Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening, interstitial lung disease of unknown etiology. The median survival of patients with IPF is only 2 to 3 years, yet some patients live much longer. Respiratory failure resulting from disease progression is the most frequent cause of death. To date we have limited information as to predictors of mortality in patients with IPF, and research in this area has failed to yield prediction models that can be reliably used in clinical practice to predict individual risk of mortality. The goal of this concise clinical review is to examine and summarize the current data on the clinical course, individual predictors of survival, and proposed clinical prediction models in IPF. Finally, we will discuss challenges and future directions related to predicting survival in IPF.
Idiopathic pulmonary fibrosis (IPF) is the most common of the idiopathic interstitial pneumonias and carries the worst prognosis, with median survival ranging from 2.5 to 3.5 years (1, 2). Although IPF has an overall poor prognosis, the clinical course of individual patients varies from slow progression to acute decompensation and death (3, 4). Several individual clinical variables have been shown to correlate with survival; however, there is no established method of combining these predictors to accurately determine prognosis or define the stage of disease. More accurate prediction of survival in IPF would be useful to facilitate counseling patients and their families, to aid communication among providers, and to guide optimal timing of transplantation (5). In clinical trials, it would allow for more accurate baseline comparisons among treatment groups and alleviate the impact of lead-time bias (5). Here we will review the clinical course, individual predictors of survival, and proposed clinical prediction models in IPF. Finally, we will discuss challenges and future directions related to predicting survival in IPF.
As shown in Figure 1, the rate of decline and progression to death in patients with IPF may take several clinical forms: 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.
Figure 1. Schematic representation of potential clinical courses of idiopathic pulmonary fibrosis (IPF). As disease progresses, there is a subclinical period in which only radiographic findings of disease may be present, followed by a symptomatic period consisting of both pre-diagnosis and post-diagnosis clinical phases. The rate of decline and progression to death may be rapid (line A), slow (lines C and D), or mixed (curve B), with periods of relative stability interposed with periods of acute decline (star).
[More] [Minimize]It is well recognized that symptoms precede diagnosis by a median of 1 to 2 years (6–12), and radiographic evidence of disease may even precede symptoms, suggesting “subclinical” periods of disease that are not well characterized (12). Progression of asymptomatic to symptomatic IPF may occur over years to decades (13). Asymptomatic, early lung fibrosis has been increasingly recognized and reported in family members of affected individuals with familial pulmonary fibrosis, especially in those with a history of smoking (14, 15). Lung biopsy samples from individuals with early asymptomatic lung disease show various histologic subtypes of interstitial lung disease (ILD) (15). Cigarette smoking, a known a risk factor for some idiopathic interstitial pneumonias, including IPF (16), may cause subclinical parenchymal lung disease detectable by spirometry and computed tomography (CT) imaging, even among a generally healthy cohort (17, 18). It appears that high-resolution CT (HRCT) scanning is more sensitive than measurements of pulmonary function and cardiopulmonary exercise test parameters in identifying subjects with asymptomatic ILD (15).
Currently, it is unclear how patients with incidental, subclinical IPF should be followed and managed. Improved understanding is important because the prevalence of subclinical IPF is likely to increase with increasing trends in the use of chest CT imaging for non-ILD diseases, such as diagnosis of pulmonary embolism and coronary artery disease. Similarly, given IPF's low prevalence and lack of effective therapies, it is also uncertain how to identify those at high risk for developing IPF in the general population and whether screening efforts to detect IPF in the subclinical phase would alter outcomes. In addition, it is possible that subclinical IPF is not a benign process. It has been shown that subclinical IPF may be a risk factor for the development of acute exacerbation, especially after surgery or invasive procedures (19–21).
The classic clinical phenotype of IPF is one of slowly progressive decline in lung function and worsening dyspnea leading to death within several years of diagnosis (22, 23). The mean annual rate of decline in progressive disease, as measured by the FVC, ranges from 0.13 L to 0.21 L (Figure 2) (24–30). It appears that this slowly progressive clinical course may actually be less common than historically described. A recent population-based cohort study in Olmsted County, Minnesota examined 47 incident cases of IPF over a 9-year period and found that only 21% of these patients demonstrated a slowly progressive course without evidence of acute decompensation (3).
Figure 2. Decline in FVC in idiopathic pulmonary fibrosis (IPF). Shown are the mean rates of FVC found in the placebo arms of clinical trials in patient with IPF. The FVC declines approximately 150 to 200 ml/yr in patients with IPF. Data from the placebo arms of the following clinical trials: 1Pirfenidone (27), 2Imatinib (29), 3Interferon γ-1b (IFNγ) (25), 4Pirfenidone (30), 5Etanercept (26), 6Bosentan (24), 7N-Acetylcysteine (NAC) (28).
[More] [Minimize]Selman and coworkers identified a subgroup of patients with IPF who displayed a rapidly progressive disease (< 6 mo of symptoms before first presentation) and showed shortened survival compared with patients following the slowly progressive clinical course (23). These were primarily men who were heavy cigarette smokers (23). Interestingly, the patients with an accelerated clinical course displayed a gene expression profile that differed from those with slower progression and longer survival despite having similar lung function, chest imaging, and histology findings at the time of diagnosis. Boon and colleagues also showed that lung molecular signatures at the time of diagnosis may identify patients with stable IPF compared with those with rapidly progressive disease (31).
Patients with IPF may suffer periods of acute respiratory decline either due to known complications, such as infection, or of unknown cause (i.e., acute exacerbation of IPF). The establishment of predefined criteria for acute exacerbation and disease progression in patients with IPF has improved our understanding of these events (Table 1). Acute exacerbation of IPF is defined by the onset of rapid deterioration (within days to a few weeks) in symptoms, lung function, and radiographic appearance (bilateral ground-glass opacities and consolidation superimposed on a reticular pattern on HRCT) in the absence of infection, heart failure, pulmonary embolism, or other identifiable cause (32–34). Patients with acute exacerbations of IPF have a very poor outcome.
Acute IPF exacerbations (within 4 wk, all of the following): |
| Decline of ≥5% in resting room air SpO2 from last recorded level OR decline of ≥8 mm Hg in resting room air PaO2 from last recorded level |
| Clinically significant worsening of dyspnea or cough within 30 d, triggering unscheduled medical care (e.g. clinic, study visit, hospitalization) |
| New, superimposed ground-glass opacities or consolidation on CT scan or new alveolar opacities on chest radiograph |
| No clinical (i.e., absence of grossly purulent sputum, fever > 39°C orally) or microbiologic evidence for infection |
| Other causes excluded (e.g., pneumothorax, cardiac events, infections, and thromboembolism) |
| Progression of IPF |
| ≥10% decrease in % predicted FVC or ≥15% decrease in % predicted DlCO/TlCO |
| Confirmation of worsening must be documented with repeat assessments at least 4 wk apart |
IPF carries a poor prognosis (1, 2). Death rates 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 infections are excluded (35). In studies that used the revised diagnostic criteria for IPF, only 20 to 30% of subjects were alive 5 years after diagnosis (6, 36–39). Most deaths occur from progression of lung fibrosis rather than from commonly occurring comorbid conditions (4, 40–43). Frequent hospitalizations for respiratory problems are common events and are often associated with death (3, 4, 43). Of patients with IPF-related deaths prospectively recorded in published clinical trials, most patients experienced subacute deterioration (worsening over a period of > 4 wk to months) before their death. However, a substantial minority of patients experienced acute deterioration leading to death (sudden worsening of less than 4 wk duration) (Figure 3) (3, 4, 26, 29, 43). Ischemic heart disease, heart failure, bronchogenic carcinoma, infection, and pulmonary embolism are also important causes of mortality in IPF (4, 42–44).
Figure 3. Respiratory versus nonrespiratory causes of death in patients with idiopathic pulmonary fibrosis (IPF). A composite of the proportions of death from acute respiratory, subacute respiratory, nonrespiratory, and unknown causes derived from data from six recent clinical studies (3, 4, 26, 29, 43). Most deaths in IPF (77%) are due to a respiratory cause. A higher proportion of the respiratory deaths occur as a subacute process (61%) compared with acute process with death occurring in less than 4 weeks after acute worsening (39%). The causes of respiratory death included progression of IPF, acute exacerbations, acute lung injury, pneumonia, and cor pulmonale. Nonrespiratory deaths were due to cardiac causes, sepsis, gastrointestinal conditions, stroke, cancer, and other causes. (See online supplement for additional data.)
[More] [Minimize]There are many individual clinical variables that have been shown to predict survival in IPF. These may be subdivided into clinical predictors obtained from the history and physical examination, radiographic predictors, physiologic predictors, pathologic predictors, and biomarker predictors (Table 2). In general, factors that are associated with shortened survival time include: older age, smoking history, lower body mass index (BMI), more severe physiologic impairment, greater radiologic extent of disease, and the development of other complications or conditions, in particular, pulmonary hypertension, emphysema, and bronchogenic cancer (10, 22, 45, 46).
Clinical Predictors | Radiographic Predictors | Physiologic Predictors | Pathologic Predictors | Biomarker Predictors |
|---|---|---|---|---|
| Demographic | HRCT | Pulmonary function tests | Histopathology | Blood |
| Age | UIP pattern | FVC | UIP pattern | BNP |
| Sex | Extent of fibrosis | TLC | Fibroblastic foci | Albumin |
| Ethnicity | DlCO | KL-6M | ||
| Smoking status | CPI | MP-7 | ||
| Symptom-based | Change in FVC | CCL-18 | ||
| Dyspnea scores | Change in DlCO | SP-A & -D | ||
| Circulating fibrocytes | ||||
| Physical examination | Exercise tests | BAL | ||
| Clubbing | 6MWT | SP-A & -D | ||
| BMI | Desaturation | MMP-3, -7, -8, -9 | ||
| Comorbidities | Distance | CCL-2, -17, -22 | ||
| Emphysema | Heart rate recovery | Neutrophilia | ||
| Pulmonary hypertension | Others | |||
| 15-step test | ||||
| 4-min step test |
Older age is a clinical feature of IPF with a median age of 66 years at the time of diagnosis (1, 47). In addition, older age has been shown to confer a poorer prognosis. One study demonstrated a hazard ratio (HR) of 0.25 (confidence interval [CI], 0.125–0.5) for survival in patients younger than age 50 years (48). In another study, median survival for patients younger than age 50 years was 116.4 months compared with 62.8 months for subjects aged 50–60 years, 27.2 months for subjects 60 to 70 years of age, and 14.6 months for subjects older than 70 years of age (22). However, a descriptive study of patients with IPF younger than 50 years old observed a median survival of only 2.1 years, comparable to that observed in older patients with IPF (46). The authors of this study suggested that previous observations of younger age as a favorable prognostic factor may have been due to the inclusion of patients with nonspecific interstitial pneumonia in older studies and/or differences in the definition of disease onset. Recently, Fell and colleagues have suggested that age, combined with findings on HRCT, is a useful diagnostic tool that identifies patients with IPF (49). Furthermore, emerging data suggest age-related changes in cellular function may play key roles in the pathogenesis of IPF (50).
IPF is more common in men, but sex differences in survival have been inconsistent (22, 48, 51). A study specifically examining sex differences in IPF found female sex to confer a significant survival advantage (HR, 0.63; CI, 0.41–0.97) after adjusting for age, smoking status, and baseline physiologic variables (52). This survival advantage remained significant even after adjusting for 6-month changes in 6-minute walk test (6MWT) desaturation and FVC % predicted, suggesting the survival advantage may not be fully explained by differences in disease progression. However, mortality rates in women with pulmonary fibrosis are climbing more rapidly than in men (42).
Limited data are available on the role of ethnicity in the prognosis of IPF. Whites are more likely to be diagnosed with IPF than blacks (42). A study prior to consensus guidelines suggested higher mortality of whites compared with blacks (40), but two more recent studies of patients listed for lung transplantation found reduced survival among both blacks and Hispanics compared with whites that persisted after adjustment for comorbidities and socioeconomic status (53, 54). Olson and coworkers showed that age-adjusted mortality rate in Hispanics is lower than in white non-Hispanics (42).
The effect of smoking status on survival has also been variable. Older studies found a survival advantage in current smokers compared with former and never smokers (22). A study specifically investigating the impact of smoking status on IPF also demonstrated this survival advantage in current smokers compared with former smokers on univariate analysis, but after adjustment for disease severity, this effect was no longer significant, indicating a “healthy smoker effect” (55). The healthy smoker effect is a selection bias observed in studies of respiratory illnesses, because individuals most sensitive to the irritating effects of tobacco are more likely to quit smoking, thereby concentrating individuals who are “resistant” to the short-term effects into the current smokers “healthier” group from a respiratory standpoint (56). Overall, nonsmokers had a higher survival rate than former smokers and all smokers (current and former).
Dyspnea scores are used in a number of pulmonary diseases to assess quality of life, disease severity, and prognosis. In IPF, the Medical Research Council chronic dyspnea score at baseline and the clinical-radiographic-physiologic (CRP) dyspnea score at baseline and change in score at 6 and 12 months have been shown to be significant and independent predictors of survival after adjustment for disease severity by physiologic parameters (10, 57).
Physical examination findings that have been shown to be associated with prognosis in IPF are digital clubbing and BMI. Digital clubbing was shown to be significantly associated with reduced survival after adjustment for age and smoking status with an HR of 2.5 that was highly significant (22). However, this association has not been specifically studied in other cohorts. BMI has shown an inverse association with survival, with a median survival of 3.6 years for BMI less than 25, 3.8 years for BMI 25 to 30, and 5.8 years for BMI greater than 30 (45). There was an HR of 0.93 per 1-unit increase in BMI. The reason for the protective effect of increased BMI in IPF is unclear, but as postulated with other chronic lung diseases, it may be that decreased BMI is a marker of malnutrition and/or elevated exertional and basal energy expenditure (45).
Pulmonary hypertension is common in IPF and is associated with lower diffusing capacity of carbon monoxide (DlCO), shorter walk distances, desaturation during exercise, and increased risk of death in patients with IPF (46, 58–61). In a study of patients with IPF listed for lung transplantation, 32% of patients had pulmonary hypertension by right-sided heart catheterization (58). Those with pulmonary hypertension had much higher mortality (1-yr mortality of 28% compared with 5.5% for patients without pulmonary hypertension), and mortality risk was linearly correlated with mean pulmonary artery pressure. Another study of serial right-sided heart catheterization in patients with IPF awaiting transplantation revealed that nearly all patients develop pulmonary hypertension later in their course (38.6% at baseline and 86.4% at transplantation) (62).
Because right-sided heart catheterization is invasive and there are limited data supporting effective specific therapies for pulmonary hypertension in patients with IPF, its routine use for prognostic assessment alone is impractical, and noninvasive means of screening would be preferable. Several studies have investigated transthoracic echocardiography as a noninvasive means of detecting pulmonary hypertension and have demonstrated that elevated estimated pulmonary artery systolic pressure is associated with reduced survival using thresholds of 40 to 50 mm Hg (46, 63). However, its test characteristics are poor, with an accuracy of only 40% when compared with right-sided heart catheterization (64). B-type natriuretic peptide levels also correlate with pulmonary hypertension and may be more predictive of mortality than pulmonary artery systolic pressure by transthoracic echocardiography (63). Main pulmonary artery diameter as measured by HRCT is an unreliable predictor of pulmonary hypertension in IPF (65). Other clinical parameters may be useful in selecting patients with higher pretest probability for having pulmonary hypertension in IPF, including reduced DlCO, use of supplemental oxygen, and poor performance on 6MWT (58). In fact, a prediction formula using room air saturation, DlCO, and FVC demonstrated modest accuracy and high sensitivity for detecting pulmonary hypertension in IPF, suggesting a role in screening for pulmonary hypertension (66).
Patients with IPF and emphysema are commonly heavy cigarette-smoking men who experience severe dyspnea on exertion and show relatively conserved lung volumes associated with disproportionate impairment of gas exchange (67–72). Emphysema affects the baseline pulmonary function tests by increasing lung volumes and decreasing DlCO and FEV1/FVC, as well as altering the change of these values over time, and therefore altering or masking the assessment of disease severity at baseline and progression over time (72, 73). Early and severe pulmonary arterial hypertension develops in these patients and they have a worse survival compared with patients with IPF without emphysema (74, 75). Some experts believe that the association of IPF with emphysema is a distinct clinical entity (71, 73–79).
Other comorbidities may also affect outcome in IPF but require further study. There is a strong association (prevalence of approximately 90%) between gastroesophageal reflux and IPF (80–83). Moreover, although a causal relationship is unclear, it has been hypothesized that gastroesophageal reflux may be a risk factor for microaspiration, and this may be important in the pathogenesis and natural history of IPF (84). Survival is reduced in patients with IPF with significant coronary artery disease compared with those with mild or no disease, an intriguing finding given the prevalence of the disease and evidence that some patients with IPF die of cardiac causes (85). Furthermore, bronchogenic carcinoma occurs with increased frequency in IPF (9.8 to 38%) and has a substantial impact on prognosis (86).
HRCT of the chest has become the radiographic standard in the evaluation of IPF, providing vital diagnostic and prognostic information. A number of parenchymal abnormalities can be assessed and quantified, including extent of ground-glass opacities, consolidation, reticulation, and honeycombing. Reticulation and honeycombing are often combined to produce an overall extent of fibrosis score. In addition, the overall pattern can be categorized by its consistency with the usual interstitial pneumonia (UIP) pattern.
Of these individual CT findings, the overall extent of fibrosis has been consistently shown to correlate with disease severity parameters on pulmonary function tests and prognosis (87–92). Interestingly, quantification of fibrosis may be automated by a computer system and predicts survival (93).
The UIP pattern on HRCT (predominately basilar and subpleural honeycombing) has also been shown to portend a worse prognosis in patients with IPF compared with those with atypical HRCT findings, suggesting that the HRCT pattern adds prognostic information to histopathologic diagnosis (94). However, other studies demonstrate that in patients with histologic UIP, the prognosis of patients with the UIP pattern on HRCT is similar to those with an atypical pattern (89, 92).
A number of physiologic variables on pulmonary function testing, including spirometry, lung volumes, and gas exchange, have been used to assess disease severity and predict survival in IPF. Those most consistently associated with prognosis are FVC, TLC, and DlCO (22, 48, 57, 59, 87, 89, 90). One difficulty with interpreting these measures is confounding by obstructive lung disease, especially emphysema, which causes less of a decline in lung volumes and a greater decline in gas exchange (72). A composite physiologic index has been developed that may account for emphysema in IPF combining FVC, DlCO, and FEV1 into a formula that correlates better with disease extent by CT than any individual pulmonary function test and may be a more accurate predictor of survival (95, 96).
Although baseline pulmonary function tests are useful for predicting prognosis, changes over time may improve predictive power (Figure 4). Several studies have demonstrated that 6- to 12-month changes in FVC and DlCO are highly predictive of outcome (10, 97, 98) and become more predictive of prognosis over time than most baseline characteristics, including histopathologic diagnosis (11, 96). Clinically significant changes in FVC and DlCO have typically been considered greater than 10% and greater than 15%, respectively. However, even marginal declines in FVC at 6 months (5–10%) are associated with higher risk for mortality (10, 99, 100). Only changes greater than 15% in DlCO were predictive of mortality risk (99).
Figure 4. Survival in relation to the magnitude of serial change in FVC at 6 months in patients with idiopathic pulmonary fibrosis (IPF). Left: Kaplan-Meier survival estimates for 6-month change in FVC % predicted (n = 79). Improved indicates an increase in percent predicted FVC of 10 or greater (n = 9). Decline 0–10% indicates that the change in percent predicted FVC was marginal (n = 50), and decline >10% indicates a decrease in percent predicted FVC of 10 or greater (n = 22). Reprinted by permission from Reference 10. Right: Four-year survival in relation to the magnitude of serial change in FVC (n = 84). Median survival was 29 months in patients with stable or improved serial FVC trends at 6 months (n = 38), 14 months in patients with a marginal decline in FVC at 6 months (n = 23), and 7 months in patients with a significant decline in FVC at 6 months (n = 23). Reprinted by permission from Reference 99.
[More] [Minimize]Another method of assessing the physiologic severity of lung disease is exercise testing. Exercise testing is more sensitive than resting physiological testing in the detection of abnormalities in oxygen transfer. As a group, patients with IPF demonstrate a limitation in exercise tolerance, with a decreased maximal work load (median, 50.4% expressed as percentage of predicted), elevated Vd/Vt, and abnormal gas exchange (decreased PaO2 and elevated alveolar arterial Po2) (22). In fact, exercise gas exchange has been demonstrated to be a sensitive parameter for following the clinical course of IPF (101, 102). Patients with V̇o2max less than 8.3 ml/kg/min at baseline have an increased risk of death (49). In most lung diseases, including IPF, the 6MWT has become the most widely used exercise test, given its ease of administration and reproducibility (103, 104). Both distance walked (105, 106) and desaturation (97, 107) during the 6MWT have been found to predict mortality, and a composite of the product of distance and desaturation in one study predicted mortality better than either measure alone (108). Also, abnormal heart rate recovery after 1 minute of rest after the 6MWT may be a novel and powerful predictor of mortality (109). Importantly, recent data show that a change in 6MWD is highly predictive of mortality (i.e., a decline in 6MWD > 50 m over 24 wk is associated with a fourfold increase in risk of death at 1 year [P < 0.001]) (110). Furthermore, it has been suggested that the minimum important difference for 6MWD is approximately 30 m (i.e, the smallest change in distance that patients can perceive as different from the previous test and that would mandate, in the absence of troublesome side effects and excessive costs, a change in management) (110, 111). Two other exercise tests, the 15-step and 4-minute step tests, add evidence to the usefulness of desaturation during exercise testing for predicting mortality (112, 113).
UIP is the histopathologic pattern that identifies IPF, and it carries the worst prognosis among the idiopathic interstitial pneumonias (2, 6, 8). Interestingly, biopsies from separate lobar specimens in the same patient may show histologic discordance, that is, patterns of UIP in one area and nonspecific interstitial pneumonia in another area (i.e., discordant UIP). Patients in the discordant UIP group show survival, clinical, and physiologic features similar to those found in the concordant UIP group, and importantly, the prognosis in both concordant and discordant UIP groups was significantly worse than that of the concordant nonspecific interstitial pneumonia group (114, 115).
UIP is characterized by dense fibrosis and honeycombing with architectural distortion, fibroblastic foci (foci of proliferating fibroblasts), heterogeneous involvement, and subpleural and paraseptal distribution (1). Among these features, fibroblastic foci are hypothesized to play a key role in the pathophysiology of IPF, and their profusion, as assessed by both semiquantitative and quantitative methods, has been shown, in some cohorts, to predict survival (9, 116, 117). Lymphoplasmacytic inflammation has been shown to predict response to immunomodulatory therapy in UIP, whereas the presence of organizing pneumonia predicts a lack of response (118). However, neither of these features was found to be predictive of survival (118). Importantly, given the growing reliance on clinical and chest imaging criteria to diagnose IPF, surgical lung biopsies are now usually performed in atypical cases in which the diagnosis remains unclear on clinical grounds alone. Consequently, this may limit the role of pathology as a routine predictor of prognosis.
Biomarkers from blood and bronchoalveolar lavage (BAL) fluid have been shown to correlate with disease progression and survival in IPF. However, most remain experimental and have not been widely used in clinical practice. B-type natriuretic peptide was shown to be a better predictor of survival than echocardiographic assessment of pulmonary hypertension (63). Albumin levels negatively correlate with prognosis in many diseases and predict survival in patients with idiopathic interstitial pneumonias awaiting transplantation (119). Krebs von den Lungen-6 (KL-6) is a high molecular weight mucin-like glycoprotein (human MUC1 mucin) that is a sensitive marker for interstitial lung diseases, and patients with IPF with higher KL-6 levels may have reduced survival (120). Surfactant proteins A and D (SP-A and SP-D) are secreted by alveolar type II pneumocytes and increase in the blood in association with breakdown of the alveolar epithelium (121). Levels in BAL fluid and blood were shown to predict survival in patients before current international consensus guidelines for IPF (122, 123). More recently, high serum levels of both SP-A and SP-D were shown to be associated with increased mortality but not extent of honeycombing on HRCT (124). In serum, SP-A and SP-D levels appear to be independent predictors of mortality (125, 126), and their addition to clinical predictors alone may improve prediction of 1-year mortality (126). Matrix metalloproteinases (MMPs) are important for extracellular matrix remodeling and appear to be elevated in both blood and BAL fluid in patients with IPF. MMP-3, -7, -8, and -9 levels in BAL fluid were elevated in patients who died early in follow-up in one study (127). Another study demonstrated that MMP-7 negatively correlated with FVC and DlCO, but an association with prognosis was not specifically studied (128). CC-chemokines (CCLs) play a role in inflammatory cell migration, and various members are elevated in IPF. In serum, CCL-18, a CC chemokine produced by alveolar macrophages, was recently shown to be a strong and independent predictor of mortality (129). In BAL fluid, elevated CCL-2, -17, and -22 may predict poor outcome (130). Fibrocytes are mesenchymal cell progenitors involved in tissue repair and fibrosis, and circulating levels are elevated in IPF and increase further during acute exacerbations (131). Their levels do not correlate with disease severity by lung function or radiologic scores but do appear to be an independent predictor of early mortality. Finally, BAL cell counts may be useful in predicting mortality. The neutrophil percentage in BAL at baseline has been shown to independently predict 1-year mortality, whereas lymphocyte and eosinophil percentages had no association with mortality (132).
Clinical prediction models are statistical models that combine clinical findings from history, physical examination, and/or test results to estimate the probability of an outcome, usually a diagnosis or prognosis (133). Their success depends on the careful selection of predictor variables that are reproducibly and commonly measured in current clinical practice, development through accepted statistical techniques including internal validation, and finally performance of external validation and clinical impact analysis (133–135).
The CRP score is a clinical prediction model that has been developed in IPF (22). It incorporates age, smoking status, clubbing, profusion of fibrosis and pulmonary hypertension on chest radiography, total lung capacity, and partial pressure of arterial oxygen at maximal exercise. The CRP score was highly predictive of survival in the cohort from which it was derived, but has not been widely adopted in clinical practice because it lacks formal external validation and uses some variables that are not routinely measured in current clinical practice (i.e., clubbing, profusion of fibrosis and pulmonary hypertension on chest radiography, and partial pressure of oxygen at maximal exercise).
A study using data from a large and well-characterized population of patients with IPF found that several parameters were independent predictors of mortality, including: age (≥ 70 yr vs. < 60; HR, 2.2 [95% CI, 1.3–3.6]), history of respiratory hospitalization (HR, 4.0 [95% CI, 2.5–6.4]), percent predicted FVC (≤ 50 vs. ≥ 80; HR, 5.9 [95% CI, 2.6–13.3]), 24-week change in percent predicted FVC (≤ −10 vs. > −5; HR, 8.3 [95% CI, 5.5–12.5]), percent predicted DLco, 24-week change in DlCO, and 24-week change in health-related quality of life (100). These investigators derived a clinical model composed of only four predictors (age, history of respiratory hospitalization, percent predicted FVC, and 24-wk change in FVC) that predicted the overall risk of 1-year mortality (100). Such a risk-scoring system, if validated, should be useful in clinical practice.
IPF is a disease of aging and a systematic review found that general health, energy level, and level of independence are impaired in patients with IPF (136). Consequently, physicians will need to pay more attention to geriatric comorbidities and increase focus on symptom-based management techniques as a complement to emerging disease-modifying therapies (49, 50).
Despite the numerous individual predictors of survival in idiopathic pulmonary fibrosis that have been identified in the last several decades, it is not clear how these predictors should be collectively used to predict clinical course or to stage disease. FVC may be the most appropriate single prognostic parameter, given its ease of measurement, reproducibility, and ability to predict prognosis at baseline and over time, with even minor changes providing prognostic information.
Clinical prediction models are used in many areas of medicine to provide accurate prognostic information and staging of disease; such a prediction model would be useful in IPF. However, the development of a prediction model in IPF is challenging given its low prevalence, because large cohorts are needed to assess large numbers of clinical predictors and ensure generalizability. Developing a reliable clinical prediction model in IPF will require continued collaboration and coordination among multiple institutions.
In summary, similar to the diagnosis of IPF, prognosis of individual patients will likely best be determined in the future using a multidisciplinary approach. Such an approach should incorporate information from multiple areas of clinical care using a well-developed and validated clinical prediction model. This will allow clinicians to better manage patients and provide a valuable tool for future clinical trials.
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