Idiopathic Pulmonary Fibrosis (IPF)

Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, primarily occurring in older adults, limited to the lungs, and associated with the histopathologic and/or radiologic pattern of usual interstitial pneumonia (UIP).[1]

Of the seven listed idiopathic interstitial pneumonias in the American Thoracic Society/European Respiratory Society consensus statement (ie, idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, cryptogenic organizing pneumonia, acute interstitial pneumonia, desquamative interstitial pneumonia, respiratory bronchiolitis-associated interstitial pneumonia, lymphoid interstitial pneumonia), idiopathic pulmonary fibrosis is the most common.[10] Idiopathic pulmonary fibrosis portends a poor prognosis, and, to date, no proven effective therapies are available for the treatment of idiopathic pulmonary fibrosis beyond lung transplantation.[2]

Most patients with idiopathic pulmonary fibrosis present with a gradual onset, often greater than six months, of dyspnea and/or a nonproductive cough. The symptoms often precede the diagnosis by a median of one to two years.[11] A chest radiograph typically reveals diffuse reticular opacities. However, it lacks diagnostic specificity.[12] High-resolution computed tomography (HRCT) findings are significantly more sensitive and specific for the diagnosis of idiopathic pulmonary fibrosis. On HRCT images, usual interstitial pneumonia is characterized by the presence of reticular opacities often associated with traction bronchiectasis. As idiopathic pulmonary fibrosis progresses, honeycombing becomes more prominent.[8] Pulmonary function tests often reveal restrictive impairment and reduced diffusing capacity for carbon monoxide.[12]

Available data suggest that no single etiologic agent serves as a common inciting event in the pathogenesis of idiopathic pulmonary fibrosis. During the past 15 years, the pathogenesis theory of generalized inflammation progressing to widespread parenchymal fibrosis has become less popular.[12] Rather, it is now believed that epithelial injury and activation in fibroblast foci are crucial early events that trigger a cascade of changes leading to reorganization of pulmonary tissue compartments.[13]

As mentioned above, idiopathic pulmonary fibrosis is an idiopathic interstitial pneumonitis characterized by usual interstitial pneumonia on histopathology. The hallmark pathologic feature of usual interstitial pneumonia is a heterogeneous, variegated appearance with alternating areas of healthy lung, interstitial inflammation, fibrosis, and honeycomb change. Fibrosis predominates over inflammation.[13]

The diagnosis of idiopathic pulmonary fibrosis relies on the clinician integrating the clinical, laboratory, radiologic, and/or pathologic data to make a clinical-radiologic-pathologic correlation that supports the diagnosis of idiopathic pulmonary fibrosis.[2]

The previous theory regarding the pathogenesis of idiopathic pulmonary fibrosis (IPF) was that generalized inflammation progressed to widespread parenchymal fibrosis. However, anti-inflammatory agents and immune modulators have proved to be minimally effective in modifying the natural course of the disease. It is currently believed that idiopathic pulmonary fibrosis is an epithelial-fibroblastic disease, in which unknown endogenous or environmental stimuli disrupt the homeostasis of alveolar epithelial cells, resulting in diffuse epithelial cell activation and aberrant epithelial cell repair.[14]

In the current hypothesis regarding the pathogenesis of idiopathic pulmonary fibrosis, exposure to an inciting agent (eg, smoke, environmental pollutants, environmental dust, viral infections, gastroesophageal reflux disease, chronic aspiration) in a susceptible host may lead to the initial alveolar epithelial damage.[15] Reestablishing an intact epithelium following injury is a key component of normal wound healing. In idiopathic pulmonary fibrosis, it is believed that after injury, aberrant activation of alveolar epithelial cells provokes the migration, proliferation, and activation of mesenchymal cells with the formation of fibroblastic/myofibroblastic foci, leading to the exaggerated accumulation of extracellular matrix with the irreversible destruction of the lung parenchyma.[15]

Activated alveolar epithelial cells release potent fibrogenic cytokines and growth factors. These include, tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), platelet-derived growth factor, insulin-like growth factor-1, and endothelin-1 (ET-1).[13, 15, 16] These cytokines and growth factors are involved in the migration and proliferation of fibroblasts and the transformation of fibroblasts into myofibroblasts. Fibroblasts and myofibroblasts are key effector cells in fibrogenesis, and myofibroblasts secrete extracellular matrix proteins.[15, 17]

For normal wound healing to occur, wound myofibroblasts must undergo apoptosis. Failure of apoptosis leads to myofibroblast accumulation, exuberant extracellular matrix protein production, persistent tissue contraction, and pathologic scar formation.[15] TGF-β has been shown to promote an antiapoptotic phenotype in fibroblasts.[15] Additionally, myofibroblasts in fibroblastic foci of idiopathic pulmonary fibrosis have been reported to undergo less apoptotic activity in comparison to myofibroblasts in the fibromyxoid lesions of bronchiolitis obliterans organizing pneumonia.[18]

Excess alveolar epithelial cell apoptosis and fibroblast resistance to apoptosis are also believed to contribute to fibroproliferation in idiopathic pulmonary fibrosis. Research has demonstrated that prostaglandin E2 deficiency, in lung tissue of patients with pulmonary fibrosis, results in increased sensitivity of alveolar epithelial cells to FAS-ligand induced apoptosis but induces fibroblast resistance to Fas-ligand induced apoptosis.[19] Therefore, apoptosis resistance in the fibroblasts and myofibroblasts participating in the repair of the alveolar epithelium may contribute to the persistent and/or progressive fibrosis in idiopathic pulmonary fibrosis.

Evidence for a genetic basis for idiopathic pulmonary fibrosis is accumulating. It has been described that mutant telomerase is associated with familial idiopathic pulmonary fibrosis.[20] Telomerase is a specialized polymerase that adds telomere repeats to the ends of chromosomes. This helps to offset shortening that occurs during DNA replication. TGF-β negatively regulates telomerase activity.[15] It is proposed that pulmonary fibrosis in patients with short telomeres is provoked by a loss of alveolar epithelial cells. Telomere shortening also occurs with aging, and it can also be acquired. This telomere shortening could promote the loss of alveolar epithelial cells, resulting in aberrant epithelial cell repair, and therefore should be considered as another potential contributor to the pathogenesis of idiopathic pulmonary fibrosis.[20]

Additionally, a common variant in the putative promoter of the gene that encodes mucin 5B (MUC5B) has been associated with the development of both familial interstitial pneumonia and sporadic pulmonary fibrosis. MUC5B expression in the lung was reported to be 14.1 times as high in subjects who had idiopathic pulmonary fibrosis as in those who did not. Therefore, dysregulated MUC5B expression in the lung may be involved in the pathogenesis of pulmonary fibrosis.[21]

Finally, caveolin-1 has been proposed as a protective regulator of pulmonary fibrosis. Caveolin-1 limits TGF-β–induced production of extracellular matrix proteins and restores the alveolar epithelial-repair process.[15] It has been observed that the expression of caveolin-1 is reduced in lung tissue from patients with idiopathic pulmonary fibrosis and that fibroblasts, the key cellular component of fibrosis, have low levels of caveolin-1 expression in patients with idiopathic pulmonary fibrosis.[22]

The recognition of the above-mentioned factors as contributors to the pathogenesis of idiopathic pulmonary fibrosis has led to the development of novel approaches to treat idiopathic pulmonary fibrosis.

The etiology of idiopathic pulmonary fibrosis (IPF) remains undefined; however, in the current hypothesis regarding the pathogenesis of idiopathic pulmonary fibrosis, exposure to an inciting agent (eg, smoke, environmental pollutants, environmental dust, viral infections, gastroesophageal reflux disease, chronic aspiration) in a susceptible host may lead to the initial alveolar epithelial damage.[15] This damage may lead to activation of the alveolar epithelial cells, which provokes the migration, proliferation, and activation of mesenchymal cells with the formation of fibroblastic/myofibroblastic foci, leading to the exaggerated accumulation of extracellular matrix with the irreversible destruction of the lung parenchyma.[15]

The following is a summary of possible inciting factors:

• Occupational dust or fume exposure (eg, hairdressers, ranchers, farmers, stonecutters, metal workers)
• Older age (approximately two thirds of patients are >60 years at diagnosis)
• Smoking history
• Male sex (higher prevalence in men vs women)
• Genetics

Other potential causes of idiopathic pulmonary fibrosis have been recognized through the study of familial pulmonary fibrosis. Familial pulmonary fibrosis, affecting two or more members of the same primary biological family, accounts for less than 5% of total patients with idiopathic pulmonary fibrosis.[23]

Genetic mutations in serum surfactant protein C have been discovered in some individuals with familial pulmonary fibrosis.[23] These mutations in serum surfactant protein C may damage type II alveolar epithelial cells.[23] Additionally, a common variant in the putative promoter of the gene encoding mucin 5B (MUC5B) has been associated with the development of both familial interstitial pneumonia and sporadic pulmonary fibrosis.[21]

Finally, mutant telomerase is associated with familial idiopathic pulmonary fibrosis.[20] Pulmonary fibrosis in patients with short telomeres is provoked by a loss of alveolar epithelial cells. Telomere shortening also occurs with aging and can also be acquired. This telomere shortening could promote the loss of alveolar epithelial cells, resulting in aberrant epithelial cell repair, and therefore should be considered as another potential contributor to the pathogenesis of idiopathic pulmonary fibrosis.[20]

Respiratory viruses have been considered a particularly likely cause of AE-IPF based on the similarities in clinical and radiologic presentation between and AE-IPF and viral pneumonitis and the poor sensitivity of standard methods of viral detection. A study by Wootton et al used genomics-based discovery methods to define the role of viral infections in AE-IPF. Initial multiplex polymerase chain reaction (PCR) revealed common respiratory viral infection in only 4 of 43 patients with AE-IPF. Pan-viral microarrays revealed torque teno virus (TTV) in 12 patients with AE-IPF. The pathogenic significance of TTV in AE-IPF is unclear. Overall, viral infection was not detected in most cases of AE-IPF.[24]

United States

No large-scale studies of the incidence or prevalence of idiopathic pulmonary fibrosis (IPF) are available on which to base formal estimates.

In a retrospective administrative patient claim data study by Raghu el al in 2016, the annual cumulative prevalence of idiopathic pulmonary fibrosis in adults aged 18-64 years in the United States has increased from 13.4 cases per 100, 000 persons in 2005 to 18.2 cases per 100, 000 persons in 2010.[25]

A population-based cohort study was completed in Olmsted County, Minnesota, between 1997 and 2005, with the intention of updating and describing the incidence and prevalence of idiopathic pulmonary fibrosis. Narrow-criteria idiopathic pulmonary fibrosis was defined by usual interstitial pneumonia on a surgical lung biopsy specimen or a definite usual interstitial pneumonia pattern on an HRCT image. Broad-criteria idiopathic pulmonary fibrosis was defined by usual interstitial pneumonia on a surgical lung biopsy specimen or a definite or possible usual interstitial pneumonia pattern on an HRCT image.[26] These criteria were obtained from the 2002 American Thoracic Society/European Thoracic Society consensus statement.[10]

The age-adjusted and sex-adjusted incidence rate of idiopathic pulmonary fibrosis among residents aged 50 years or older ranges from 8.8 cases per 100,000 person-years (narrow-case criteria) to 17.4 cases per 100,000 person-years (broad-case criteria).[26]

The age-adjusted and sex-adjusted prevalence among residents aged 50 years or older ranges from 27.9 cases per 100,000 persons (narrow-case criteria) to 63 cases per 100,000 persons (broad-case criteria).[26]

Whether the incidence and prevalence of idiopathic pulmonary fibrosis are influenced by geographic, ethnic, cultural, or racial factors is unclear.[1]

International

Worldwide, the incidence of idiopathic pulmonary fibrosis is estimated to be 10.7 cases per 100,000 person-years for males and 7.4 cases per 100,000 person years for females. The prevalence of idiopathic pulmonary fibrosis is estimated to be 20 cases per 100,000 persons for males and 13 cases per 100,000 persons for females.[12]

Race

Epidemiologic data from large, geographically diverse populations are limited, and, therefore this data cannot be used to accurately determine the existence of a racial predilection for idiopathic pulmonary fibrosis.

Sex

Using data obtained from a large US healthcare claims database, the incidence and prevalence of idiopathic pulmonary fibrosis is higher in men aged 55 years or older, compared with women of the same age.[27]

Age

Idiopathic pulmonary fibrosis mainly affects persons aged 50 years or older. Approximately two thirds of persons diagnosed with idiopathic pulmonary fibrosis are aged 60 years or older at the time of diagnosis. Using data obtained from a large US healthcare claims database, the incidence of idiopathic pulmonary fibrosis was estimated to range from 0.4-1.2 cases per 100,000 person-years for persons aged 18-34 years. However, the estimated incidence of idiopathic pulmonary fibrosis in persons aged 75 years or older was significantly higher and ranged from 27.1-76.4 cases per 100,000 person-years.[27]

Idiopathic pulmonary fibrosis (IPF) portends a poor prognosis. With regard to idiopathic pulmonary fibrosis life expectancy, the estimated mean survival is 2-5 years from the time of diagnosis.[2] Estimated mortality rates are 64.3 deaths per million in men and 58.4 deaths per million in women.[28]

Death rates in patients with idiopathic pulmonary fibrosis increase with increasing age, are consistently higher in men than women, and experience seasonal variation, with the highest death rates occurring in the winter, even when infectious causes are excluded.[11]

Estimates are that 60% of patients with idiopathic pulmonary fibrosis die from their idiopathic pulmonary fibrosis, as opposed to dying with their idiopathic pulmonary fibrosis. Of those patients who die with idiopathic pulmonary fibrosis, most commonly it is after an acute exacerbation of idiopathic pulmonary fibrosis. When an acute exacerbation of idiopathic pulmonary fibrosis is not the cause of death, an increased cardiovascular risk and an increased venous thromboembolic disease risk contribute to the cause of death. The most common causes of death in patients with idiopathic pulmonary fibrosis include acute exacerbations of idiopathic pulmonary fibrosis, acute coronary syndromes, congestive heart failure, lung cancer, infectious causes, and venous thromboembolic disease.[2]

A worse prognosis can be expected based on various clinical parameters, physiologic factors, radiographic findings, histopathologic findings, laboratory findings, and bronchoalveolar lavage findings. du Bois et al evaluated a scoring system to predict individual risk of mortality. They used a Cox proportional hazards model and data from two clinical trials (n = 1,099) to identify independent predictors of 1-year mortality among patients with idiopathic pulmonary fibrosis. The findings demonstrated that 4 readily ascertainable predictors (age, history of respiratory hospitalization within the previous 24 weeks, percent predicted FVC, and 24-week change in FVC) could be used in a scoring system to estimate 1-year mortality. However, this scoring system needs to be validated in other populations of patients with idiopathic pulmonary fibrosis.[29]

Ley et al used competing risks regression modeling to retrospectively screen potential predictors of mortality in a derivation cohort of patients with idiopathic pulmonary fibrosis (n = 228). They identified a model consisting of 4 predictors (sex, age, % predicted FVC, and % predicted DLCO). Based on these 4 predictors, they developed a simple point-score model and staging system that was retrospectively validated in a separate cohort of patients with idiopathic pulmonary fibrosis (n = 330).[30]

Table 1. Scoring for mortality risk in IPF. (Open Table in a new window)

Table 2. Staging and mortality risk for IPF. (Open Table in a new window)

The authors believe that the index and staging system provide clinicians with a framework for discussing prognosis, policy-makers with a tool for investigating stage-specific management options, and researchers with the ability to identify at-risk study populations that maximize the efficiency and power of clinical trials.[30]

Patients with idiopathic pulmonary fibrosis who have concomitant pulmonary hypertension have more dyspnea, greater impairment of their exercise capacity, and increased 1-year mortality compared with their counterparts without pulmonary hypertension.[2] Additionally, a multicenter prospective cohort study of 126 lung transplant procedures performed for idiopathic pulmonary fibrosis revealed elevated pulmonary artery pressure as a risk factor for primary graft dysfunction (PGD) following lung transplantation.[31] The mean pulmonary artery pressure (mPAP) for patients with PGD following lung transplantation was 38.5 ± 16.3 mm Hg compared with a mPAP of 29.6 ± 11.5 mm Hg in patients without PGD following lung transplantation.

Patients with idiopathic pulmonary fibrosis pattern on HRCT imaging have a worse prognosis compared with patients with biopsy-proven usual interstitial pneumonia and atypical changes of idiopathic pulmonary fibrosis on HRCT imaging.[11, 32]

Patients who have a greater than 10% decline in forced vital capacity (FVC) (percent predicted) over 6 months have a 2.4-fold increased risk of death. Additionally, in patients who do not desaturate to less than 88% during a 6-minute walk test (6MWT), the only strong predictor of mortality is a progressive decline in FVC (>10% after 6 mo).[33]

A baseline diffusion capacity of carbon monoxide (DLCO) below 35% is correlated with increased mortality. Additionally, a decline in DLCO greater than 15% over 1 year is also associated with increased mortality.[33]

Desaturation below the threshold of 88% during the 6MWT has been associated with an increased mortality.[33] Additionally, in patients with idiopathic pulmonary fibrosis who desaturate to less than 88% during a 6MWT, a progressive decline in DLCO (>15% after 6 mo) is a strong predictor of mortality.[7]

BAL fluid neutrophilia has been demonstrated to predict early mortality. One study demonstrated a linear relationship between increasing neutrophil percentage and the risk of mortality. Each doubling in baseline BAL fluid neutrophil percentage was associated with a 30% increased risk of death or transplantation in the first year after presentation.[34]

Serum surfactant protein A (SP-A) is a member of the collectin family. SP-A is secreted by type II pneumocytes, and the level of SP-A appears to be increased early after breakdown in the alveolar epithelium. SP-A has been shown to be present in abnormal amounts in the BAL fluid of patients with idiopathic pulmonary fibrosis.[35] In a cohort study, after controlling for known clinical predictors of mortality, each increase of 49 ng/mL in baseline serum SP-A level was associated with a 3.3-fold increased risk of mortality in the first year after presentation.[35] Therefore, serum SP-A is independently and strongly associated with death or lung transplantation 1 year after presentation.[35]

Patients should be presented information regarding the full range of options available for treating idiopathic pulmonary fibrosis (IPF). The pros, cons, risks, benefits, and alternatives should be discussed in a balanced and comprehensive fashion. For patient education resources, see the Lung Disease and Respiratory Health Center.

The clinical symptoms of idiopathic pulmonary fibrosis (IPF) are nonspecific. Most patients present with exertional dyspnea and a nonproductive cough. Such symptoms can be shared with a variety of pulmonary and cardiac diseases. Dyspnea, which is the most prominent symptom in idiopathic pulmonary fibrosis, usually begins insidiously and is often progressive. Associated systemic symptoms can occur but are not common. Some of these systemic symptoms include weight loss, low-grade fevers, fatigue, arthralgias, or myalgias.

The reported median duration of symptoms before the diagnosis of idiopathic pulmonary fibrosis is established is one to two years.[12] Most patients are referred to a cardiologist for evaluation of exertional dyspnea prior to being referred to a pulmonologist. Approximately 5% of patients have no presenting symptoms when idiopathic pulmonary fibrosis is diagnosed. Among asymptomatic patients with idiopathic pulmonary fibrosis (diagnosed by radiographic abnormalities found on routine chest radiograph screening and lung biopsy showing usual interstitial pneumonia), symptoms developed approximately 1000 days after the recognition of the radiographic abnormality.[12]

It is critical to obtain a complete history, including medication history, drug use, social history, occupational, recreational, and environmental respiratory exposure history, risk factors for human immunodeficiency virus infection, and review of systems, to ensure other causes of interstitial lung disease are excluded. Amiodarone, bleomycin, and nitrofurantoin are notable medications associated with pulmonary fibrosis. Oxidant stress from smoking may damage alveolar epithelial cells and contribute to the pathogenesis of idiopathic pulmonary fibrosis.[36] Any patient with idiopathic pulmonary fibrosis who is a current smoker should be encouraged to quit. Any prior exposure to asbestos, silica, heavy metals, contaminated ventilation systems, moldy foliage, and/or pigeon droppings should be investigated. Evidence of arthralgia, arthritis, photosensitivity, Raynaud phenomenon, dry eyes, and/or dry mouth on review of systems may indicate the presence of a collagen-vascular disease.

Physicians should pay attention to historical clues that may suggest the presence of obstructive sleep apnea (OSA) because a 2009 study demonstrated the high prevalence of OSA in patients with idiopathic pulmonary fibrosis. Fifty outpatients with stable idiopathic pulmonary fibrosis were prospectively evaluated for the presence of OSA. OSA was defined as an apnea-hypopnea index (AHI) of greater than 5 events per hour. Ten subjects (20%) had mild OSA (AHI of 5-15 events per hour) and 34 subjects (68%) had moderate-to-severe OSA (AHI of >15 events per hour).[37] Therefore, the prevalence of OSA in this sample was 88%, suggesting that OSA in patients with idiopathic pulmonary fibrosis may have been previously underrecognized.

In most patients with idiopathic pulmonary fibrosis (IPF), the physical examination reveals fine bibasilar inspiratory crackles (Velcro crackles). Additionally, digital clubbing is seen in 25-50% of patients with idiopathic pulmonary fibrosis.[12] Extrapulmonary involvement does not occur with idiopathic pulmonary fibrosis, and, therefore, physical examination findings do not help to confirm the diagnosis.

Pulmonary hypertension is a common comorbidity in patients with idiopathic pulmonary fibrosis, and an estimated 20-40% of patients with idiopathic pulmonary fibrosis who are evaluated or listed for lung transplantation have pulmonary hypertension at rest.[4] Physical examination findings may be suggestive of the presence of pulmonary hypertension. Patients may have a loud P2 component of the second heart sound, a fixed split S2, a holosystolic tricuspid regurgitation murmur, and pedal edema. As right ventricular hypertrophy ensues, a right ventricular heave may be palpated at the lower left sternal border and increased right atrial pressure may cause elevation of the jugular venous pressure.[5]

A summary of possible symptoms is as follows:

• Dry cough
• Fatigue
• Dyspnea (particularly during or after physical activity)
• Digital clubbing
• Weight loss
• Leg edema

The following are complications that can be seen in patients with idiopathic pulmonary fibrosis (IPF):

• Pulmonary hypertension

• Acute exacerbation of pulmonary fibrosis

• Respiratory infection

• Acute coronary syndrome

• Thromboembolic disease

• Adverse medication effects

• Lung cancer

Complications and mortality

Idiopathic pulmonary fibrosis carries a poor prognosis, with a median survival of 3.8 years among adults aged 65 years or older in the United States. Although this statistic is disappointing, in practice it is not uncommon for patients to live 5 years or more after receiving the diagnosis. Many patients die from progressive, chronic hypoxemic respiratory failure. Palliative care is rarely instituted in patients with idiopathic pulmonary fibrosis before the end of life. Each year, approximately 10-20% of patients with idiopathic pulmonary fibrosis have an acute exacerbation, characterized by worsened hypoxemic respiratory failure, with bilateral ground-glass opacities, consolidation, or both on HRCT imaging that are not fully explained by volume overload. Exacerbations may be triggered by a clinical event (eg, infection, aspiration, drug toxicity) but are frequently idiopathic. Most patients with an acute exacerbation die from acute respiratory failure. Available guidelines make weak recommendations for the use of glucocorticoids and do not recommend the use of mechanical ventilation in patients with an acute exacerbation, emphasizing the need to establish physician orders regarding life-sustaining treatment before the onset of a life-threatening event.

Patients with idiopathic pulmonary fibrosis are at increased risk for venous thromboembolism, lung cancer, and pulmonary hypertension.[38, 39, 40] A high index of suspicion should be maintained for pulmonary embolism as the cause of any acute respiratory deterioration. Incidental pulmonary nodules should be managed according to established guidelines for high-risk patients. Annual low-dose CT scanning should be considered for patients meeting the US Preventive Services Task Force criteria for lung cancer screening.

Although pulmonary hypertension occurs in some patients with idiopathic pulmonary fibrosis, management in the outpatient setting should consist solely of supplemental oxygen, without pulmonary vasodilator therapy. Until further data are available, targeted therapies approved for pulmonary arterial hypertension should be avoided in patients with idiopathic pulmonary fibrosis unless they are enrolled in a clinical trial investigating such therapies.

Results from routine laboratory studies are nonspecific for the diagnosis of idiopathic pulmonary fibrosis; however, some laboratory studies may be helpful for ruling out other causes of interstitial lung disease. Reportedly, up to 30% of patients with idiopathic pulmonary fibrosis (IPF) have positive tests for antinuclear antibodies or rheumatoid factor; however, these titers are generally not high.[5] The presence of high titers of antinuclear antibodies or rheumatoid factor may suggest the presence of a connective-tissue disease. The C-reactive protein value and erythrocyte sedimentation rate can be elevated in patients with idiopathic pulmonary fibrosis; however, this finding is nondiagnostic. Although chronic hypoxemia is a common finding in patients with idiopathic pulmonary fibrosis, polycythemia is a rare finding on laboratory studies.

It is strongly recommended to not measure matrix metalloproteinase (MMP)–7, surfactant protein D (SPD), chemokine ligand (CCL)–18, or Krebs von den Lungen-6 for the purpose of distinguishing IPF from other interstitial lung diseases.[3]

Chest radiography

The chest radiograph lacks diagnostic specificity for idiopathic pulmonary fibrosis. Virtually all patients with idiopathic pulmonary fibrosis (IPF) have an abnormal chest radiograph at the time of diagnosis. The typical findings are peripheral reticular opacities (netlike linear and curvilinear densities) predominantly at the lung bases (see image below). Honeycombing (coarse reticular pattern) and lower lobe volume loss can also be seen.[8]

Chest radiograph of a patient with idiopathic pulmonary fibrosis showing bilateral lower lobe reticular opacities (red circles).

High-resolution computed tomography

High-resolution computed tomography (HRCT) findings are significantly more sensitive and specific for the diagnosis of idiopathic pulmonary fibrosis and are an essential component of the diagnostic pathway of idiopathic pulmonary fibrosis.[41] On HRCT images, idiopathic pulmonary fibrosis is characterized by patchy, peripheral, subpleural, and bibasilar reticular opacities (see image below).

Classic subpleural honeycombing (red circle) in a patient with a diagnosis of idiopathic pulmonary fibrosis.

Reticular opacities refer to the fine network of lines that sometimes include interlobular septal thickening and/or intralobular lines. Areas that are severely involved with reticular markings may also demonstrate traction bronchiectasis. Subpleural honeycombing (< 5-mm round translucencies with a density equal to that of air) is also a common finding (see image below).

A patient with IPF and a confirmed histologic diagnosis of usual interstitial pneumonia. Note the reticular opacities (red circle) distributed in both lung bases and the minimal ground-glass opacities (blue circle).

Ground-glass opacities can be found but are less extensive than reticular abnormalities.[8] Reticular opacities and honeycombing seen on HRCT imaging correlates histologically with fibrosis and honeycombing. The presence of subpleural honeycombing, traction bronchiectasis, and thickened interlobular septae increase the specificity of HRCT for diagnosing idiopathic pulmonary fibrosis.[8] Patients with typical changes of idiopathic pulmonary fibrosis on HRCT imaging have a worse prognosis compared with patients with biopsy-proven usual interstitial pneumonia and atypical changes of idiopathic pulmonary fibrosis on HRCT imaging.[32]

Multiple studies have documented that the accuracy of a confident diagnosis of usual interstitial pneumonia made on the basis of HRCT imaging findings by an experienced observer exceeds 90%.[8] However, several clinical conditions may be associated with the radiologic or histologic pattern of usual interstitial pneumonia and must therefore be considered in the differential diagnosis of usual interstitial pneumonia diagnosed on the basis of HRCT imaging.

The differential diagnosis of ground-glass opacities on HRCT imaging include heart failure, nonspecific interstitial pneumonia (NSIP), desquamative interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, and hypersensitivity pneumonitis. Fine nodules are suggestive of hypersensitivity pneumonitis, granulomatous infection, or metastatic malignancy. Upper lobe disease is the predominant pattern in hypersensitivity pneumonitis, a variety of pneumoconioses, sarcoidosis, and eosinophilic pneumonia.[5] Lymphadenopathy is associated with sarcoidosis and other granulomatous disease. Idiopathic pulmonary fibrosis and NSIP can have indistinguishable clinical presentations, and understanding how HRCT imaging can help to distinguish between these two entities is important (see image below).

A patient with nonspecific interstitial pneumonia. Note the predominance of ground-glass opacities (blue circles) and a few reticular lines (red arrow).

The abnormalities in NSIP usually predominate in the middle and lower lungs. NSIP is less likely to have a subpleural distribution compared with usual interstitial pneumonia. Ground-glass opacities are a frequent feature of NSIP and are reported to be found in 76-100% of cases.[8] Finally, honeycombing is less common than in usual interstitial pneumonia, with the prevalence ranging from 0-30% in different series.[8] Honeycombing is mainly seen in patients with purely fibrotic NSIP.

Based on an updated review by Lynch et al for the diagnosis of idiopathic pulmonary fibrosis, four radiologic diagnostic categories are recommended for use in interpreting HRCT patterns.[42]

See the image below.

High-resolution CT coronal view showing lower lobe predominant honeycombing (blue arrow) with irregular septal thickening and traction bronchiectasis compatible with typical usual interstitial pneumonia pattern.

Typical radiologic UIP pattern is as follows:

• Subpleural and basal predominant; distribution is often heterogeneous
• Honeycombing with or without peripheral traction bronchiectasis or bronchiolectasis

Probable UIP pattern is as follows:

• Subpleural and basal predominant; distribution is often heterogeneous
• Reticular pattern with peripheral traction bronchiectasis or bronchiolectasis
• May have mild ground-glass opacities

Indeterminate pattern for UIP is as follows:

• Subpleural and basal predominant
• Subtle reticulation; may have mild ground-glass opacities or distortion ("early UIP pattern")
• CT features and/or distribution of lung fibrosis that do not suggest any specific etiology ("truly indeterminate")

Alternative diagnosis pattern is findings suggestive of another diagnosis based on (1) CT features, (2) predominant distribution, and (3) others.

CT features include the following:

• Cysts
• Marked mosaic attenuation
• Predominant ground-glass opacities
• Profuse micronodules
• Centrilobular nodules
• Nodules
• Consolidation

Predominant distribution is as follows:

• Peribronchovascular
• Perilymphatic
• Upper or mid lung

Other findings are as follows:

• Pleural plaques (consider asbestosis)
• Dilated esophagus (consider connective-tissue disease)
• Distal clavicular erosions (consider rheumatoid arthritis)
• Extensive lymph node enlargement (consider other etiologies)
• Pleural effusions, pleural thickening (consider connective-tissue disease/drugs)

Pulmonary function testing

The typical findings on pulmonary function tests in patients with idiopathic pulmonary fibrosis are a restrictive ventilatory defect and a reduced diffusion capacity for carbon monoxide.[6] These findings are nonspecific and should be used in conjunction with clinical, radiologic, and pathologic information to ensure an accurate diagnosis of idiopathic pulmonary fibrosis (IPF).

In patients with idiopathic pulmonary fibrosis, a restrictive ventilatory defect is typically present. Vital capacity, functional residual capacity, total lung capacity, and forced vital capacity (FVC) all are reduced. Additionally, the static pressure-volume curve is shifted downward and to the right as a result of decreased lung compliance.[6] Obstructive ventilatory defects are not common. However, if present, they may suggest the coexistence of chronic obstructive pulmonary disease.

Prognostication in idiopathic pulmonary fibrosis relies on serial assessments of FVC. Patients who have a greater than 10% decline in FVC (percent predicted) over 6 months, have a 2.4-fold increased risk of death. Additionally, in patients who do not desaturate to less than 88% during a 6-minute walk test (6MWT), the only strong predictor of mortality is a progressive decline in FVC (>10% after 6 mo).[33] As a result of these findings, change in FVC is being used more frequently as a primary end point in clinical trials.

A large study was completed in 2012 to estimate the minimal clinically important difference (MCID) of FVC in patients with IPF. In this study, data was used from 1,156 patients included in two clinical trials investigating IFN-γ1β. This study found that the hazard ratio for the one-year risk of death was 2.14 (1.43-3.20) in patients with a 24-week decline in FVC between 5% and 10%. The estimated MCID was 2-6%.[43]

Impaired gas exchange is demonstrated by the decreased diffusion capacity of carbon monoxide (DLCO). In idiopathic pulmonary fibrosis, the reduced DLCO may precede the development of abnormal lung volumes. Additionally, DLCO is reduced to a greater extent in idiopathic pulmonary fibrosis compared with other idiopathic interstitial pneumonias.[6] Prognostication in idiopathic pulmonary fibrosis also relies on serial assessments of DLCO. A baseline DLCO below 35% is correlated with increased mortality. Additionally, a decline in DLCO greater than 15% over 1 year is also associated with increased mortality.[33]

6-Minute walk testing

The 6MWT is a marker of functional exercise capacity that is being increasingly used in the initial and longitudinal clinical assessment of patients with idiopathic pulmonary fibrosis. Desaturation below the threshold of 88% during the 6MWT has been associated with an increased mortality.[33] Additionally, in patients with idiopathic pulmonary fibrosis who desaturate to less than 88% during a 6MWT, a progressive decline in DLCO (>15% after 6 mo) is a strong predictor of increased mortality.[7]

Heart rate recovery (HRR), specifically the failure of the heart rate to decline at 1 or 2 minutes postexercise, is associated with increased mortality. A 2009 retrospective analysis found that the failure of the heart rate to decline after exertion (by >13 beats at 1 min or by >22 beats at 2 min) is a strong predictor of increased mortality.[44]

A study by du Bois and colleagues estimated the minimal clinically important difference in the 6MWT in 822 patients with idiopathic pulmonary fibrosis. For patients who had a decline in 6MWT of 26-50 meters at 24 weeks, the hazard ratio for death at 1 year was 3.59 (1.95-6.63). For patients who had a decline in the 6MWT of more than 50 meters at 24 weeks, the hazard ratio for death at 1 year was 4.27 (2.57-7.10). The minimal clinically important difference in 6MWT was distance is 24-45 meters.[45]

Bronchoalveolar lavage

Bronchoalveolar lavage (BAL) has been an immensely useful research tool in idiopathic pulmonary fibrosis. However, the role of BAL in the clinical diagnosis of idiopathic pulmonary fibrosis remains limited. Increased numbers of neutrophils in BAL fluid are found in 70-90% of all patients with idiopathic pulmonary fibrosis, and increased numbers of eosinophils in BAL fluid are found in 40-60% of all patients with idiopathic pulmonary fibrosis. Previous studies have demonstrated that the absence of BAL fluid lymphocytosis is important for the diagnosis of idiopathic pulmonary fibrosis. A 2009 study suggests that BAL fluid analysis has an additional benefit for the diagnosis of idiopathic pulmonary fibrosis. The study demonstrated the discriminating power of a cut-off level of less than 30% lymphocytosis in BAL fluid in distinguishing idiopathic pulmonary fibrosis from nonidiopathic pulmonary fibrosis diagnoses.[46]

BAL is not required for the diagnosis of idiopathic pulmonary fibrosis and is not recommended for patients with newly detected interstitial lung disease of apparently unknown cause who are clinically suspected of having idiopathic pulmonary fibrosis and have an HRCT pattern of UIP.[3] However, BAL fluid analysis can be useful to exclude other alternative diagnoses. Appropriate analysis of BAL fluid may demonstrate the presence of infection, malignancy, alveolar proteinosis, eosinophilic pneumonia, or occupational dusts.

Cellular analysis of BAL fluid is suggested (conditional recommendation) for patients with new detected interstitial lung disease who are clinically suspected of having idiopathic pulmonary fibrosis and have an HRCT pattern of probable UIP, indeterminate, or an alternative diagnosis.[3]

BAL fluid neutrophilia has been demonstrated to predict early mortality. One study demonstrated a linear relationship between increasing neutrophil percentage and the risk of mortality. Each doubling in baseline BAL fluid neutrophil percentage was associated with a 30% increased risk of death or transplantation in the first year after presentation.[34] Additionally, studies of BAL matrix metalloproteinase (MMP) levels suggest that MMP1 and MMP7 are increased in patients with idiopathic pulmonary fibrosis and that MMP7 levels may correlate with disease severity.[1]

Transthoracic echocardiography

Studies have demonstrated that pulmonary hypertension is present at rest in approximately 20-40% of idiopathic pulmonary fibrosis patients who are listed for lung transplantation.[4] The US National Institutes of Health (NIH) definition of pulmonary arterial hypertension is a mean pulmonary artery pressure greater than 25 mmHg at rest with a normal pulmonary capillary wedge pressure measured by right-sided heart catheterization. Generally, transthoracic echocardiography is an excellent modality to detect pulmonary hypertension. However, in patients with chronic lung disease, including idiopathic pulmonary fibrosis, studies have shown a variable performance for transthoracic echocardiography to detect pulmonary hypertension.[4]

Bronchoscopy

As previously stated, bronchoscopy with BAL and/or transbronchial biopsy is not required for the diagnosis of idiopathic pulmonary fibrosis. However, it can be used to ensure that alternative diagnoses are excluded. In cases requiring histopathology, the specificity and positive predictive value of UIP pattern identified by transbronchial biopsy has not been rigorously studied.[1]

BAL is not required for the diagnosis of idiopathic pulmonary fibrosis and is not recommended for patients with newly detected interstitial lung disease of apparently unknown cause who are clinically suspected of having idiopathic pulmonary fibrosis and have an HRCT pattern of UIP.[3]

Cellular analysis of BAL fluid is suggested (conditional recommendation) for patients with newly detected interstitial lung disease who are clinically suspected of having idiopathic pulmonary fibrosis and have an HRCT pattern of probable UIP, indeterminate, or an alternative diagnosis.[3]

The 2018 guidelines made no recommendation for or against transbronchial lung biopsy for patients with newly detected interstitial lung disease of unknown cause who are clinically suspected of having idiopathic pulmonary fibrosis and have an HRCT pattern of probable UIP, indeterminate, or an alternative diagnosis.[3]

Transbronchial cryobiopsy

A detailed search of the current evidence was concluded in the 2018 guidelines regarding the use of transbronchial cryobiopsy, and this search indicated enthusiasm regarding the current evidence suggesting a positive role for it in the workup of patients with interstitial lung disease with probable, indeterminate, or compatible with alternative pattern to UIP; however, this was offset by concern about the lack of standardized procedure and approach and the heterogeneous rates of adverse events noted in previous studies.[47, 48, 49] Therefore, the panel identified many questions that need to be answered before recommending widespread use of cryobiopsy, including the number of samples that should be obtained, the location from which the biopsies should be obtained, and the duration of time the Cryo probe should be cooled, among others, and it concluded the urgent need for standardization of this procedure to balance its diagnostic yield compared with its complications.

Surgical lung biopsy

A surgical lung biopsy specimen can be obtained through either an open lung biopsy or video-assisted thoracoscopic surgery (VATS). A surgical lung biopsy provides the best sample for which to distinguish usual interstitial pneumonia from other idiopathic interstitial pneumonias. VATS is preferred because it is associated with less morbidity and a shorter hospital stay compared with open lung biopsy.

Given the high-quality evidence regarding HRCT specificity for the recognition of histopathologic UIP pattern, surgical lung biopsy is not essential in making the diagnosis.[1] In patients with UIP pattern on HRCT a surgical lung biopsy is not needed for the diagnosis of idiopathic pulmonary fibrosis.

However, for patients with newly diagnosed interstitial lung disease of unknown cause who are clinically suspected of having idiopathic pulmonary fibrosis and have an HRCT pattern of probable UIP, indeterminate, or an alternative diagnosis, a surgical lung biopsy is suggested (conditional recommendation).[3]

The previously described major and minor criteria for the clinical diagnosis of idiopathic pulmonary fibrosis have been eliminated.[10]

The diagnosis of idiopathic pulmonary fibrosis now requires the following[1, 3] :

• The exclusion of other known causes of interstitial lung disease (ILD), including domestic and occupational environmental exposures, connective tissue disease, and drug toxicity

• The presence of a UIP pattern on HRCT in patients not subjected to a surgical lung biopsy

• Specific combinations of HRCT and surgical lung biopsy pattern in patients subjected to surgical lung biopsy

The histopathological lesion associated with idiopathic pulmonary fibrosis is usual interstitial pneumonia. Usual interstitial pneumonia is characterized by a heterogeneous, variegated appearance with alternating areas of healthy lung, interstitial inflammation, fibrosis, and honeycomb change, which results in a patchwork appearance at low magnification (see image below).[13]

Patchwork distribution of abnormalities in a classic example of usual interstitial pneumonia (low-magnification photomicrograph; hematoxylin and eosin stain; original magnification, X4). Courtesy of Chad Stone, MD.

Fibrosis predominates over inflammation in usual interstitial pneumonia. Fibroblastic foci represent microscopic zones of acute lung injury and are randomly distributed within areas of interstitial collagen deposition and consist of fibroblasts and myofibroblasts arranged in a linear fashion within a pale-staining matrix.[13] Although fibroblastic foci are not specific for usual interstitial pneumonia, they represent an important diagnostic criterion.

Another important diagnostic criterion for usual interstitial pneumonia is honeycomb change. Microscopically, honeycomb change is defined by cystically dilated bronchioles lined by columnar respiratory epithelium in scarred, fibrotic lung tissue.[13] Dense eosinophilic collagen without associated honeycomb change signifies fibrotic scars and is also characteristic of usual interstitial pneumonia. Interstitial inflammation, consisting of patchy alveolar septal infiltrates of mononuclear cells, is not predominant in usual interstitial pneumonia.

The usual interstitial pneumonia histologic pattern can be associated with other diseases besides idiopathic pulmonary fibrosis. These include asbestosis, collagen-vascular disease, fibronodular sarcoidosis, hypersensitivity pneumonitis, and toxic drug reactions (eg, to amiodarone, bleomycin, or nitrofurantoin). Correlation with clinical history is needed to identify these conditions.

In pathology specimens taken during acute exacerbations of idiopathic pulmonary fibrosis, microscopy reveals a combination of usual interstitial pneumonia with superimposed diffuse alveolar damage. Alveolar septa are expanded by more extensive fibroblast proliferation than is seen in conventional fibroblast foci. Additionally, marked hyperplasia of type 2 pneumocytes and hyaline membrane remnants is present.[13]

UIP histopathology patterns and features are as follows[3] :

• Dense fibrosis with architectural distortion (ie, destructive scarring and/or honeycombing)
• Predominant subpleural and/or paraseptal distribution of fibrosis
• Patchy involvement of lung parenchyma by fibrosis
• Absence of features to suggest an alternate diagnosis

Probable UIP histopathology patterns and features are as follows[3] :

• Some histologic features from UIP are present but to an extent that precludes a definite diagnosis of UIP AND
• Absence of features to suggest an alternative diagnosis OR honeycombing only

Indeterminate for UIP histopathology patterns and features are as follows[3] :

• Fibrosis with or without architectural distortion, with features favoring either a pattern other than UIP or features favoring UIP secondary to another cause
• Some histologic features of UIP but with other features suggesting an alternative diagnosis

Alternative diagnosis histopathology patterns and features are as follows[3] :

• Features of other histologic patterns of idiopathic interstitial pneumonias (eg, absence of fibroblast foci or loose fibrosis) in all biopsy specimens
• Histologic findings indicative of other diseases (eg, hypersensitivity pneumonitis, Langerhans cell histiocytosis, sarcoidosis, lymphangioleiomyomatosis)

If the HRCT pattern is consistent with an alternative diagnosis but histopathology demonstrates UIP, then idiopathic pulmonary fibrosis is likely.[3]

If the HRCT pattern is consistent with an alternative diagnosis and histopathology demonstrates probable UIP or indeterminate UIP, then the diagnosis is likely not IPF.[3]

If the HRCT pattern is indeterminate and histopathology is probable UIP, then the diagnosis is likely idiopathic pulmonary fibrosis.[3]

If the HRCT pattern is probable UIP and histopathology is indeterminate for UIP, the diagnosis is likely idiopathic pulmonary fibrosis.[3]

If the HRCT pattern is indeterminate and histopathology is indeterminate for UIP, the diagnosis is indeterminate.[3]

Any pattern on HRCT associated with a surgical lung biopsy finding of alternative diagnosis is not consistent with the diagnosis of idiopathic pulmonary fibrosis.[3]

Multidisciplinary discussion amongst pulmonologists, radiologists, and pathologists experienced in the diagnosis of interstitial lung disease is of utmost importance to an accurate diagnosis.[1, 3]

The goal of any disease management strategy should include assessment and treatment of comorbid medical conditions. Common comorbid medical conditions found in patients with idiopathic pulmonary fibrosis (IPF) include chronic obstructive pulmonary disease, obstructive sleep apnea, gastroesophageal reflux disease, and coronary artery disease. Therefore, if any of these comorbid illnesses are present, they should be managed according to current practice guidelines.

Given the high prevalence of gastroesophageal reflux (GER) in patients with idiopathic pulmonary fibrosis, a retrospective study was conducted to investigate the relationship of reflux-related variables and survival time in patients with idiopathic pulmonary fibrosis. Of the 204 included patients, 34% reported symptoms of GER, 45% had a history of GER disease, 47% reported use of medications for GER, and 5% of patients had previously undergone Nissen fundoplication. On adjusted analysis, the use of GER medications was associated with a longer survival time. Additionally, patients taking GER medications had a lower fibrosis score on HRCT.[50]

Any patient with idiopathic pulmonary fibrosis who is a current smoker should be encouraged to quit and offered pharmacologic therapy if needed.

Patients with hypoxemia (PaO2< 55 mmHg or oxygen saturation as measured using pulse oximetry [SpO2] < 88%) at rest or with exercise should be prescribed oxygen therapy to maintain a saturation of at least 90% at rest, with sleep, and with exertion.

The current clinical practice guidelines from 2011 and 2015 strongly recommend supplemental oxygen therapy for patients with idiopathic pulmonary fibrosis, as oxygen administration reduces exertional dyspnea and improves exercise tolerance. The oxygen prescription should be informed by 6-minute walk tests or treadmill testing of oxygen saturation, as well as by nocturnal oximetry or polysomnography as indicated.

Vaccination against influenza and pneumococcal infection should be encouraged in all patients with idiopathic pulmonary fibrosis.

See Medication for a discussion of the various drugs, experimental and otherwise, used in the treatment of idiopathic pulmonary fibrosis.

See Guidelines for recommendations from the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Association.

Patients with idiopathic pulmonary fibrosis (IPF) require consideration for lung transplantation owing to the natural progression of the disease. Two main challenges in the process of lung transplantation evaluation are to be considered.

The first challenge is the timing of referral to the transplantation program, as antifibrotic medications attenuate disease progression and make the decision on referral timing more complex as physicians elect to wait longer for those patients with moderate disease, pending a treatment response. Given that idiopathic pulmonary fibrosis is a universally progressive condition, regardless of antifibrotic initiation, one approach is to refer all suitable patients at the time of diagnosis. Another approach is to identify patients who are progressing rapidly and refer them early. Alternatively, studies have identified circulating biomarkers that correlate with disease progression, such as Krebs von den Lungen-6 (more commonly known as KL-6) and surfactant protein D, although these are not used in routine clinical practice. The development of pulmonary hypertension in idiopathic pulmonary fibrosis is an independent marker of poor prognosis and should prompt consideration for referral.

The second challenge is that acute exacerbations are unpredictable, are associated with inpatient mortality rates of more than 50%, and occur more frequently as idiopathic pulmonary fibrosis progresses.[51] Although studies have attempted to predict exacerbations on the basis of a previous drop in forced vital capacity (FVC), the evidence remains weak. The inability to accurately predict an event means that future exacerbations cannot be considered when referring for lung transplantation. However, suitable patients who survive an acute exacerbation should be fast-tracked for referral or prioritized if already listed.

The International Society of Heart and Lung Transplantation (ISHLT) suggests criteria for referral of patients with interstitial lung diseases (ILDs), including patients with idiopathic pulmonary fibrosis, which include the following:

• Histopathological or radiographical evidence of usual interstitial pneumonitis (UIP) or fibrosing nonspecific interstitial pneumonitis, regardless of lung function
• FVC less than 80 % of predicted or diffusion capacity less than 40 % of predicted
• Dyspnea or functional limitation attributable to their lung disease
• The requirement for supplemental oxygen, even if only on exertion

However, if every patient meeting these criteria were referred, transplantation services would rapidly become overwhelmed and unable to respond to those with the greatest need.

In May 2005, the lung allocation score (LAS) was implemented, which dramatically changed lung allocation from a system based purely on waiting time to an algorithm based on survival probability on the waiting list and after lung transplantation.[52] Therefore, the LAS is used to prioritize patients based on the difference between post-transplant 1-year survival and pretransplant urgency. Consequent to the use of LAS, idiopathic pulmonary fibrosis has now replaced chronic obstructive pulmonary disease as the most common indication for lung transplantation in the United States.[53]

Any patient diagnosed with idiopathic pulmonary fibrosis or probable idiopathic pulmonary fibrosis should be referred for lung transplantation evaluation, regardless of the vital capacity.[9] After a patient is referred for transplantation evaluation, the appropriate timing to list a patient on the lung transplantation list needs to be determined.

Guidelines for listing a patient with idiopathic pulmonary fibrosis include the following[9] :

• Diffusion capacity of carbon monoxide (DL _CO) less than 39% predicted
• A 10% or greater decrement in FVC during 6 months of follow-up
• A decrease in pulse oximetry below 88% during a 6-minute walk test (6MWT)
• Honeycombing on high-resolution computed tomography (HRCT) imaging (fibrosis score >2)

A 2009 retrospective review of the United Network for Organ Sharing data to identify lung transplant recipients with idiopathic pulmonary fibrosis between 2005 and 2007 examined risk for 30-day, 90-day, and 1-year mortality for single lung transplant versus bilateral lung transplant. Data were examined across levels of the LAS (quartile 1, quartile 2, quartile 3, and quartile 4).

Patients in LAS quartile 4 were defined as high risk. A clear inverse relationship between wait-list times and LAS was seen, with a higher LAS score associated with shorter wait-list times.[53] Patients in the LAS quartile 4 had a 7.1% lower cumulative survival at 1 year when compared with patients in quartiles 1 to 3. Just over 21% more patients received bilateral lung transplantation in the highest LAS quartile than in the lowest LAS quartile. In the high-risk quartile, bilateral lung transplantation was associated with a 14.4% decrease in mortality 1 year after lung transplantation.[53] However, this study is limited by the retrospective nature and the need to see if these trends persist at 3 years and 5 years. The reported 5-year survival rates after lung transplantation in idiopathic pulmonary fibrosis are estimated at 50-56%.[1]

Outcomes were published in 2015 comparing single- and double-lung transplantation since the implementation of the Lung Allocation Score. Adults with idiopathic pulmonary fibrosis who underwent lung transplantation between May 04, 2005 and December 31, 2012 were identified in the United Network for Organ Sharing thoracic registry. In total, 4134 patients with idiopathic pulmonary fibrosis underwent lung transplantation. Of these, 2010 patients underwent sing-lung transplantation and 2124 patients underwent double-lung transplantation. After confounders for double-lung transplantation were controlled for with propensity score analysis, double-lung transplant was associated with better graft survival in patients with idiopathic pulmonary fibrosis, with an adjusted median survival of 65.2 months versus 50.4 months in single-lung transplant (P < .001).[54]

Further inpatient care

The clinical course of patients with idiopathic pulmonary fibrosis (IPF) is generally marked by a decline in pulmonary function over time. Increasingly, patients have been recognized as having an acute, and often fatal, clinical deterioration, termed an acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF).[55] Up to one in five patients with idiopathic pulmonary fibrosis experience an acute exacerbation each year.

The following are diagnostic criteria for an AE-IPF[56] :

• Previous or concurrent diagnosis of idiopathic pulmonary fibrosis

• Unexplained worsening or development of dyspnea within 30 days

• High-resolution computed tomography (HRCT) scan with new bilateral ground-glass abnormality and/or consolidation superimposed on a background reticular or honeycomb pattern consistent with a usual interstitial pneumonia pattern

• Worsening hypoxemia from a known baseline arterial blood gas measurement

• No evidence of pulmonary infection by endotracheal aspiration or bronchoalveolar lavage (BAL)

• Exclusion of alternative causes, including left-sided heart failure, pulmonary embolism, and an identifiable cause of acute lung injury

In a retrospective review, of 461 patients with idiopathic pulmonary fibrosis, 20.8% of all subjects experienced an AE-IPF during the median follow-up period of 22.9 months. Approximately 50% of patients hospitalized for an AE-IPF died during the hospitalization. The 1-year and 5-year survival rates from the initial diagnosis of an AE-IPF were 56.2% and 18.4%, respectively.[57] Therefore, an AE-IPF has a serious impact on the overall survival of patients with idiopathic pulmonary fibrosis.

Despite the high morbidity and mortality associated with AE-IPF, there are limited data to guide management decisions. Supportive care and symptom management, most notably with supplemental oxygen, are well-accepted approaches. However, only very low-quality evidence is available to direct the use of specific treatment strategies, including antibiotics, antacid therapies, and corticosteroids. Corticosteroids are arguably the most controversial of these options.

Patients with idiopathic pulmonary fibrosis who develop an acute clinical deterioration often require hospitalization. These patients should undergo HRCT imaging of the chest to document the interval development of significant ground-glass opacities, which are suggestive of an AE-IPF. Additionally, a BAL may be completed to examine the possibility of infectious etiologies if clinically appropriate. Support with supplemental oxygen should be given to alleviate hypoxemia.[56]

Corticosteroids are recommended for the treatment of “the majority of patients with AE-IPF” by the most recent international idiopathic pulmonary fibrosis treatment guidelines in 2018. The guidelines are transparent about the lack of evidence and state that the recommendation is based largely on small, uncontrolled case series. Complicating this recommendation is evidence from clinical trials demonstrating that corticosteroids, in combination with immunomodulatory therapy, cause harm in chronic idiopathic pulmonary fibrosis, as previously mentioned.

In a 2020 retrospective observation of 82 AE-IPF subjects by Farrand et al, 37 patients (45%) received corticosteroids for the management of AE-IPF. It was noted that AE-IPF subjects treated with corticosteroids were more likely to require ICU level care and mechanical ventilation. There was no statistically significant association between corticosteroid treatment and in-hospital mortality. However, the overall survival was reduced in AE-IPF subjects receiving corticosteroids (hazard ratio, 6.17; 95% confidence interval, 1.35-28.14; P = .019).[58]

If a patient with an AE-IPF develops respiratory failure and requires invasive mechanical ventilation, plateau pressures should be maintained at less than 30 cm water.[56] It is of note that patients with idiopathic pulmonary fibrosis who require mechanical ventilation have a poor prognosis.

In a review published in 2008 by Mallick,[59] patients from nine studies consisting of 135 patients with established diagnosis of idiopathic pulmonary fibrosis who were admitted to the intensive care unit and required mechanical ventilation were evaluated. Only patients who were ventilated in intensive care were included from these studies. The pooled data showed an aggregated mortality of 118 (87%) among 135 idiopathic pulmonary fibrosis patients ventilated in intensive care units. The short-term mortality (mortality within 3 months of hospital discharge) was 127 (94%). The mean duration of mechanical ventilation was 8.6 days. Of the very few patients who survived, respiratory failure was precipitated by surgery/anaesthesia in two patients, one had undergone lung transplantation, and three patients were lost in follow-up.

Transfer

Lung transplantation for idiopathic pulmonary fibrosis has been shown to confer a survival benefit over medical therapy. Any patient diagnosed with idiopathic pulmonary fibrosis or probable idiopathic pulmonary fibrosis should be referred to a lung transplantation center for lung transplant evaluation, regardless of the vital capacity unless contraindications for transplantation exist.[9]

Patients with idiopathic pulmonary fibrosis should be referred to institutions where they can be counseled regarding enrollment in a trial of an investigational agent for the treatment of idiopathic pulmonary fibrosis.

Chronic cough is a distressing and disabling symptom with a major impact on quality of life. Progress has been made in gaining insight into the pathogenesis of cough in idiopathic pulmonary fibrosis, which is most probably multifactorial and influenced by mechanical, biochemical, and neurosensory changes, with an important role for comorbidities as well.

Conventional antitussive therapy is often not beneficial; furthermore, low-dose steroids were studied in the management of chronic cough; low doses of prednisone are sometimes tried in daily practice to relieve cough, and later are slowly tapered if beneficial. However, no effect on quality of life and survival has been reported in the literature, and the possible adverse effects also must be taken into consideration. A 24-week, single-center, double-blind cross-over study with thalidomide for the treatment of cough showed a positive effect on quality of life, as measured with the Cough Quality of Life Questionnaire.[60] However, only 20% of the screened subjects completed the study and the potential adverse effects of thalidomide can be severe. Finally, an inhaled cromolyn preparation was shown to ameliorate cough in patients with idiopathic pulmonary fibrosis.[61]

Early palliative care referral is recommended as an adjunct to disease-focused care in idiopathic pulmonary fibrosis (IPF). The UK National Institute for Health and Care Excellence defines palliative care in terms of patient and care-giver involvement, psychological support, symptom management and control, and spiritual support.

In the absence of palliative support, a large proportion of patients with end-stage lung disease die in a critical care environment, receiving care that might not be focused on comfort.

Differentiating between idiopathic pulmonary fibrosis (IPF) and non–idiopathic pulmonary fibrosis diagnosis in the workup of patients with interstitial lung disease (ILD) is of extreme importance. In addition, establishing an accurate diagnosis is paramount. The 2018 American Thoracic Society (ATS)/European Respiratory Society (ERS) consensus statement on the diagnosis of idiopathic pulmonary fibrosis strongly recommends a multidisciplinary evaluation in establishing the diagnosis that includes a pulmonologist, a radiologist, and a pathologist if a lung biopsy was pursued.[3] The importance of such evaluation is highlighted by observations that isolated radiographic or histologic UIP can represent processes other than idiopathic pulmonary fibrosis and that idiopathic pulmonary fibrosis does not always demonstrate radiographic or histologic UIP. Discussion among these specialists has been well-studied and has been shown to improve diagnostic agreement,[62] and it has become a cornerstone of evaluation at ILD referral centers.

Whether ILD is best diagnosed in a community or academic setting remains controversial. Flaherty and colleagues conducted an investigation of clinicians, radiologists, and pathologists from community and academic settings to determine the level of diagnostic agreement in evaluating ILD.[63] Using a stepwise approach that provided an increasing amount of clinical, radiographic, and histopathologic information, the authors demonstrated that diagnostic agreement has increased in both groups with each step. The authors noted that the greater agreement among academic versus community physicians was likely influenced by the fact that these individuals had collaborated on previous projects, including consensus statements, and that the community clinician with the most ILD experience tended to agree more often with the academicians.

Currently, early referral of patients to an ILD specialty center is highly recommended when multidisciplinary evaluation cannot be performed locally, or when diagnostic doubt exists following community multidisciplinary evaluation. Referral has the added advantage of providing patients access to specialized care, including clinical trial enrollment and lung transplantation evaluation. Whether referral of patients to an ILD center improves outcomes is unknown, however, and remains an interesting area for further investigation.

Any patient with idiopathic pulmonary fibrosis who is overweight should be encouraged to meet with a nutritionist and make dietary changes to achieve ideal body weight. Maintaining adequate nutritional intake is important for quality of life in patients with idiopathic pulmonary fibrosis.

Improving quality of life is an important goal in disease management.[64] Deconditioning and subsequent functional impairment is a common problem in patients with idiopathic pulmonary fibrosis (IPF) and negatively impacts quality of life. Two controlled trials of pulmonary rehabilitation in idiopathic pulmonary fibrosis have demonstrated an improvement in walk distance and symptoms or quality of life.[1] Therefore, patients with idiopathic pulmonary fibrosis should be evaluated for pulmonary rehabilitation and encouraged to participate in regular exercise to maintain a maximal degree of musculoskeletal conditioning.[2, 65] More evidence of pulmonary rehabilitation to improve exercise capacity and health-related quality of life for patients with idiopathic pulmonary fibrosis was published in 2017.[42]

The rate of decline and progression to death in patients with idiopathic pulmonary fibrosis (IPF) may take several clinical forms, including slow physiologic deterioration with worsening severity of dyspnea, rapid deterioration and progression to death, or periods of relative stability interposed with periods of acute respiratory decline sometimes manifested by hospitalizations for respiratory failure.[11] Therefore, all patients with idiopathic pulmonary fibrosis should be seen by a pulmonologist on a regular basis for a complete history and physical examination. Patients must undergo disease-specific monitoring with serial assessments of lung physiology, gas exchange, exercise performance, and HRCT to further refine prognosis and management decisions. Patients must be asked about adverse medication effects.

Any patient with idiopathic pulmonary fibrosis who is a current smoker should be encouraged to quit and offered pharmacologic therapy if needed.

Vaccination against influenza and pneumococcal infection should be encouraged in all patients with idiopathic pulmonary fibrosis.

Patients with idiopathic pulmonary fibrosis should be evaluated for pulmonary rehabilitation and should be encouraged to participate in regular exercise to maintain a maximal degree of musculoskeletal conditioning.

Although current guidelines recommend the use of antacid therapy to treat idiopathic pulmonary fibrosis,[3] there are no data from clinical trials to support this recommendation. In two studies, antacid use was associated with a slower decline in lung function and a lower mortality rate.[66, 67] These observational studies of treatment effect are, by nature, confounded by indication and should not be used to inform clinical practice.[68] Other data suggest that antacid therapy may increase the risk of respiratory infections in patients with idiopathic pulmonary fibrosis.[69]

A growing knowledge of the biologic underpinnings of fibroproliferation has opened new therapeutic avenues. Gorina and colleagues report the safety and efficacy of pamrevlumab, a human monoclonal antibody against connective-tissue growth factor, in a randomized, double-blind, placebo-controlled phase 2 trial on patients with idiopathic pulmonary fibrosis and showed slowing in the decline in FVC, as compared with placebo, over a period of 48 weeks.[70] A phase 3 trial targeting 340 participants is expected to be completed by December 2022 (Clinicaltrials.gov, NCT03955146).

GLPG1690, which targets autotaxin, an enzyme responsible for lysophosphatidic acid production, was also examined in a phase 2 trial in 2018 and may reduce circulating lysophosphatidic acid levels while influencing lung function and findings on functional respiratory imaging.[71]

Multiple other studies are being conducted to evaluate the safety and efficacy of other therapeutic options for the management of idiopathic pulmonary fibrosis and are yet to be reported.[72, 73]

Compelling data have linked disease progression in patients with idiopathic pulmonary fibrosis with lung dysbiosis and the resulting dysregulated local and systemic immune response. Moreover, prior therapeutic trials have suggested improved outcomes in these patients treated with either sulfamethoxazole/trimethoprim or doxycycline.[74, 75] The CleanUP-IPF study is a randomized double-blinded clinical trial with a target of approximately 500 individuals in a 1:1 ratio to either antimicrobial therapy or usual care, with a primary endpoint of the time to first nonelective respiratory hospitalization or all-cause mortality.[76]

The 2015 guidelines on idiopathic pulmonary fibrosis (IPF) by the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Association include the following points[77, 78] :

• The guidelines recommend against the use of the following agents for the treatment of idiopathic pulmonary fibrosis: anticoagulation (warfarin); imatinib, a selective tyrosine kinase inhibitor against platelet-derived growth factor (PDGF) receptors; combination prednisone, azathioprine, and N-acetylcysteine; and selective endothelin receptor antagonist (ambrisentan).
• The guidelines also give a conditional recommendation against the use of sildenafil, macitentan, and bosentan.
• The panel has continued the 2011 conditional recommendation against the use of N-acetylcysteine monotherapy for IPF. They have also continued the 2011 conditional recommendation for the use of antacid therapy in patients without symptoms of GER.
• The recommendation for the use of the following agents for the treatment of idiopathic pulmonary fibrosis is conditional: nintedanib, a tyrosine kinase inhibitor that targets multiple tyrosine kinases, including vascular endothelial growth factor, fibroblast growth factor, and PDGF receptors; and pirfenidone.

The clinical practice guidelines on the diagnosis of idiopathic pulmonary fibrosis were released on September 1, 2018, also by the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society.[3, 79] The collaborative guidelines outline basic recommendations for clinical observation, HRCT scanning, bronchoscopy, histopathology, and serum biomarker measurements, as follows:

• Obtain a detailed history for possible environmental exposures or medication use to exclude potential causes of interstitial lung disease (ILD).
• Perform serologic testing to exclude connective-tissue disease.
• With newly diagnosed ILD, perform HRCT scanning of the chest; determine if findings indicate a pattern of (1) usual interstitial pneumonia (UIP), (2) probable UIP, (3) indeterminate of UIP, or (4) alternate diagnosis.
• For probable UIP, indeterminate findings, or alternate diagnosis, bronchoalveolar lavage and surgical lung biopsy are recommended; evidence is insufficient to recommend for or against transbronchial lung biopsy or lung cryobiopsy.
• For a UIP pattern, bronchoalveolar lavage (cellular analysis) and surgical lung biopsy are not recommended (risks outweigh benefits); guidelines strongly recommend against transbronchial lung biopsy or lung cryobiopsy in this situation.
• Multidisciplinary discussions (MDDs) should include interactions between pulmonologists, possibly rheumatologists (on a case-by-case basis), pathologists, and radiologists. MDDs are recommended with newly detected ILD of an unknown cause in patients whose findings clinically suggest idiopathic pulmonary fibrosis. MDDs likely provide the greatest benefit in situations in which HRCT patterns indicate probable UIP, indeterminate findings, or alternative diagnoses, or when clinical, histologic, or radiologic data are incongruous.
• For serum biomarker measurements, measuring serum matrix metalloproteinase 7, chemokine ligand 18, Krebs von den Lungen-6, or surfactant protein D is not recommended solely to distinguish idiopathic pulmonary fibrosis from other ILDs, owing to high false-positive and false-negative results.

The previous theory regarding the pathogenesis of idiopathic pulmonary fibrosis (IPF) was that generalized inflammation progressed to widespread parenchymal fibrosis. It was believed that an unidentified insult to the alveolar wall initiated a cycle of chronic alveolar inflammatory injury (alveolitis) leading to fibrosis.[80] Based on this pathogenetic concept, anti-inflammatory agents and immune modulators were used to treat idiopathic pulmonary fibrosis.

Depending on available data in the year 2000, a typical regimen of immunosuppression using prednisone and azathioprine was a standard of care; furthermore, a double-blinded clinical trial in 2005 by Demets et al (IFIGENIA Study) on 182 patients with the diagnosis of idiopathic pulmonary fibrosis concluded that a therapy with acetylcysteine at a dose of 600 mg three times daily, added to prednisone and azathioprine, preserves vital capacity and diffusion capacity of carbon monoxide (DLCO) in patients with idiopathic pulmonary fibrosis.[81]

However, in the year 2010, the Prednisolone, Azathioprine, and N-Acetylcysteine: A Study That Evaluates Response (PANTHER) was published and found that patients taking this triple-combination therapy were at increased risk of death and hospitalization compared with patients receiving placebo alone.[82] In addition, when compared with placebo, acetylcysteine in isolation offered no significant benefit with respect to the preservation of forced vital capacity (FVC) in patients with idiopathic pulmonary fibrosis compared with placebo.[83]

These findings have led to a shift away from immunosuppression and antioxidants and left a gap in the years after with no apparent effective options available.

It is currently believed that idiopathic pulmonary fibrosis is an epithelial-fibroblastic disease, in which unknown endogenous or environmental stimuli disrupt the homeostasis of alveolar epithelial cells, resulting in diffuse epithelial cell activation and aberrant epithelial cell repair.[14] The recognition of new factors contributing to the pathogenesis of idiopathic pulmonary fibrosis has led to the development of novel approaches to treat idiopathic pulmonary fibrosis.

This change in understanding the pathogenesis of idiopathic pulmonary fibrosis was translated into the therapeutic options studied in the last two decades, especially with the development of two novel antifibrotic therapies, pirfenidone and nintedanib, that have been developed and approved in the last 8 years, providing treatment options for many patients with idiopathic pulmonary fibrosis.

Tyrosine kinase inhibitors (nintedanib)

Nintedanib is a tyrosine kinase inhibitor that was initially developed as an anti-tumor agent before it was noted to have activity against fibroblasts through inhibition of vascular endothelial growth factor (VEGF) and other profibrotic mediators such as platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and transforming growth factor (TGF)–β.[84, 85]

In October 2014, the US Food and Drug Administration (FDA) approved nintedanib (Ofev) for treatment of idiopathic pulmonary fibrosis. Approval was based on conducted two replicate 52-week, randomized, double-blind, phase 3 trials (INPULSIS-1 and INPULSIS-2). Each trial showed a statistically significant improvement in FVC compared with placebo (P = .001).[86] Nintedanib was associated with the development of diarrhea; however, it led to discontinuation of the medication in less than 5% of the patients.[86]

A 12-month, phase 2 trial, completed by Richeldi and colleagues, assessed the efficacy and safety of four different oral doses of the tyrosine kinase inhibitor nintedanib (formerly BIBF 1120) compared with placebo in patients with idiopathic pulmonary fibrosis. Nintedanib targets PDGF receptors α and β; VEGF receptors 1, 2, and 3; and FGF receptors 1, 2 and 3. The primary endpoint was the annual rate of decline of FVC.

A total of 432 patients were randomly assigned to receive one of four doses of nintedanib (50 mg once a day, 50 mg twice a day, 100 mg twice a day, or 150 mg twice a day) or placebo. In patients receiving 150 mg twice daily, there was a trend toward a reduction in the decline of lung function when compared with placebo. The annual rate of decline in FVC was 0.06 L in those taking 150 mg twice daily compared with 0.19 L in the placebo group (P = .06 with the closed testing for multiplicity).

In regard to secondary endpoints, the incidence of acute exacerbations of idiopathic pulmonary fibrosis was lower in the group receiving nintedanib at 150 mg twice daily compared with placebo (2.4 vs 15.7 per 100 patient-years, P = .02). The highest proportion of patients who discontinued the study medication because of adverse events was those subjects taking 150 mg twice daily. The adverse events most frequently leading to discontinuation included diarrhea, nausea, and vomiting. Overall, the phase 2 study revealed an acceptable safety profile and potential clinical benefits of treatment with nintedanib 150 mg twice daily, thus warranting phase 3 clinical investigations.[87]

It is of note that no mortality benefit was noted with nintedanib treatment in the INPULSIS trials or when the data was pooled with the TOMORROW study.[88] In addition, there was no evidence from pooled data that mortality post exacerbation improved with nintedanib.[89]

Antifibrotic agents (pirfenidone)

Pirfenidone has a number of anti-inflammatory and antifibrotic effects, including inhibition of collagen synthesis, down-regulation of TGF-β and tumor necrosis factor-α, and a reduction in fibroblast proliferation.

The FDA approved pirfenidone (Esbriet) for the treatment of idiopathic pulmonary fibrosis in October 2014. Approval was based on the ACSEND and CAPACITY 1 and 2 trials. Pirfenidone slowed the decline and, in some patients, halted the decline of FVC and improved progression-free survival.[90, 91]

A phase 3 multicenter, double-blind, placebo-controlled, randomized clinical trial in Japan examined the use of pirfenidone.[92] Two-hundred and seventy-five Japanese patients with idiopathic pulmonary fibrosis were randomized to high-dose pirfenidone (n = 108; 1800 mg/d PO), low-dose pirfenidone (n = 55; 1200 mg/d PO), or placebo (n = 104). The primary endpoint was a change in vital capacity from baseline to week 52. Secondary endpoints were progression-free survival time and the change in the lowest SpO2 during a 6-minute steady-state exercise test.

This was followed internationally by the Clinical Studies Assessing Pirfenidone in idiopathic pulmonary fibrosis: Research of Efficacy and Safety Outcomes (CAPACITY) trials (PIPF-004 and PIPF-006), where two concurrent randomized control trials in idiopathic pulmonary fibrosis compared pirfenidone at doses of 2403 mg/day and 1197 mg/day against placebo over 72 weeks.

In study 004, 435 subjects were randomized to a pirfenidone dose of 2403 mg/d (n = 174), a pirfenidone dose of 1197 mg/d (n = 87), or placebo (n = 174). At week 72, a significant reduction in decline of FVC was noted in the group assigned to a pirfenidone dose of 2403 mg/d (-8%) compared with placebo (-12.4%).

In study 006, 344 subjects were randomized to a pirfenidone dose of 2403 mg/d (n = 171) or placebo (n = 173). At week 72, no significant reduction in decline of FVC in the pirfenidone group (-9%) was found compared with placebo (-9.6%).[90]

When data from both studies were pooled together comparing a pirfenidone dose of 2403 mg/d with placebo, a significant reduction in decline of FVC was noted in the pirfenidone group (-8.5%) compared with placebo (-11%). Additionally, in the pooled analysis, pirfenidone prolonged progression-free survival by 26% compared with placebo. Finally, in the pooled analysis, pirfenidone reduced the proportion of patients with a 10% or more decline in FVC by 30% compared with placebo.[90]

In February 2014, InterMune released preliminary data from the phase 3 ASCEND (Assessment of Pirfenidone to Confirm Efficacy and Safety in IPF) trial.[93] The study was a multinational, randomized, double-blind placebo-controlled phase 3 trial to evaluate the safety and efficacy of pirfenidone in patients with idiopathic pulmonary fibrosis and was requested by the FDA because of discrepancies between the two CAPACITY trials in meeting their primary endpoints. Patients (N = 555) were randomly assigned 1:1 to receive oral pirfenidone (2403 mg/day) or placebo and were enrolled at 127 centers in the United States, Australia, Brazil, Croatia, Israel, Mexico, New Zealand, Peru, and Singapore.

The primary endpoint was comparing the proportion of patients in the pirfenidone and placebo groups experiencing either a clinically significant change in FVC or death. At week 52, 16.5% of patients in the pirfenidone group experienced an FVC decline of 10% or more or death, compared with 31.8% in the placebo group. Additionally, at week 52, the data demonstrated that 22.7% of patients in the pirfenidone group experienced no decline in FVC, compared with 9.7% in the placebo group. Pirfenidone alone improved progression-free survival and reduced the decline in the 6-minute walk distance. Gastrointestinal and skin-related adverse events were more common in the pirfenidone group than in the placebo group but rarely led to discontinuation of treatment.[91]

Pooled analysis of the CAPACITY and ASCEND studies found that treatment with pirfenidone at 2403 mg/day reduced the proportion of patients experiencing an FVC of 10% or greater or death by 43.8%[94] In addition, there was a reduction in the relative risk of all-cause and idiopathic pulmonary fibrosis–related mortality at 52 weeks with pirfenidone treatment.[85]

Combination therapy with pirfenidone and nintedanib

To date there is no compelling evidence to support the dual use of pirfenidone and nintedanib for the management of idiopathic pulmonary fibrosis. In 2018, Vancheri et al published a clinical trial investigating the safety, tolerability, and pharmacokinetic and exploratory efficacy endpoints in idiopathic pulmonary fibrosis patients treated with nintedanib at 150 mg twice daily for at least 4 weeks and add-on pirfenidone compared with a group of patients treated with nintedanib alone.[95] While on treatment, gastrointestinal adverse effects were reported in 69.8% of the patients treated with nintedanib with add-on pirfenidone, compared with 52.9% in the patients in the nintedanib arm. The investigators concluded there was a manageable safety and tolerability profile in patients with idiopathic pulmonary fibrosis for the combination therapy.

Similar results were reported in a recent phase 2 study in Japan on 50 idiopathic pulmonary fibrosis patients that assessed combination therapy with both antifibrotics and reported adequate tolerability and no effect for nintedanib on the pharmacokinetics of pirfenidone, with promising secondary efficacy data.[96] Future studies to compare the efficacy of combination therapy with single antifibrotic therapy are warranted.

Class Summary

Inhibition of various tyrosine kinases decreases the proliferative activities that lead to fibrosis.

Nintedanib (Ofev)

Nintedanib inhibits multiple tyrosine kinases and targets growth factors, which have been shown to be potentially involved in pulmonary fibrosis (eg, vascular endothelial growth factor receptor [VEGFR], fibroblast growth factor receptor [FGFR], platelet-derived growth factor receptor [PDGF]). It binds competitively to the adenosine triphosphate–binding pocket of these receptors and blocks intracellular signaling, which is crucial for the proliferation, migration, and transformation of fibroblasts, representing essential mechanisms of the idiopathic pulmonary fibrosis pathology.

Class Summary

Reduction of fibroblast proliferation may decrease the formation and/or accumulation of fibrotic materials within the lungs.

Pirfenidone (Esbriet)

The precise mechanism by which pirfenidone may work in pulmonary fibrosis has not been established. It inhibits transforming growth factor (TGF)-β, a chemical mediator that controls many cell functions, including proliferation and differentiation. It also inhibits the synthesis of TNF-α, a cytokine that is known to have an active role in inflammation.