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Supplements Examining the Current Landscape of Idiopathic Pulmonary Fibrosis: Reducing the Health and Economic Burden of Disease
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Overview of Idiopathic Pulmonary Fibrosis, Evidence-Based Guidelines, and Recent Developments in the Treatment Landscape
Marilyn K. Glassberg, MD
Participating Faculty

Overview of Idiopathic Pulmonary Fibrosis, Evidence-Based Guidelines, and Recent Developments in the Treatment Landscape

Marilyn K. Glassberg, MD
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive-fibrosing interstitial lung disease of unknown origin that affects 3 million people worldwide and imparts substantial burdens to patients, their families, and the healthcare system. The IPF disease course is highly variable and presents several diagnostic and management-related challenges. Two therapies, nintedanib and pirfenidone, are FDA approved and are recommended by clinical practice guidelines for the treatment of IPF. Although neither of these treatments is curative, both slow disease progression and impact survival of patients with IPF. To ensure optimal management, this supplement will provide an overview of the epidemiology, pathophysiology, and diagnosis of IPF, along with management-based considerations including evidence-based guideline recommendations, in-depth reviews of nintedanib and pirfenidone, and outcomes from other completed clinical trials.

Am J Manag Care. 2019;25:-S0
Overview of Idiopathic Pulmonary Fibrosis and Evidence-Based Guidelines

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive-fibrosing interstitial lung disease (ILD) of unknown origin characterized by progressive lung scarring and the histologic picture of usual interstitial pneumonia.1,2 Disorders belonging to the ILD category cause damage to the lung interstitium through various mechanisms, including inflammation, edema, and/or fibrosis.3 Despite sharing common clinical and pathophysiologic features, ILDs are a group of heterogenous diseases with diverse etiologies and prognoses.4 Accounting for 55% of all ILDs, IPF results in dilation of the bronchi, alveolar remodeling, and bibasilar parenchymal fibrosis, all of which contribute to scarring that leads to impaired gas exchange, particularly oxygenation, as shown in Figure 1.5

The disease course of IPF is highly variable; most patients progress more slowly while others experience rapid lung decline.6 In addition, patients with IPF may have periods of relatively stable disease interspersed with acute deteriorations in lung function.7 Therefore, the clinical course of an individual patient is difficult to predict; however, the median survival for patients with IPF before the era of antifibrotics has been 3 to 5 years following diagnosis.8

The incidence of IPF increases with age, and diagnosis before age 50 is rare.9,10 Among adults aged 18 to 64 years, the annual incidence is approximately 6 cases per 100,000 person-years,11 yet in adults 65 years and older, this incidence climbs to 94 cases per 100,000 person-years.12 Similarly, the prevalence of IPF is 18 cases per 100,000 adults aged 18 to 64 years,11 whereas in individuals 65 years and older, the prevalence is 495 cases per 100,000.12 Incidence and prevalence data vary widely due to fundamental differences in data collection methods and definitions of IPF. Collectively, it has been estimated that 130,000 people in the United States have been diagnosed with IPF.3 A claims analysis of US Medicare beneficiaries from 2000 to 2011 found that older age and male sex were significantly associated with a higher incidence of IPF and shorter survival time following diagnosis.12 In addition, thyroid disease, diabetes, coronary artery disease (CAD), and lung cancer have been associated with shorter survival in patients with IPF.13,14

Along with increasing age and male sex, potential risk factors for IPF include cigarette smoking, environmental exposures, microbial pathogens, and genetic factors.1 Anyone with a smoking history has a 60% higher risk of developing IPF.15 A retrospective analysis found that current smokers are 13 to 14 years younger at diagnosis compared with nonsmokers and former smokers (58.1, 71.4, and 72.5 years, respectively).13 Occupational exposures that may contribute to IPF include agriculture and farming; livestock; silica; and wood, metal, or stone dust.16 Some viruses, such as the Epstein-Barr virus, may also play a part in IPF development.3 The lung microbiota has a much higher bacterial load in patients with IPF than those without; understanding the possible role of bacteria in IPF pathogenesis is the focus of the current trial Clean-UP IPF for the Pulmonary Clinical Trials Cooperative (NCT02759120).17

A cohort study by Adegunsoye et al investigated survival rates in African American patients diagnosed with IPF. Despite being diagnosed at an earlier age, having poor measures of lung function and similar rates of hospitalizations as the cohort population, African Americans exhibited longer survival times. These findings suggest that race and genetics may play a role in the survival advantage exhibited by African American patients.18 A recent study has identified American Indians/Alaska Natives as the racial group with the highest IPF-related mortality rate.19 The interracial differences observed may support a genetic basis for predisposition to disease. Other factors to explore are whether behavioral or environmental risk factors differ by race. For instance, it is known that smoking rates differ by race, with the highest rates observed among American Indians.20

Comorbidities are substantial among patients with IPF and include hypertension, pulmonary hypertension (PH), obstructive sleep apnea, lung cancer, chronic obstructive pulmonary disease, CAD, vascular disease, diabetes, and gastroesophageal reflux disease (GERD).13 Effective management of comorbidities contributes to survival and may positively impact the IPF disease course.21 Micro-aspirations of gastric content may be involved in the lung injury leading to IPF3; however, the relationship between GERD and IPF may be confounded by smoking. A recent meta-analysis reported that a significant association between GERD and IPF (odds ratio, 2.94; P <.0001) was found when 18 case-control studies (3206 cases of IPF and 9368 controls) were pooled, but this association disappeared when investigators controlled for smoking status.22

The pathogenesis of IPF is multifactorial and involves the convergence of 3 elements: (1) epithelial damage, (2) lung tissue destruction, and (3) accelerated aging-associated changes.3 The combination of these elements leads to the release of mediators that induce migration, proliferation, and activation of fibroblasts and myofibroblasts that resist apoptosis and secrete extracellular matrix. Growth factors are released that contribute to the relentless progression of the disease.3 

The hallmark clinical signs of IPF are nonproductive cough and progressive exertional dyspnea, and approximately one-third of patients with IPF will have digital clubbing. Scalene muscle hypertrophy and bibasilar fine crackles should also raise suspicion of IPF.23 The diagnosis of IPF in suspected cases involves an in-depth review of both medication and environmental exposure histories followed by a high-resolution computed tomography scan (HRCT). Depending on the results of the HRCT, an analysis of the bronchoalveolar lavage fluid or surgical lung biopsy may be performed.8 An evaluation of the HRCT results combined with a histopathology pattern confirms a diagnosis of IPF.8 Other conditions, such as systemic sclerosis ILD (SSc-ILD, a type of connective tissue disease [CTD]) and rheumatoid arthritis-associated ILD (RA-ILD), have a similar pathophysiology as IPF and should be considered in a differential diagnosis.23 Findings that are suggestive of an alternative diagnosis include pleural plaques (consider asbestosis), dilated esophagus (consider CTD including SSc), distal clavicular erosions (consider RA), extensive lymph node enlargement (consider other etiologies), and pleural effusions and/or thickening (consider CTD/drugs).8

As a result of overlapping comorbidities and lack of specific symptoms, delays in the diagnosis of IPF are common. Lamas et al found a median delay of 2.2 years (interquartile range [IQR], 1.1-3.8 years) between the onset of dyspnea and the date of the initial evaluation for IPF. As shown in Figure 2,24 a longer delay was associated with shortened survival following initial evaluation (hazard ratio [HR], 1.3; 95% CI, 1.03-1.6; P = .03). Patients who waited 4 years or longer for a diagnosis had higher rates of CAD, diabetes, and GERD at baseline.24 Therefore, any efforts to improve the early recognition and diagnosis of patients with IPF can greatly impact outcomes.

Evaluating Treatment Options

The goals of IPF management are to ameliorate symptoms, improve health status, preserve lung function, maintain adequate oxygenation with supplemental oxygen (when needed), minimize adverse events (AEs) of therapy, reduce the frequency of acute exacerbations and, ideally, improve survival.3 Disease progression is monitored through the use of pulmonary function tests, particularly forced vital capacity (FVC) and the 6-minute walk test (6MWT).23 There is currently no cure for IPF but the antifibrotic agents, nintedanib and pirfenidone, have been shown to slow the decline of FVC, prevent acute exacerbations, and slow disease progression.23 Given the progressive nature of the disease, lung transplantation is a common consideration among patients with advanced IPF. Early referral for lung transplant is recommended in light of the variable disease course and occurrence of acute exacerbations.25,26

The management of IPF is multifaceted and involves various members of the healthcare team collaborating to provide patient education and support, vaccinations, and management of symptoms, comorbidities, and palliative care.27 According to the CDC, patients with lung disease should receive influenza, pneumococcal, zoster, and tetanus-diphtheria-and-pertussis (Tdap) vaccines.28 Smoking cessation counseling should be a high priority in patients with IPF.

Education and support should focus on 4 areas that have been identified as topics of concern for patients: (1) the physical problem, (2) family support, (3) interactions with the healthcare system, and (4) hope for research.29 Along with individual counseling, pharmacists can assist patients by recommending resources for accurate information, patient support groups, pulmonary rehabilitation, and community-based conferences.27 Patient education should begin at the time of diagnosis and continue throughout the disease progression.

Acute exacerbations can occur at any time and are associated with a 50% mortality rate.30 Among 225 patients with a first hospitalization for acute respiratory deterioration, 30% of cases were attributable to acute exacerbations related to IPF, which were independently associated with poor survival.31 Some risk factors for acute exacerbations include low or worsening FVC, GERD, new ground-glass opacities on the HRCT, and air pollution.27 Once an exacerbation occurs, the patient may likely be hospitalized and receive supplemental oxygen and broad-spectrum antibiotics. No single algorithm is accepted as standard-of-care management for patients with acute exacerbations; however, acceptable and expected management can include corticosteroids and immunosuppressants.1 A recent retrospective investigation compared the postexacerbation 90-day survival rates in patients treated with corticosteroids alone or corticosteroids plus immunotherapy with cyclophosphamide. Compared with corticosteroids alone, combination therapy did not significantly improve survival in patients after an acute exacerbation.32 The use of antifibrotic agents and minimal exposure to infectious agents, airborne irritants, and pollutants may minimize the occurrence of exacerbations.33 Because of the high mortality following acute exacerbations, more trials are needed to focus on optimal management to improve outcomes.

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