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Overview of Idiopathic Pulmonary Fibrosis (IPF) and Evidence-Based Guidelines

Roozbeh Sharif, MD, MEd, MSc
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive form of interstitial lung disease (ILD), characterized by fibrosis and worsening lung function, that primarily occurs in those 50 years and older. Various causes including genetic susceptibility, environmental risk factors, and exposures have been suggested in the literature. All of these cause repetitive micro-injury to the lung tissue and vasculature, which triggers a cascade of inflammatory response and fibrosis. Symptoms are nonspecific and most patients present several years after the initial radiographic changes occur. Diagnosis requires a high index of clinical suspicion supported by distinct radiographic and/or histopathologic findings. Median survival is estimated at between 2 and 3 years after diagnosis. Other than lung transplantation, no treatment has shown survival benefit. Two most recently approved medications for IPF, pirfenidone and nintedanib, can slow disease progression. Most patients have several comorbid conditions that can affect the course of their disease, including gastroesophageal reflux disease, obstructive sleep apnea, cardiomyopathy, and pulmonary hypertension. Observational studies suggested possible benefits in transplant-free survival and patients’ outcomes with these medications. In addition to the new treatment options and optimal management of the comorbidities in patients with IPF, pulmonary rehabilitation remains a critical part of management and has been shown to improve quality of life and functional level. Considering the complexity of the diagnosis and management, the American Thoracic Society and European Respiratory Society published a joint statement on diagnosis and treatment of IPF.
This article provides an overview of the epidemiology, pathophysiology, and guideline-recommended approaches for the diagnosis and management of IPF.
Am J Manag Care. 2017;23:-S0
Idiopathic pulmonary fibrosis (IPF), previously known as cryptogenic fibrosing alveolitis, is a chronic, progressive disease, characterized by fibrosis and worsening lung function, that primarily occurs in individuals 50 years and older.1 It is the most common form of idiopathic interstitial pneumonia (IIP).2 The IIPs encompass a heterogeneous group of nonneoplastic interstitial lung diseases (ILDs) resulting from direct injury to the lung parenchyma through an inflammatory response and fibrosis.3 IIP includes conditions such as IPF, nonspecific interstitial lung disease, respiratory bronchiolitis-associated ILD, desquamative interstitial pneumonia, and lymphocytic interstitial pneumonia. In this article, we will focus on the pathogenesis and management of IPF.

Patients with IPF have variable clinical courses and usually report slow but progressive onset of symptoms.4 The diagnosis requires high clinical suspicion and distinct radiographic and histopathologic patterns.5,6

The American Thoracic Society (ATS) and European Respiratory Society (ERS) published a statement in 2000 on management of IPF,7 which has been updated several times since.1,8,9

IPF has very high morbidity and mortality rates, with almost half of patients dying 2 to 3 years after diagnosis.10 Most patients experience prolonged hospitalizations during the last year of life and unfavorable outcomes, contributing to significant healthcare resource usage. Population-based studies showed that patients with IPF have a 126% increased risk of emergency department visits and a 134% higher risk of hospitalization compared with age-, gender-, race-, and region-matched controls.11,12

Epidemiology of IPF

IPF is the most common type of IIP. The incidence and prevalence in epidemiologic studies after 2000 are estimated at between 0.5-27.9 and 0.22-8.8 per 100,000, respectively.13 Patients are typically diagnosed after age 50 years, and the incidence of the disease increases with age. It is also more prevalent in men and cigarette smokers.7

Historically, it has been difficult to accurately assess the epidemiology of IPF due, in part, to the fact that there was no unified definition of the disease until early 2000.7 That definition is based on diagnoses of patients with a radiographic and histopathologic pattern of usual interstitial pneumonia (UIP) and no other identifiable cause for their ILD.14 In addition, differing methodologies and heterogeneous study designs that are used to determine the incidence and prevalence across populations make accurate epidemiologic estimates challenging.

A retrospective study of a Medicare population between 2001 and 2011 found that while the incidence of IPF in this population remained steady at a rate of 93.7 cases per 100,000 per year, the prevalence increased sharply, from 202.2 in 2001 to 495.5 in 2011. One reason, the authors suggested, could be increased survival time and earlier diagnosis. The annual increase was higher in older individuals, males, and Hispanic individuals.15

Conversely, an analysis of claims from US adults aged 18 to 64 years showed that the incidence of IPF decreased from 2004 to 2010, with the reduction occurring primarily in younger patients. The authors suggest that this may be due to more accurate diagnosis of IPF, especially in younger adults aged 18 to 44 years.16 Although early onset of IPF is possible in rare cases, the majority of patients in this age group with a diagnosis of IPF would more likely have other conditions such as autoimmune diseases and chronic hypersensitivity pneumonitis, which could mimic the radiographic and histologic pattern of IPF. This issue has been addressed by the expert societies, and now, according to new ATS/ERS guidelines, the exclusion of other causes of ILD, such as autoimmune conditions and chronic hypersensitivity pneumonitis, is required as a part of diagnostic work-up.1,8,9

Risk factors

Several risk factors have been linked to the development of IPF, including genetic susceptibility, environmental and occupational exposures, tobacco smoking, comorbidities (particularly gastroesophageal reflux disease [GERD]), and possible association of viral infections.2,17

Substances linked to IPF include tobacco smoke, asbestos, silicone, mold, animal/vegetal dust, textile dust, wood smoke, and aluminum. The variation in exposure to inhaled substances may explain some of the geographic disparity observed in epidemiologic studies.2 Another underlying cause may be the burden of bacteria in the lung microbiome.18

While the genome-wide association studies have identified the common genetic variants accounting for almost one-third of risk factors of development of IPF, they are limited by a lack of definite causal relationship.2

Pathogenesis

The understanding of the complex pathogenesis of IPF has evolved significantly over the past 2 decades. It is now generally agreed that the pathogenesis of IPF is related to epithelial injury from endogenous or exogenous events, which results in widespread fibrosis, which replaces the normal lung parenchyma. Clinically, these changes can result in decreased oxygenation, respiratory failure, and eventually death.19

Diagnosis

Clinical presentation

Patients with IPF typically present in their sixth or seventh decade of life with gradual onset of nonspecific symptoms such as cough, dyspnea on exertion, fatigue, lack of energy, and gradual decline in their ability to execute daily activities. The physical examination findings are nonspecific, as well. Common findings on examination include bibasilar mid- to end-inspiratory crackles, end-inspiratory “squeaks” due to traction bronchiectasis, and, in advanced disease, clubbing of the fingernails.19

Differential diagnosis

The diagnostic work-up for IPF requires high clinical suspicion and a thorough history and physical examination. As illustrated in Figure 18, excluding other causes is now the first diagnostic criterion (along with specific radiographic and/or histopathologic findings).8 Clinicians are highly encouraged to obtain a careful history and inquire about comorbidities, medication use, environmental exposure, and family history.8 Patients with advanced chronic hypersensitivity pneumonitis can present with honeycombing changes at the later stages of the disease, which could be misdiagnosed as IPF.8,19

Clinicians should also inquire about symptoms and signs of autoimmune conditions such as systemic sclerosis (Raynaud’s phenomenon, skin rash, telangiectasia, skin tightening, severe GERD refractory to treatment, digital pitting, and sclerodactyly), rheumatoid arthritis (morning stiffness; polyarthralgia, particularly in hand and wrist; synovitis; subcutaneous nodules), myositis, and Sjogren’s syndrome, which may manifest early on with lung involvement.8,20 In these cases, serologic studies can be helpful in diagnosing the underlying cause. This type of ILD is often termed connective tissue disease ILD and is usually coded as post-inflammatory pulmonary fibrosis.

Pulmonary function test

A complete pulmonary function test—including spirometry, lung volumes, and diffusing capacity of the lungs for carbon monoxide (DLCO) test—should be obtained in all patients with suspected IPF. Restrictive pattern (reduction in lung volumes), reduction in DLCO, and/or obstructive pattern are common findings. In cases when IPF co-exists with emphysema (ie, combined pulmonary fibrosis and emphysema), an obstructive pattern could be seen.21-23

Radiographic and histopathologic findings

All patients with a high clinical suspicion of IPF should undergo high-resolution computed tomography (HRCT). Imaging may reveal reticular opacities, associated with traction bronchiectasis and honeycombing, with limited ground-glass opacities (Table 11,8).1,8

Despite higher than 90% positive predictive value of UIP pattern on HRCT, it could also be seen in other conditions as well.24 Nonetheless, given the accuracy of HRCT in recognizing a histopathologic UIP pattern, the 2011 guidelines from the ATS, ERS, Japanese Respiratory Society (JRS), and Latin American Thoracic Association (ALAT) no longer require a surgical lung biopsy (SLB) for a definitive diagnosis in most patients. Instead, they note that the diagnosis may be based on the presence of a UIP pattern on HRCT alone in conjunction with the other diagnostic components.8,25 Several observational studies demonstrated that certain HRCT findings correlate with progression of the disease and outcomes.26 In our institutional cohort, we have shown that the detailed findings and extent of the fibrotic changes directly correlate with disease progression, change in spirometry indices, and overall survival.27

Many patients do not require SLB for definite diagnosis of IPF. Some experts suggest that older patients with unexplained ILD are likely to have IPF.26 Clinicians should base their decision on the potential benefits for the definite diagnosis relative to the potential high risks associated with SLB. While there is some recent evidence regarding the ability of bronchoscopic lung cryobiopsy to improve diagnostic accuracy, more evidence is required.28

Multidisciplinary discussion

Given the complexity of diagnosis, it is highly recommended to hold a multidisciplinary discussion for more accurate diagnosis. Recent guidelines call for a multidisciplinary approach involving pulmonologists, rheumatologists, radiologists, and pathologists, which has been shown to improve diagnostic accuracy (Figure 18).1

Prognosis and outcomes

Natural history of IPF

Despite current advances, IPF remains a fatal disease, albeit one with a heterogeneous course ranging from stable to rapidly deteriorating respiratory failure and death.

The risk of mortality in patients with IPF can be predicted based on several baseline and longitudinal factors, including the level of dyspnea, diffusion capacity for DLCO, desaturation during 6-minute walk test (6MWT), extent of honeycombing on HRCT, and pulmonary hypertension at baseline, as well as longitudinal changes in the levels of dyspnea, forced vital capacity (FVC), DLCO, and fibrosis on HRCT.7

While several clinical models have been suggested to predict the course of the disease, the gender, age, and physiology (GAP) index is most commonly used. The GAP index is calculated based on gender, age, and the pulmonary physiology (percent predicted FVC and DLCO) (Table 229).29 The predictive value of the GAP index is hampered by limited clinical parameters. More accurate prognostic tools are needed.

 
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