Prognosis and monitoring of idiopathic pulmonary fibrosis

INTRODUCTION — Idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP), previously known as cryptogenic fibrosing alveolitis (CFA) in Europe, is the most common type of idiopathic interstitial pneumonia (IIP) [1].

An American Thoracic Society (ATS)/European Respiratory Society (ERS) consensus statement defines IPF as a spontaneously occurring (idiopathic) specific form of chronic fibrosing interstitial pneumonia limited to the lung and associated with a pattern of UIP on high-resolution computed tomography (HRCT) or surgical (thoracoscopic or open) lung biopsy [2]. The importance of careful monitoring and accurate prognostication has increased with the availability of new medications to treat IPF and expanding eligibility for lung transplantation.

The prognosis and monitoring of IPF will be reviewed here. The clinical manifestations, diagnosis, and treatment of IPF are discussed separately. (See "Clinical manifestations and diagnosis of idiopathic pulmonary fibrosis" and "Treatment of idiopathic pulmonary fibrosis" and "Acute exacerbations of idiopathic pulmonary fibrosis".)

PROGNOSIS — The natural history of IPF is most often described as one of insidious decline in lung function resulting in progression to respiratory failure and death on average within approximately four to five years after the initial diagnosis [2]. However, there is great variability in disease course among individual patients with IPF, and survival is influenced by several factors including variable progression rates, occurrence of acute exacerbations, and comorbid disease (figure 1) [3].

Mortality — The median survival of IPF has been reported to range from two to five years [4,5]. This estimate reflects the range of average life expectancies observed in cohorts of IPF patients, rather than the limits of an individual patient's life expectancy. This nuance is important, as the actual range of survival of individual IPF patients is quite broad, with up to 20 to 25 percent of patients living beyond 10 years [4].

There are several caveats to interpretation of reported survival estimates for IPF.

●First, available estimates have largely been generated from cohorts of patients seen at specialty referral centers, and thus may not account for the significant time lags between development of first symptoms, initial detection of pulmonary fibrosis, and referral to an interstitial lung disease (ILD) center [6].

●Second, up to 20 percent of patients with IPF will die from causes not directly attributable to their disease (eg, lung cancer, cardiovascular disease) [3,7]. Patients with these and other significant comorbidities are often excluded from clinical trials, resulting in lower than expected short-term (eg, one year) mortality rates compared with general clinical cohorts [8].

●Third, it remains unknown how the introduction of approved IPF medications (ie, nintedanib and pirfenidone) and the decreased use of harmful immunosuppressive agents (ie, combination of prednisone and azathioprine) will influence long-term survival in patients with IPF [9-12]. More recent cohorts suggest longer survival of IPF, which is likely at least partially related to these changes in management [13].

Predictors of mortality — In light of the variable clinical course, several studies have sought to identify predictors of survival in IPF. Predictors of reduced survival at baseline include older age, male sex, lower forced vital capacity (FVC) percent predicted, lower diffusing capacity of carbon monoxide (DLCO) percent predicted, resting or exertional hypoxemia, greater severity of dyspnea, reduced BMI, lower distance walked on six-minute walk test (6MWT), and greater extent of fibrosis on high-resolution computed tomography (HRCT), among others (table 1) [5,8,14-20].

●Gender-Age-Physiology (GAP) model – The most widely used clinical prediction model is the GAP model, which incorporates age, gender, FVC, and DLCO into a simple point-score index and staging system predictive of one-, two-, and three-year mortality (table 2) [5]. Likely due to changes in IPF diagnosis and treatment since its initial validation, the GAP model tends to overestimate mortality, particularly in patients with mild disease [8,20]. Several extensions of the GAP model have been derived and validated. These include validation of a modified index that also includes baseline six-minute walk distance and exertional hypoxemia, showing improved discrimination in more recent cohorts [20]. We use the GAP index and staging system, combined with clinical impression that considers multiple additional variables (eg, unintended weight loss, severity of dyspnea, extent of fibrosis on imaging, change in walk distance, exertional hypoxemia) to guide initial patient discussions regarding prognosis, therapeutic options, urgency of lung transplantation, and timeline of palliative approaches.

●Longitudinal clinical course – Longitudinal clinical course powerfully predicts subsequent survival. In particular, a 10 percent or greater decline in FVC over 6 to 12 months, occurrence of an acute exacerbation, or worsening respiratory symptoms requiring hospitalization all herald high risk for short-term mortality [14,21,22]. IPF is often considered to be an inexorably progressive disease; however, a substantial percentage of patients have a slow progression that suggests improved survival. This has been most clearly demonstrated in the application of recently proposed criteria for progressive pulmonary fibrosis (PPF) to IPF populations [23], with only half of patients meeting criteria for PPF in the first two years of follow-up [24]. Although the concept of PPF is intended for use in non-IPF ILDs primarily to inform management decisions in this population, there is likely applicability to IPF in terms of the prognostic significance of meeting PPF criteria.

We follow the trajectory of lung function decline in IPF patients, specifically in FVC and DLCO, every three to six months in order to update prognostic discussions with patients, determine urgency of lung transplantation for potential candidates, and inform treatment decisions (for example, whether to continue antifibrotic therapy, switch antifibrotic therapy, or change focus to palliative and/or hospice care for those who are not candidates for lung transplantation). Longitudinal lung function trajectory is further contextualized with symptomatic and radiologic findings, particularly when marginal physiologic worsening is present.

●Molecular biomarkers – Beyond clinically available information, there is great interest in identifying noninvasive molecular biomarkers to refine prognostication in IPF. Some of the most exciting candidates include several blood proteins that reflect alveolar epithelial cell injury or activation of fibrotic pathways [25], peripheral blood gene expression profiles [26], peripheral blood leukocyte telomere length [27], peripheral blood monocyte count [28], and the mucin 5B (MUC5B) promoter polymorphism (table 1) [29].

Acute exacerbations — An acute exacerbation of IPF is defined as an acute respiratory deterioration in a patient with IPF along with evidence of new widespread alveolar abnormalities (ie, new bilateral ground glass opacities and/or consolidation on chest HRCT) not otherwise explained by another cause such as heart failure [30]. (See "Acute exacerbations of idiopathic pulmonary fibrosis".)

Acute exacerbations occur in approximately 5 to 10 percent of IPF patients per year and carry a very poor prognosis with median survival after an exacerbation of only three to four months and high in-hospital mortality for those presenting with respiratory failure (50 percent overall and 90 percent for those requiring invasive mechanical ventilation) [30,31]. More broadly, several studies have confirmed that hospitalizations for worsening respiratory symptoms, regardless of whether they meet criteria for acute exacerbations, confer a high risk for subsequent mortality [21,22]. The occurrence of acute exacerbation or respiratory hospitalization should therefore prompt reanalysis of expected prognosis and, potentially, goals of care. (See "Palliative care for adults with nonmalignant chronic lung disease" and "Discussing goals of care".)

Predicting disease progression — There are several ways that disease progression can be measured in patients with IPF; however, there is no single standard method or set of clinical criteria, and predictors of survival tend to be poor predictors of disease progression [32].

●Clinical parameters – Clinical information that is predictive of survival does not appear to meaningfully predict rate of progression [32]. One notable exception is that patients with a family history of pulmonary fibrosis due to mutations in telomere-maintenance genes may have a faster average rate of progression than those with sporadic IPF [33].

●FVC – Decline in FVC, as an indirect measure of worsening fibrosis that results in increased lung stiffness, has become the most commonly accepted measure of disease progression in IPF. Data from the placebo groups of multiple IPF trials indicate that the average annual rate of FVC decline is approximately 200 mL, which is approximately halved by both nintedanib and pirfenidone [3,9,34]. Rate of decline in FVC among individuals again is highly variable, with approximately one-third each in placebo arms experiencing stability, marginal decline (ie, 5 to 10 percent), or significant decline (ie, >10 percent) in FVC over one year [22]. Interestingly, decline in FVC at the individual patient level may be more stepwise than linear over time, and past trajectory of FVC does not predict future trajectory of FVC in the short term [32,35].

Reduction in FVC decline was the primary efficacy end point in the landmark trials that led to US Food and Drug Administration (FDA) approval of nintedanib and pirfenidone for IPF [11].

●DLCO – DLCO is limited as a practical measure of progression over time due to its lower interest reproducibility and relative nonspecificity for ILD, but large declines (ie, 15 percent or greater) have been considered an indication of significant progression [3]. Smaller declines in DLCO (ie, 5 to 15 percent) may be clinically meaningful when contextualized with other measures of disease progression.

●HRCT – Quantification of lung fibrosis on HRCT over time is an attractive and potentially more direct measure of disease progression than FVC but is not currently applicable to clinical practice due to lack of rapid and reproducible quantification methods. Automated software algorithms for quantification of HRCT fibrosis may change this in the future [36]. (See 'Imaging' below.)

●Molecular biomarkers – There is great interest in identifying molecular biomarkers that can predict rate of disease progression and help identify patients who are more or less likely to benefit from IPF medications or who need urgent evaluation for lung transplantation (table 1) [25,37-39]. While several molecular biomarkers predict survival and/or disease progression, none has been demonstrated to predict response to antifibrotic therapy, thus limiting their clinical value [40,41]. One exception is that shorter peripheral blood telomere length appears to predict harm from immunosuppressive therapies, but immunosuppression is no longer recommended for patients with IPF [42]. Molecular biomarkers are not widely available nor commonly measured in clinical practice for the management of IPF.

MONITORING

Overview — The major reasons to monitor patients with IPF are to assess potential disease progression that might prompt a change in therapy and to identify comorbidities and complications that will influence when to initiate or stop antifibrotic therapy, when to initiate or titrate oxygen therapy, when to refer and list for lung transplantation, and when to initiate palliative measures. The management of IPF is discussed separately. (See "Treatment of idiopathic pulmonary fibrosis".)

As there are limited data and no clear consensus on how to monitor patients with IPF, most recommendations are based on extrapolated evidence and expert opinion. The specific monitoring strategy is driven by clinical need that is assessed on a case-by-case basis. The type and frequency of monitoring evolves over the course of the disease, with symptom assessment and pulmonary function measurements being the cornerstones of disease monitoring.

Early in disease, patients are typically monitored at three- to six-month intervals, with more frequent monitoring considered in patients with more advanced or rapidly progressive disease. Specific monitoring is also required by some funding agencies in order to acquire or maintain financial coverage for antifibrotic medication.

Patients with worsening symptoms, pulmonary function, or chest imaging should have these findings contextualized with results from other domains to determine whether IPF progression is the cause of this worsening. Progression of IPF may prompt additional confirmatory tests, initiation or change in IPF pharmacotherapy, consideration of lung transplantation, or initiation of palliative therapies.

Symptoms — The most common symptoms of IPF are dyspnea, reduced exertional capacity, and cough that is nonproductive or minimally productive. These symptoms are present in the majority of patients at the time of diagnosis and increase in prevalence and severity during the course of disease.

●Dyspnea – Worsening dyspnea is a primary indicator of disease progression [43-45], including acute exacerbations of IPF [30], and should be assessed at every patient encounter. The optimal method of assessment has not been determined, but in clinical practice dyspnea is typically assessed by a qualitative history or simple measurements such as the modified Medical Research Council (mMRC) breathlessness scale (calculator 1) (table 3) [46]; however, this scale is relatively limited and may lack sensitivity to anything less than major progression.

Structured dyspnea questionnaires that provide a summary score (eg, University of San Diego Shortness of Breath Questionnaire) have been frequently used in IPF clinical trials; however, the clinical utility of these more detailed and time-consuming assessments is unclear, and most questionnaires lack complete validation in IPF.

Dyspnea is also a common manifestation of multiple comorbidities in IPF (eg, chronic obstructive pulmonary disease, pulmonary hypertension, cardiovascular disease), and it is necessary to consider worsening dyspnea in the context of other measures of disease progression. This allows determination of whether worsening dyspnea is due to IPF progression, thus informing management decisions related to IPF pharmacotherapy, lung transplantation, and palliative therapies.

●Exercise capacity – Exercise capacity worsens as IPF progresses and is a major source of morbidity and loss of independence. There is no established strategy for measurement of physical function in IPF, with possibilities including patient history, standardized questionnaires, and direct measurements of exercise performance or physical activity.

Patients should be questioned about their exercise capacity at each clinical encounter. These questions focus on what distance patients can walk and whether they can climb stairs, with or without oxygen, as well as other questions related to how well the patient is managing in his or her home environment.

●Cough – Cough adversely affects quality of life in patients with IPF and tends to worsen as the disease progresses [47,48]. The best method of assessment for individual patients has not been determined; in our practice we use a qualitative assessment of frequency and severity. Research studies have assessed cough by using a visual analog scale (eg, marking an "x" on a 10 cm straight line), cough counters, structured questionnaires (eg, Leicester Cough Questionnaire), and as a dichotomous variable based on patient report [49,50]. These methods are not commonly used in a clinical setting, as they are often time consuming and lack complete validation in IPF.

●Other symptoms – At each encounter we explore the following additional symptoms:

•Other consequences of IPF (eg, impaired sleep, depression, anxiety, pulmonary hypertension) (see 'Complications and comorbidities' below)

•Common comorbidities (eg, COPD, lung cancer, cardiovascular disease) (see 'Complications and comorbidities' below)

•Features that may identify a diagnosis other than IPF (eg, rheumatic disease, hypersensitivity pneumonitis, pneumoconiosis)

•Potential adverse effects of IPF pharmacotherapies (see "Treatment of idiopathic pulmonary fibrosis", section on 'Dose and administration' and "Treatment of idiopathic pulmonary fibrosis", section on 'Dose and administration')

Pulmonary function tests — Pulmonary function tests (PFTs) are a key component of disease monitoring in IPF. The most common PFT variables that are regularly monitored in IPF are forced vital capacity (FVC) and diffusing capacity of carbon monoxide (DLCO) [51-53]; lung plethysmography provides additional useful data in some patients [54]. FVC and DLCO are consistently strong predictors of mortality in IPF and are key variables in determining the timing for lung transplantation [5,14,15]. (See 'Predictors of mortality' above and "Treatment of idiopathic pulmonary fibrosis", section on 'Lung transplantation' and "Lung transplantation: General guidelines for recipient selection".)

●Tests to order – PFTs (ie, spirometry, DLCO, six-minute walk test [6MWT]) are usually performed at intervals of three to six months in patients with IPF, with more or less frequent testing depending on the degree of symptoms and rate of worsening. For patients with combined pulmonary fibrosis and emphysema (CPFE) or discordant changes in FVC and DLCO, lung volumes by plethysmography may help clarify the physiology. (See "Overview of pulmonary function testing in adults" and "Diffusing capacity for carbon monoxide".)

●Interpretation – An absolute decline in FVC or DLCO of at least 10 percent over 6 to 12 months predicts an increased risk of mortality [8,14,21,22,35,44,55-58], and some studies have suggested smaller absolute declines in FVC of 5 percent also portend a worse prognosis [59,60].

Patients with a decline in FVC and/or DLCO should have this worsening interpreted in the context of other key features of disease progression, such as symptoms and high-resolution computed tomography (HRCT), given the inherent variability of PFTs and lack of specificity. Correlation of PFT changes with imaging findings should be considered in patients with marginal decline in PFT (eg, decline in FVC of 5 to 10 percent) and/or marginally worse symptoms. Similarly, repeat PFTs may be appropriate in patients with discordant findings in which disease progression is suggested by one modality but not another.

Patients with CPFE have relative preservation of spirometric values and slower decline in FVC compared with patients with isolated IPF [57,61], indicating the need to consider other measures of disease progression in these patients. (See 'Combined pulmonary fibrosis and emphysema' below.)

●Six-minute walk test – The 6MWT is the most common method of measuring exercise capacity in patients with IPF (see "Overview of pulmonary function testing in adults", section on 'Six-minute walk test'). The 6MWT is a well-described standardized test that has been extensively studied in chronic lung diseases, including IPF [62,63]. The key variables obtained from the 6MWT are the distance walked and extent of hypoxemia measured by pulse oximetry. A change in six-minute walk distance (6MWD) of approximately 30 meters is considered a clinically important change in IPF [64-66]; however, it is unknown what amount of change in oxygenation is clinically significant.

Both baseline and change in 6MWD over six months are strong and independent predictors of mortality [18,64,67]. Lower values for the oxygen saturation nadir also indicate a worse prognosis [43,68]. These findings suggest there may be a prognostic role for repeating the 6MWT every six months, and particularly in patients with more severe disease.

The 6MWT furthermore provides data on when to initiate ambulatory oxygen supplementation. Based on anecdotal experience, patients with IPF who have exertional desaturation derive symptomatic benefit from supplemental oxygen during exertion, although the long-term benefit of supplemental oxygen is not established in patients with isolated exertional hypoxemia and preserved oxygen saturation at rest [69].

●Home spirometry – More frequent monitoring of pulmonary function with daily home spirometry is being explored as a way to identify acute exacerbations more quickly. One study suggested that daily home spirometry is feasible and may allow earlier identification of worsening disease [70]. Another study monitored 25 patients with daily home spirometry and questionnaires. Adherence to monitoring for 24 weeks was over 90 percent, although it declined over time [71]. Baseline in-laboratory spirometry correlated well with home spirometry results. While home spirometry may be helpful as an outcome measure for clinical trials, it requires further validation prior to routine clinical use.

●Portable activity monitors – There are multiple portable activity monitors that provide a variety of data related to physical function that may be relevant to patients [72]. These can help motivated patients track their own activity level on a day-to-day basis; however, there are currently insufficient data to justify a recommendation for their clinical use.

Oxygenation — Patients with advanced IPF frequently have resting hypoxemia that meets the threshold for oxygen supplementation (ie, pulse oxygen saturation [SpO₂] ≤88 percent), which can be provided continuously, with ambulation, and nocturnally as necessary. (See "Long-term supplemental oxygen therapy", section on 'Indications'.)

Development of worsening hypoxemia and increasing oxygen requirements are common indicators of disease progression and increased risk of mortality [43-45,68,73,74]; however, there is no established method for identifying which patients require assessment for resting, exertional, or nocturnal hypoxemia. Severe dyspnea with ambulation, functional limitation secondary to dyspnea, moderately or severely reduced DLCO, and the presence of pulmonary hypertension are common features that indicate the need to consider ambulatory oxygen supplementation.

●Pulse oximetry – Assessment of resting oxygenation by pulse oximetry is easily performed and often obtained at each clinical encounter, particularly in patients with advanced disease. Walking oximetry, often obtained as a component of a 6MWT [62,63], requires a modest amount of additional time and health care resources and should be performed in patients with clinical suspicion of exertional hypoxemia. (See 'Pulmonary function tests' above and "Overview of pulmonary function testing in adults", section on 'Six-minute walk test'.)

●Portable oximeters – Some patients use portable pulse oximeters to monitor disease progression and titrate home oxygen use. These devices can provide useful data on the extent of hypoxemia with a patient's usual amount of physical activity, but may be less reliable than regularly calibrated in-hospital devices. Low readings can be helpful to indicate the need for a formal oxygen needs assessment through a pulmonary function laboratory.

●Overnight oximetry – Overnight oximetry is obtained in patients with clinical suspicion of nocturnal hypoxemia and/or sleep-disordered breathing (eg, due to poor sleep quality, morning headaches, daytime sleepiness, snoring). Given the absence of clear guidance on how frequently patients should be assessed, most patients are tested at baseline and when there is evidence of worsening disease with concern of nocturnal hypoxemia. As described below, the high prevalence of obstructive sleep apnea in patients with IPF indicates the need to consider overnight oximetry and polysomnography in all IPF patients even when there is a low suspicion for nocturnal hypoxemia. (See 'Complications and comorbidities' below.)

●Arterial blood gas – An arterial blood gas is obtained in some patients as a complementary study to pulse oximetry in patients with borderline findings; however, this is a more invasive test and is often not necessary to demonstrate the presence of clinically significant hypoxemia. Respiratory acidosis is a rare finding in IPF and an arterial blood gas is infrequently obtained for acid-base assessment.

Imaging — HRCT is an essential component of the diagnostic process for all interstitial lung diseases (ILDs), but the role of HRCT for monitoring IPF progression is less clear. In clinical practice, HRCTs are primarily assessed qualitatively to confirm or exclude significant disease progression, particularly in patients with discordant symptoms and physiology. Many clinicians, including ourselves, repeat the HRCT every one to two years in patients with IPF, with the primary goals of identifying any change in morphology, clarifying disease progression, or detecting a new comorbidity (eg, lung malignancy).

By contrast, conventional chest radiography has a limited role for routine monitoring of disease progression in patients with IPF but can be useful as an initial screen for potential etiologies of acute respiratory worsening and can occasionally suggest other comorbidities.

HRCT with or without a rule-out pulmonary embolism protocol is an important test in the evaluation of an acute respiratory worsening (eg, acute exacerbation of IPF). Given the baseline abnormalities in IPF, comparison of HRCT findings during an episode of acute worsening of dyspnea with a previous examination is essential. (See "Acute exacerbations of idiopathic pulmonary fibrosis".)

Formal scoring of fibrosis severity on HRCT is primarily used in research and specialized settings. HRCTs can be scored visually by an experienced CT radiologist to provide a total fibrosis score (ie, percent of affected lung), or quantitatively calculated using a computer-based algorithm to again produce a fibrosis score. Previous studies have shown that both visual and computer-based scoring of fibrosis severity provide prognostic information beyond standard clinical and physiologic variables [36,75-82].

Laboratory tests — No laboratory studies have been established as having a prognostic role in IPF. Laboratory testing is focused on characterization of intercurrent illnesses, acute exacerbations, and adverse effects of medication. The evaluation of acute exacerbations of IPF is described separately. (See "Acute exacerbations of idiopathic pulmonary fibrosis", section on 'Laboratory testing'.)

Serologic evaluation for a connective tissue disease is recommended in the initial evaluation of IPF [2], including antinuclear antibody, rheumatoid factor, and anti-cyclic citrullinated peptide. Follow-up serologic testing may be appropriate in some patients, although consensus is lacking. Up to 10 percent of patients with a previous diagnosis of IPF can later develop a connective tissue disease [83,84], indicating that repeat serologic testing should be performed intermittently in IPF patients with features suggestive of a potential rheumatic disease. Conversely, up to 30 percent of IPF patients have positive autoimmune serology despite no other evidence of a rheumatic disease [83,85-88], indicating the poor specificity of autoimmune serologies for overt connective tissue disease in this population.

Previous studies have suggested a potential prognostic role for molecular markers of lung damage (table 1); however, these markers lack sufficient validation to support their clinical use for monitoring of IPF progression.

The laboratory tests used to monitor for adverse effects of IPF pharmacotherapies are described elsewhere. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Dose and administration' and "Treatment of idiopathic pulmonary fibrosis", section on 'Dose and administration'.)

COMPLICATIONS AND COMORBIDITIES — IPF is associated with several complications and comorbidities that are related to the underlying physiologic consequences of IPF or to common IPF risk factors that include older age and a history of cigarette smoking. These complications and comorbidities include chronic obstructive pulmonary disease (COPD), cardiovascular disease, pulmonary hypertension, lung cancer, and obstructive sleep apnea as described below. These add to the symptomatic, functional, and physiologic consequences of IPF and are frequently associated with high mortality; however, there are no standardized recommendations for how patients with IPF should be screened for these disorders.

In addition, IPF patients have a high frequency of gastroesophageal reflux, depression, and anxiety that often reach clinically relevant thresholds of severity, indicating the need for regular assessment of these conditions [89,90]. (See "Treatment of idiopathic pulmonary fibrosis".)

Combined pulmonary fibrosis and emphysema — Significant comorbid emphysema is often identified on chest imaging in patients with IPF [89], although patients with combined pulmonary fibrosis and emphysema (CPFE) frequently do not meet physiologic criteria for COPD. (See "Clinical manifestations and diagnosis of idiopathic pulmonary fibrosis", section on 'Differential diagnosis'.)

Disease monitoring is not different in patients with CPFE compared with patients with isolated IPF, with the exception that patients with concurrent emphysema appear to have relatively preserved spirometric values and less rapid decline in forced vital capacity (FVC), thus indicating the need to consider other measures of disease progression in these patients (eg, diffusing capacity of carbon monoxide [DLCO], oxygenation, imaging) [57,61,91]. The management of COPD is reviewed elsewhere. (See "Stable COPD: Initial pharmacologic management".)

Patients with CPFE have a high incidence of pulmonary hypertension and lung cancer [92-97], suggesting the potential need for a more routine and thorough assessment for these complications in this population.

Cardiovascular disease — Cardiovascular comorbidities, such as dysrhythmias (5 to 20 percent), heart failure (4 to 26 percent), and coronary artery disease (CAD; 3 to 68 percent), are common in the age group of patients with IPF [89]. Among a group of 73 patients with IPF undergoing evaluation for potential lung transplantation, 29 percent had significant CAD, and mortality in these patients was higher than in those without significant CAD [98].

As dyspnea can be caused by any of these cardiovascular comorbidities, evaluation with electrocardiogram, stress radionuclide myocardial perfusion imaging, or stress echocardiography may be prudent when worsening dyspnea is not fully explained by the severity of IPF. (See "Selecting the optimal cardiac stress test", section on 'Patient cannot exercise to a satisfactory workload'.)

Pulmonary hypertension — Pulmonary hypertension is common in patients with advanced IPF (30 to 50 percent) and particularly in patients with CPFE, but with substantial variability in prevalence that is related to differences in study populations [89]. There are no consensus recommendations for when patients with IPF should be screened for pulmonary hypertension by echocardiography.

For patients with chronic lung disease in general, the following findings may suggest the development of pulmonary hypertension and warrant further assessment of pulmonary artery systolic pressure with transthoracic echocardiography:

●Exertional dyspnea or hypoxemia that is not fully explained by the degree of parenchymal lung disease or severity of the underlying sleep disorder.

●Disproportionately low DLCO compared with degree of spirometric or lung volume reduction.

●Rapid decline of pulse oxygen saturation with exertion.

●Exertional chest pain (eg, atypical or nonanginal chest pain), syncope or near-syncope, increased intensity of or a palpable pulmonic component of the second heart sound, a narrowly split-second heart sound, elevated jugular venous pressure, peripheral edema, right-axis deviation on electrocardiogram, right atrial enlargement, and/or right ventricular hypertrophy.

●Enlarged pulmonary arteries (eg, main pulmonary artery >29 mm) on high-resolution computed tomography (HRCT).

The evaluation and treatment of pulmonary hypertension in patients with chronic lung disease is reviewed elsewhere. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults" and "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis".)

Lung malignancy — Patients with IPF have an approximately fivefold higher risk of lung malignancy compared with a matched control population [89,99,100], and this increased risk exists independent of smoking history [100]. Mortality is also significantly higher when IPF is complicated by lung cancer compared with IPF without lung cancer [89,95,101]. Despite the relatively high incidence and poor outcome, the role of lung cancer screening in IPF is unclear, as many IPF patients would not tolerate surgical resection or other primary treatment modalities of chemotherapy and radiotherapy.

Intermittent screening for lung malignancy with low-dose computed tomography (CT) is reasonable for patients with IPF who meet guideline criteria for lung cancer screening (table 4) and would tolerate potential therapy. Screening for lung malignancy is also appropriate in patients undergoing transplant evaluation and in other patients for whom identification of a lung malignancy would alter other therapeutic or prognostic decisions.

The frequency of monitoring in these situations is not standardized, and it is unknown whether the annual low-dose CT protocol from the National Lung Screening Trial is appropriate in patients with IPF in whom screening is being considered [102]. The screening and evaluation of lung cancer is reviewed elsewhere. (See "Screening for lung cancer" and "Overview of the initial evaluation, diagnosis, and staging of patients with suspected lung cancer" and "Evaluation and management of lung cancer in patients with interstitial lung disease".)

Obstructive sleep apnea — Several small cohort studies have suggested that moderate-to-severe obstructive sleep apnea is present in approximately half of patients with IPF [89], with some studies showing increased morbidity and mortality in patients with sleep desaturation [103-106]. Risk factors for sleep-disordered breathing are similar to those of a general population, with no clear association of IPF severity with obstructive or central events [103,107].

Common screening tools for sleep-disordered breathing have not been validated in IPF and may be inadequate to exclude disease in this setting [108], indicating the need for a high clinical suspicion and low threshold for screening with overnight oximetry and potentially polysomnography. The screening and evaluation of sleep-disordered breathing is reviewed elsewhere. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Interstitial lung disease".)

SUMMARY AND RECOMMENDATIONS

●Natural history – The natural history of idiopathic pulmonary fibrosis (IPF) is most often described as one of insidious decline in lung function with progression to respiratory failure and death over approximately four years. However, there is great variability in individual progression rate, occurrence of acute exacerbation, and comorbid disease. (See 'Prognosis' above.)

●Risk of disease progression – At baseline, we use the Gender-Age-Physiology (GAP) index and staging system, combined with clinical impression, to guide patient discussion regarding prognosis, therapeutic options, urgency of lung transplantation, and timeline of palliative approaches (table 2). (See 'Predictors of mortality' above.)

We update the initial risk assessment over time, primarily based on dyspnea, oxygen requirement, pulmonary function tests (PFTs), respiratory hospitalizations, and "acute exacerbations" of idiopathic pulmonary fibrosis (AE-IPF) (table 1). (See 'Predicting disease progression' above.)

●Monitoring strategy

•Symptoms of IPF, particularly dyspnea, cough, and exertional capacity, should be monitored at every patient encounter, typically occurring every three to six months or more frequently, if clinically indicated. (See 'Symptoms' above.)

•We monitor pulmonary function every three to six months, or more frequently if symptoms change. The rate of decline in forced vital capacity (FVC) is highly variable; each year, approximately one-third of patients experience stability, one-third marginal decline (ie, 5 to 10 percent), and one-third significant decline (ie, >10 percent). (See 'Pulmonary function tests' above and 'Predicting disease progression' above.)

•Oxygenation is monitored using in-office pulse oximetry at rest and during six-minute walk testing, with these measurements obtained every three to six months, or more frequently if symptoms change. (See 'Oxygenation' above.)

•Monitoring for adverse effects of IPF pharmacotherapies should be performed as per recommendations for each medication. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Dose and administration'.)

●Follow-up imaging – Qualitative high-resolution computed tomography (HRCT) severity assessment should be performed at baseline. Repeat imaging is usually performed in response to changes in symptoms, pulmonary function, or oxygenation. In addition, HRCT may be obtained every one to two years to evaluate changes in morphology, investigate potential causes of acute worsening, clarify discordant changes in symptoms and physiology, and identify malignancy. (See 'Imaging' above.)

●Serologic testing – We suggest obtaining autoimmune serologies (ie, antinuclear antibody, rheumatoid factor, and anti-cyclic citrullinated peptide) at baseline. Repeat or additional serologic testing is performed in patients with features suggestive of an underlying rheumatic disease. (See 'Laboratory tests' above.)

●Assessment of worsening symptoms – Patients with worsening symptoms, pulmonary function, or chest imaging should have these findings contextualized with results from other domains to determine whether IPF progression is the cause of this worsening, or whether a comorbidity or complication is responsible. (See 'Overview' above and 'Complications and comorbidities' above.)

Progression of IPF may prompt additional confirmatory tests, initiation or change in IPF pharmacotherapy, consideration of lung transplantation, or initiation of palliative therapies. (See 'Overview' above.)

●Complications and comorbidities – Assessment for complications and comorbidities of IPF (eg, emphysema, cardiovascular disease, pulmonary hypertension, lung cancer, obstructive sleep apnea) is typically performed at baseline; reassessment during follow-up is guided by the initial results and changes in symptoms, lung function, and imaging. (See 'Complications and comorbidities' above.)