Treatment

The pharmacologic treatment of IPF has evolved substantially over the last 2 decades. Historically, many pulmonologists used various immunosuppressive and anti-inflammatory agents, until the results from a randomized clinical trial on the combination of prednisone, azathioprine, and N-acetylcysteine (PANTHER-IPF) showed increased harm from this approach.42 In 2014, the FDA approved 2 treatments for IPF: pirfenidone, an antifibrotic and anti-inflammatory agent, and nintedanib, a kinase inhibitor.43

The 2015 guidelines strongly recommend against the use of imatinib, a selective tyrosine kinase inhibitor, based on the results from a single randomized controlled trial that failed to show a mortality benefit or any reduction in time to disease progression.1,44 Similarly, ambrisentan, an ETA-endothelin receptor antagonist, also earned a strong recommendation against its use based on the ARTEMIS-IPF study. That study was stopped early because of an increased risk of disease progression and respiratory hospitalizations.45 The dual endothelin receptor antagonists, bosentan and macitentan, have weak recommendations against their use due to the findings of the BUILD-3 and MUSIC studies, which failed to demonstrate beneficial outcomes.46,47 The 2015 update recommends against the use of warfarin in patients with IPF, unless otherwise indicated for conditions such as atrial fibrillation; however, the panel notes that other anticoagulants including the new oral agents might be beneficial.

Pharmacologic treatment of IPF is thoroughly discussed in subsequent articles of this supplement.

Nonpharmacologic treatment

Nonpharmacologic treatment modalities of IPF include supplemental oxygen therapy, pulmonary rehabilitation, mechanical ventilation, and palliative care services.

Supplemental oxygen is typically recommended when a patient’s desaturation is below 88% during a 6MWT or its equivalent.8 Physicians should monitor patient oxygenation with pulse oximetry at rest and exertion at baseline and at 3- to 6-month intervals. Nocturnal oxygen may also be indicated in patients with IPF with concurrent obstructive sleep apnea. There is no evidence of survival benefit from supplemental oxygen therapy, but some studies suggest better patient comfort and improved function.48,49

Pulmonary rehabilitation remains a robust part of nonpharmacologic treatment of IPF. It includes aerobic conditioning, strength and flexibility training, education about the condition, nutritional counseling, and psychosocial support.7 Clinical trials have demonstrated its beneficial impact on patients’ functional status and quality of life.50,51 Its long-term impact remains unclear and requires further studies, but its implementation is a crucial part of management.

Data on the role of palliative care in management of IPF are lacking and deserve more attention. Palliative services can be beneficial, particularly in advanced stages of IPF. Symptoms such as dyspnea and cough pose high symptom burden on patients and affect quality of life.

Multidisciplinary management of IPF: unmet needs of patients

Over the last 2 decades, ATS/ERS guidelines have provided individual recommendations for the diagnosis and treatment of patients with IPF. Although the strong association of comorbid conditions and poor outcome among patients with IPF is well known, no randomized clinical trial has examined the impact of management of comorbid conditions on their survival.

Observational studies have demonstrated the ability of a bundled, multidisciplinary approach to improve transplant-free survival among patients with IPF.52 This included biannual specialized interstitial lung disease visits with pulmonary function tests, annual referral to pulmonary rehabilitation, annual timed walk test and echocardiogram, therapy for GERD, screening for sleep-related disorders, and assessment for potential referral for lung transplantation.

Better adherence to this approach was associated with significantly improved survival of patients.52 Although these results are not generalizable to the entire population of patients with IPF, given that the study was conducted at a tertiary referral academic medical center with a sicker cohort of patients, this approach could assist providers in better assessing patients’ overall prognosis.

Lung transplantation

Lung transplantation can improve survival among patients with IPF and should be considered in patients with moderate to severe IPF.8 In May 2005, the United Network for Organ Sharing implemented the Lung Allocation Score to predict the survival benefit and determine the priority of a candidate. Since then, the actual number and the rate of patients with IPF on the lung transplantation wait list has increased.53 An important criterion for receiving a lung transplant is adherence to medications, thus the pharmacist should work with patients closely to promote proper medication use.

The ideal time to refer a patient for transplantation evaluation and the choice of single or bilateral lung transplantation remain controversial, with further studies required.7,54-57 However, the consensus is in favor of earlier referral considering the unpredictable course of disease.

Conclusion

IPF is the most common type of idiopathic interstitial pneumonia, usually diagnosed in the sixth or seventh decade of life. The accurate and timely diagnosis of IPF remains a diagnostic challenge in clinical practice and requires a high level of clinical suspicion as well as consideration of other possible causes. Clinicians are highly encouraged to obtain a thorough history and physical examination. Serological studies, particularly in younger and female patients, are encouraged to evaluate for possible underlying autoimmune disease. Exclusion of alternative diagnosis remains the first step in diagnosis. High-resolution computed tomography of the chest with both inspiratory and expiratory images remains the pivotal component of the diagnostic work-up. A surgical lung biopsy would be necessary in a highly selected patient population, but should be obtained with careful assessment of risks and benefits.

The diagnostic assessment should involve a multidisciplinary approach among the pulmonologist, chest radiologist, and pathologist.

IPF has very high morbidity and mortality rates. Most patients rapidly progress during the last year of life and experience prolonged hospitalization.

Several aspects of IPF pathophysiology and management are not clearly understood and are the subject of ongoing research. However, advances in recent years have kept hopes high for more optimal management of and better therapies for this fatal condition.

Author affiliation: Fellow, Division of Pulmonary, Allergy and Critical Care Medicine, The University of Alabama at Birmingham, Birmingham, Alabama.
Funding source: This activity is supported by educational grants from Genentech and Boehringer Ingelheim Pharmaceuticals, Inc.
Author disclosure: Dr Sharif has no relevant financial relationships with commercial interests to disclose.
Authorship information: Concept and design, drafting of the manuscript, critical revision of the manuscript for important intellectual content, and supervision.
Address correspondence to: roozbeh.sharif@gmail.com.
Acknowledgment: Debra Gordon, MS, provided medical writing and editorial support for this manuscript.
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