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  • IPF Natural History and Prognostic Indicators The learning objective of this slide section is to critically evaluate the prognostic indicators used in clinical practice.
  • IPF Prognosis The prognosis of patients with IPF can be evaluated both at the time of diagnosis and by assessing functional changes over time. Baseline predictors include clinical signs (dyspnea), physiologic variables (gas exchange [DL CO ], 6MWT desaturation, A-a gradient, pulmonary hypertension [PH]) and radiologic variables (HRCT pattern). Dynamic changes in dyspnea as well as physiologic parameters such as FVC and DL CO are also associated with mortality in patients with IPF. Nathan SD, Noble PW, Tuder RM. Idiopathic pulmonary fibrosis and pulmonary hypertension: connecting the dots . Am J Respir Crit Care Med. 2007;175:875-880.
  • Baseline Dyspnea The two studies on this slide examined the relationship of the degree of dyspnea at diagnosis with survival of patients with IPF. Turner-Warwick et al retrospectively compared dyspnea and survival data and found that patients with mild dyspnea survived a median of 94 months after diagnosis, while patients with more severe dyspnea survived a median of 42 months ( P < 0.03). Longer survival was also seen in younger patients ( P < 0.001) and women ( P < 0.01). After correction for age and sex, several other factors related to longer survival: lesser radiographic abnormality ( P < 0.001), absence of right axis deviation ( P < 0.001), and a higher PaO 2 ( P < 0.01). Factors having no influence on survival included duration of dyspnea before presentation, degree of reduction of FEV1, FVC, and TLC, the presence of connective tissue disorders, autoantibodies, smoking history, cough, sputum, crackles, clubbing, ESR, and immunoglobulins. King et al did a similar analysis and found that a change of 4 points on a 20 point dyspnea scale was an independent predictor of death (HR 1.23, P = 0.006). Other independent predictors of survival were presence of finger clubbing; the extent of profusion and honeycombing, as well as evidence of pulmonary hypertension on chest radiograph; the severity of impairment of lung volume, spirometry, lung mechanics, DL CO , and gas exchange while at rest (each P < 0.05). Turner-Warwick M, Burrows B, Johnson A. Cryptogenic fibrosing alveolitis: clinical features and their influence on survival. Thorax. 1980;35:171-180. King TE, Tooze JA, Schwarz MI, Brown KR, Cherniack RM. Predicting Survival in Idiopathic Pulmonary Fibrosis: Scoring System and Survival Model. AJRCCM. 2001;164:1171-1181.
  • Mortality According to Baseline Lung Function This study retrospectively analyzed mortality according to baseline functional parameters among 168 IPF patients in the placebo arm of a randomized Phase III clinical trial. In this analysis, a high alveolar-arterial oxygen pressure gradient (P[A-a]O 2 ) and a low baseline diffusion capacity for carbon monoxide (DL CO ) appeared to correlate with an elevated risk of death, but the % predicted FVC did not. Numbers above the bars indicate the number of patients in each group. King TE Jr, Safrin S, Starko KM, et al. Analyses of efficacy end points in a controlled trial of interferon  -1b for idiopathic pulmonary fibrosis. Chest. 2005;127:171-177.
  • Baseline Diffusing Capacity at Presentation and Survival This study evaluated prognostic factors for survival in 104 patients with fibrotic idiopathic interstitial pneumonia (UIP pattern n = 63; NSIP pattern n = 41). Three-year survival was better in patients with a DL CO of more than 35% predicted (n = 76) than in a pooled group of patients with UIP and NSIP patterns with DL CO of less than 35% predicted (n = 28). In the latter group, survival did not differ between patients with UIP and NSIP patterns ( P = 0.28). In another study, Jegal and colleagues evaluated the prognostic factors for fibrotic interstitial pneumonia among 179 patients (131 with IPF; 48 with NSIP). A higher DL CO at presentation was associated with improved survival. Patients with a baseline DL CO  60% had statistically significantly greater survival compared with those with an initial DL CO < 60% ( P = 0.017). Jegal Y, Kim DS, Shim TS, et al. Physiology is a stronger predictor of survival than pathology in fibrotic interstitial pneumonia. Am J Respir Crit Care Med. 2005;171:639-644. Latsi PI, du Bois RM, Nicholson AG, et al. Fibrotic idiopathic interstitial pneumonia: the prognostic value of longitudinal functional trends. Am J Respir Crit Care Med. 2003;168:531-537.
  • Baseline Desaturation on 6MWT Predicts Decreased Survival in IPF Lama and colleagues assessed the prognostic utility of O 2 saturation during a 6-minute walk test (6MWT) in 83 consecutive patients with biopsy-proven IPF from the University of Michigan Fibrotic Lung Disease database. Patients with oxygen desaturation (SaO 2  88% during the 6MWT) had significantly reduced survival when compared with those who did not desaturate ( P = 0.0018). After adjusting for age, sex, smoking history, baseline, DL CO % predicted, FVC % predicted, resting saturation, and histologic diagnosis, IPF patients with 6MWT desaturation had 4.2 times the risk of death compared with the IPF patients who did not have desaturation ( P = 0.01). The relative 4-year survival rates for patients with IPF in this study were 69% for those without desaturation during the 6MWT and 35% for those with desaturation. Lama VN, Flaherty KR, Toews GB, et al. Prognostic value of desaturation during a 6-minute walk test in idiopathic interstitial pneumonia. Am J Respir Crit Care Med. 2003;168:1084-1090.
  • Mean Pulmonary Artery Pressure: A Predictor of Survival in IPF Patients Lettieri and colleagues assessed whether PAH was a risk factor for mortality in patients with IPF. They used right heart catheterization to measure resting mean pulmonary artery pressure (mPAP). They defined PAH as a mPAP of > 25 mm Hg. There was a significant difference in survival between those with and without PAH ( P < 0.001) . For example, the 1-year mortality rates were 28% and 5.5%, respectively, for those with and without PAH. In a recent review, Nathan, Noble, and Tuder discuss the assessment methods for PAH. Right heart catheterization is preferred to echocardiography because of its greater accuracy, especially at higher systolic pulmonary artery pressures. Lettieri CJ, Nathan SD, Barnett SD, Ahmad S, Shorr AF. Prevalence and outcomes of pulmonary arterial hypertension in advanced idiopathic pulmonary fibrosis. Chest. 2006;129:746-752. Nathan SD, Noble PW, Tuder RM. Idiopathic pulmonary fibrosis and pulmonary hypertension: connecting the dots . Am J Respir Crit Care Med. Articles in Press. Published on January 25, 2007 as doi:10.1164/rccm.200608-1153CC.
  • Baseline HRCT Appearance In this study, Flaherty and colleagues assessed the survival of patients with definite or indeterminate HRCT features in patients with histologic UIP (n = 73) or histologic NSIP (n = 23). The combination of biopsy and HRCT findings separated the patients into groups with different prognoses. Patients with both a definite IPF HRCT finding and histologic diagnosis of UIP had the shortest median survival (2.1 years). Those with histologic UIP and an indeterminate HRCT diagnosis had an intermediate survival (5.8 years) while those with histologic NSIP and an indeterminate IPF or NSIP diagnosis on HRCT had the best median survival (> 9 years, data not shown in slide). In another study by Lynch and colleagues, thoracic radiologists scored HRCT scans from 315 IPF patients enrolled in a trial evaluating IFN  -1b. High overall disease extent, reticulation, and honeycombing each increased the hazard ratio of mortality to about 3. Flaherty KR, Thwaite EL, Kazerooni EA, et al. Radiological versus histological diagnosis in UIP and NSIP: survival implications. Thorax. 2003;58:143-148. Lynch DA, Godwin JD, Safrin S, et al. High-resolution computed tomography in idiopathic pulmonary fibrosis: diagnosis and prognosis. Am J Respir Crit Care Med. 2005;172:488-493.
  • Baseline HRCT Findings Sumikawa et al studied 98 patients with a histologic diagnosis of UIP and a clinical diagnosis of IPF to clarify the correlation between the CT findings and mortality. Thirty-three of the 98 CT scans were classified as definite UIP, 36 as consistent with UIP, 29 as suggestive of an alternative diagnosis. The mean survival was 45.7, 57.9, and 76.9 months, respectively. There was no significant difference in survival among the three categories (all P > 0.05). On univariate Cox regression analysis, all abnormalities, including airspace consolidation, honeycombing, architectural distortion, traction bronchiectasis, fibrosis score, and heterogeneous overall impression, were significant predictors (hazard ratios: 1.05, 1.10, 1.05, 1.72, 1.31, 1.12, and 4.30, respectively). On multivariate analysis, only traction bronchiectasis and fibrosis score were significant predictors of mortality (hazard ratios: 1.30 and 1.10, respectively). Best et al retrospectively evaluated quantitative CT indexes, pulmonary function test results, and visual CT scoring as predictors of mortality and described serial changes in quantitative CT indexes over 12 months in patients with IPF. Upon univariate analysis, baseline variables predictive of death included TLC and fibrosis. Upon multivariate analysis, FVC ( P = 0.006) and fibrosis ( P = 0.002) were predictors of short-term mortality. In 95 patients who had both baseline and follow-up CT scans, fibrosis ( P = 0.030) and MLA (mean lung attenuation, P = 0.003) showed change indicating disease progression. Visually determined disease extent on CT images is a strong independent predictor of mortality in IPF. Serial evaluation of quantitative CT measures can show disease progression in these patients. Sumikawa H, Johkoh T, Colby TV, et al. Computed tomography findings in pathological usual interstitial pneumonia; relationship to survival. Am J Respir Crit Care Med. 2008;177:433-439. Best AC, Meng J, Lynch AM, et al. Idiopathic pulmonary fibrosis: physiologic tests, quantitative CT indexes, and CT visual scores as predictors of mortality. Radiology. 2008;246:935-940.
  • KL-6 May Predict Survival in IPF KL-6, a high molecular weight glycoprotein, is a marker of type 2 alveolar epithelial cell injury and repair. Satoh et al studied 219 patients diagnosed with ILDs (152 with idiopathic interstitial pneumonia and 67 with collagen disease-associated pulmonary fibrosis). Patients who died of respiratory failure (58/219) during the follow-up period had higher levels of KL-6 than did those who did not ( P = 0.0004). The receiver operating characteristic curve analysis showed 1000 U/mL as the most suitable cut-off level to distinguish the two groups of patients. In univariate and multivariate analyses, elevated serum KL-6 (> 1000 U/mL) indicated poor prognosis ( P = 0.0005, log-rank test; P = 0.0001, Cox proportional hazard model). Thus, elevated KL-6 level may be a way to identify patients with ILDs who are at increased risk for mortality. The KL-6 assay is not available in the US. Satoh’s publication is consistent with other studies by Yokoyama and colleagues. Satoh H, Kurishima K, Ishikawa H, Ohtsuka M. Increased levels of KL-6 and subsequent mortality in patients with interstitial lung diseases. J Intern Med. 2006;260:429–434. Yokiyama A, Kondo K, Nakajima M, et al. Prognostic value of circulating KL-6 in idiopathic pulmonary fibrosis. Respirology . 2006;11:164-168. Yokoyama A, Kohno N, Hamada H, et al. Circulating KL-6 predicts the outcome of rapidly progressive idiopathic pulmonary fibrosis. Am J Respir Crit Care Med . 1998;158:1680-1684.
  • Baseline Factors Associated With Risk of Mortality in IPF The following baseline factors have been shown to be predictive for an increased risk of subsequent mortality: Diffusing capacity for carbon monoxide (DL CO ) Alveolar-arterial oxygen pressure gradient (P[A-a]O 2 ) Desaturation during a 6-minute walk test (SpO 2 < 88%) Presence of pulmonary arterial hypertension (mPAP > 25 mm Hg) Definite IPF pattern on HRCT of fibrosis with honeycomb
  • Other Predictors Under Investigation King et al 1 found that while the degree of alveolar space cellularity, alveolar wall fibrosis, and cellularity did not affect survival, a history of cigarette smoking, the level of dyspnea, the degree of lung stiffness at presentation and the extent of fibroblastic foci (FF) present on lung biopsy were factors predicting survival. Another study by Nicholson et al 2 confirmed the finding that FF were linked to mortality; their weighted kappa analysis also showed moderate to good agreement between pathologists in observation of FF and other features. Flaherty et al 3 surgically sampled multiple lung lobes and correlated the UIP and NSIP patterns with survival. They found that the presence of a UIP pattern is associated with increased mortality. The risk of mortality was 24.3 times greater ( P < 0.0001) for patients concordant for UIP at multiple sites than for those with NSIP. The risk of mortality was 16.8 times greater ( P < 0.0001) for patients with both patterns than for patients who had the NSIP pattern exclusively. The amount of fibrosis seen on HRCT differed in all groups, being greatest in the group with concordant UIP and successively less in the groups with discordant UIP, fibrotic NSIP, and cellular NSIP. Perhaps the degree of fibrosis on HRCT can be used as a surrogate marker for UIP or for prognosis in the absence of an SLB, but further investigation is needed to validate degree of fibrosis on HRCT as a surrogate marker for UIP in patients unable to undergo SLB. The surfactant proteins SP-A and SP-D are elevated in serum from patients with IPF and PSS, but not in patients with sarcoid or beryllium disease. 4 In a Cox proportional hazards model, the death hazard’s ratio for the log of SP-A and SP-D are 1.73 ( P = 0.031) and 2.04 ( P = 0.003), respectively. This indicates that a one-unit increase in the log of serum surfactant protein results in about twice the instantaneous risk of death due to ILD. Selman et al 5 retrospectively grouped IPF patients according to the time between onset of symptoms and diagnosis of IPF. Patients who were “rapid” progressors (< 6 months interval) had a lower survival from beginning of symptoms than “slow” progressors (> 24 months interval, HR = 9.0, P < 0.0001). King TE, Schwarz MI, Brown K, et al. Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality Am J Respir Crit Care Med. 2001;164:1025-1031. Nicholson AG, Fulford LG, Colby TV, du Bois RM, Hansell DM, Wells AU. The relationship between individual histologic features and disease progression in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2002;166:173–177. Flaherty KR, Travis WD, Colby TV, et al. Histopathologic variability in usual and nonspecific interstitial pneumonias. Am J Respir Crit Care Med. 2001;164:1722–1727. Greene KE, King TE Jr, Kuroki Y, et al. Serum surfactant proteins-A and -D as biomarkers in idiopathic pulmonary fibrosis. Eur Respir J. 2002;19: 439–446. Selman M, Carrillo G, Estrada G, et al. Accelerated variant of idiopathic pulmonary fibrosis: clinical behavior and gene expression pattern . PLoS ONE . 2007;2(5):e482:1-11.
  • Dynamic Predictor: Decline in FVC Predicts Mortality Changes in physiologic variables over time represent dynamic predictors of survival in patients with IPF. In this study, Collard and colleagues evaluated the dependence of survival on changes in clinical and physiologic variables. Eighty-one patients with biopsy-proven IPF were classified as improved, stable, or declined on the basis of the change in each physiologic variable at 6 and 12 months. As seen in this graph, changes in FVC over 6 months were predictive for survival. Similar results were seen for changes in FVC over 12 months. Latsi and colleagues and Flaherty and colleagues published accompanying papers in the same issue as Collard, with consistent findings. Collard HR, King TE Jr, Bartelson BB, Vourlekis JS, Schwarz MI, Brown KK. Changes in clinical and physiologic variables predict survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2003;168:538-542. Flaherty KR, Mumford JA, Murray S, et al. Prognostic implications of physiologic and radiographic changes in idiopathic interstitial pneumonia. Am J Respir Crit Care Med. 2003;168:543-548. Latsi PI, du Bois RM, Nicholson AG, et al. Fibrotic idiopathic interstitial pneumonia: the prognostic value of longitudinal functional trends. Am J Respir Crit Care Med. 2003;168:531-537. Noble PW, Morris DG. Time will tell: predicting survival in idiopathic interstitial pneumonia. Am J Respir Crit Care Med. 2003;168:510-511.
  • Dynamic Predictor: Change in Dyspnea Score In the Collard study, 6-month changes in dyspnea score were also predictive of survival. Patients were classified as improved (  2-point decrease in dyspnea score), stable (< 2-point change), or declined (  2-point increase). This graph shows differences in survival based on these 3 categories of change in dyspnea score. Patients with improvement in dyspnea scores had the greatest survival, while those with declines in dyspnea scores had the lowest survival. Similar results were obtained for changes in dyspnea scores over 12 months. Collard HR, King TE Jr, Bartelson BB, Vourlekis JS, Schwarz MI, Brown KK. Changes in clinical and physiologic variables predict survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2003;168:538-542.
  • Dynamic Predictor: Change in Diffusing Capacity (DL CO ) at 12 Months This study by Latsi and colleagues evaluated prognostic factors for survival in 104 patients with fibrotic idiopathic interstitial pneumonia (UIP = 63; NSIP = 41). This graph illustrates survival in the 41 patients with UIP who remained under follow-up at 12 months relative to serial changes in total gas transfer (DL CO ). Mortality was substantially higher in those with more than 15% deterioration in gas transfer compared with those with stable/improved DL CO ( P < 0.0005). A similar trend was evident for patients with NSIP. Other studies have found that the change in FVC is a better predictor than DL CO . Jegal Y, Kim DS, Shim TS, et al. Physiology is a stronger predictor of survival than pathology in fibrotic interstitial pneumonia. Am J Respir Crit Care Med . 2005;171:639- 644. Latsi PI, de Bois RM, Nicholson AG, et al. Fibrotic idiopathic interstitial pneumonia: the prognostic value of longitudinal functional trends. Am J Respir Crit Care Med . 2003;168:531-537.
  • Prognostic Utility This slide summarizes the prognostic utility of various baseline and dynamic parameters in patients with IPF. Baseline parameters that are predictive of clinical outcome include dyspnea, DL CO , A-a gradient, desaturation on the 6MWT, pulmonary arterial pressure, HRCT pattern (key feature is honeycomb), and pathologic diagnosis of UIP. Dynamic prognostic indicators include dyspnea, FVC, and DL CO,. The robustness of the A-a gradient as a dynamic predictor is controversial.
  • Predicting Disease Progression While clinical predictors are useful in describing the natural history of IPF, disease progression in individuals remains difficult to predict. N early half of the deaths in a recent large prospective randomized trial occurred prior to evidence of disease progression: Primary Cause of Death Acute Deaths* (n = 15) Subacute Deaths* (n = 16) Progression of IPF 6 14 Pneumonia 4 0 ARDS 2 0 Cor pulmonale 1 0 Other 0 1 † Unknown or unwitnessed 2 1 Martinez FJ, Safrin S, Weycker D, et al. The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med. 2005;142:963-967. Raghu G, Brown KK, Bradford WZ, et al. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med . 2004;350:125-133. *Acute deaths occurred after a period of decompensation lasting 4 weeks or less; subacute deaths occurred after a period of progressive respiratory deterioration over weeks or months. The pace of death was unknown in 1 patient. † Complications of lung transplantation.
  • Clinical Progression of IPF In the traditional view of IPF progression, there is a slow and linear decline in respiratory function that ultimately leads to respiratory failure and death. An emerging paradigm suggests that the clinical progression of IPF is variable and unpredictable. The majority of patients with IPF show a relatively slow decline in functional status that may be interrupted by episodes of acute clinical deterioration (acute exacerbations) that precede and possibly initiate the terminal phase of their disease. The etiology and predictive indicators of acute exacerbations remain unclear. A minority of patients appear to have a short duration of illness with a more rapidly progressive clinical course. Noble PW. Idiopathic pulmonary fibrosis. New insights into classification and pathogenesis usher in a new era of therapeutic approaches. Am J Respir Cell Mol Biol. 2003;29(3 Suppl):S27-S31. Kim DS, Collard HR and King TE. Classification and Natural History of the Idiopathic Interstitial Pneumonias. Proc Am Thoracic Soc . 2006;3:285-292. Raghu G, Brown KK, Bradford WZ, et al. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med . 2004;350:125-133.
  • Proposed Definition and Diagnostic Criteria Collard et al 1 proposed the following definition for acute exacerbation of IPF: an acute, clinically significant deterioration of unidentifiable cause in a patient with underlying IPF. Proposed diagnostic criteria for acute exacerbation of IPF are listed in the slide. Clinical deteriorations of IPF that are of unknown cause but do not fulfill the criteria listed due to missing data should be termed ‘‘suspected acute exacerbations of IPF.’’ This could include the following cases: those that are of more than 30 days’ duration, those that have unilateral ground-glass abnormalities, or those that have not undergone endotracheal aspirate or BAL evaluation. If the diagnosis of idiopathic pulmonary fibrosis is not previously established according to ATS/ERS consensus criteria 2 , this criterion can be met by the presence of radiologic and/or histopathologic changes consistent with UIP pattern on the current evaluation. (If no previous HRCT is available, the qualifier ‘‘new’’ can be dropped.) Evaluation of samples should include studies for routine bacterial organisms, opportunistic pathogens, and common viral pathogens. Causes of acute lung injury include sepsis, aspiration, trauma, reperfusion pulmonary edema, pulmonary contusion, fat embolization, inhalational injury, cardiopulmonary bypass, drug toxicity, acute pancreatitis, transfusion of blood products, and stem cell transplantation 3 . Collard HR, et al. Acute Exacerbations of Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. 2007;176:636–643. American Thoracic Society/European Respiratory Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. Am J Respir Crit Care Med .2000;161:646–664. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342:1334–1349.
  • Radiograph of Acute Exacerbation Above is an HRCT of a 50-year-old man with known IPF who was stable for 18 months. He developed increasing shortness of breath over 3 weeks. He was examined by bronchoscoped and there was no alternative diagnosis; infection was excluded. He went on to extracorporeal membrane oxygenation (ECMO) and received a lung  transplant. The explanted lung pathology revealed diffuse alveolar damage on a background of UIP.
  • Histopathology of Acute Exacerbation Low power view shows characteristic subpleural honeycomb fibrosis (HCF) of usual interstitial pneumonia (UIP). The central lung (CL) appears less involved.
  • Histopathology of Acute Exacerbation High power view of the central lung tissue in the previous slide shows reactive type 2 hyperplasia, alveolar septal thickening, and airspace fibrin (af) accumulation consistent with a superimposed acute lung injury corresponding to acute exacerbation of the chronic disease.
  • Histopathology of Acute Exacerbation The central less fibrotic lung shows alveolar septal edema and airspace hemorrhage and hyaline membranes (HM). The findings are those of diffuse alveolar damage in UIP or acute exacerbation of IPF.
  • Take Home Messages In summary, the prognosis for patients with IPF is variable. There are a number of baseline predictors associated with an increased risk of mortality: Low DL CO A-a gradient Desaturation during a 6MWT (SaO 2 < 88%) Pulmonary arterial hypertension (mPAP > 25 mm Hg) Honeycombing on HRCT The best dynamic predictors of prognosis are: Change in FVC % predicted Change in DL CO % predicted Dyspnea Despite the usefulness of these prognostic indicators, disease progression is not always linear. Patients can have relatively stable lung function or rapid decline in lung function. The acute exacerbation model of IPF progression involves many subclinical events that lead to acute or subacute functional decline and often death. Prognostic indicators do not predict the course of disease for an individual patient.

Section21 Section21 Presentation Transcript

  • IPF Natural History and Prognostic Indicators Learning Objective: Critically evaluate the prognostic indicators used in clinical practice
  • IPF Prognosis At Time of Diagnosis (Baseline)
    • Clinical
    • Dyspnea
    • Physiologic
    • DL CO
    • 6MWT desaturation
    • A-a gradient
    • Pulmonary hypertension
    • Radiologic
    • HRCT pattern
    Follow Up (Dynamic)
    • Physiologic
    • Forced vital capacity
    • DL CO
    • Clinical
    • Dyspnea
    Updated
  • Baseline Dyspnea
    • Turner-Warwick
      • 220 cases
      • 4 level dyspnea scale
      • Survival: mild dyspnea (94 mo) vs moderate/severe dyspnea (42 mo) ( P < 0.03)
    • King
      • 238 cases
      • 11 level dyspnea scale
      • Survival: Change of 2 levels associated with increased hazard (1.23) of death; P = 0.006
    Turner-Warwick M, et al. Thorax. 1980;35:171-180. King TE, et al. AJRCCM. 2001;164:1171-1181.
  • Mortality According to Baseline Lung Function King TE, et al. Chest . 2005;127:171-177. DL co ≥ 50 40 –49 30 –39 20 –29 10 –19 % Predicted DL CO 0 5 10 15 20 25 35 30 < 10 10 –19 20 –29 30 –39 40 –49 50 –59 0 10 20 30 40 50 60 P(A-a)O 2 , mm Hg n = 168 P(A-a)O 2 FVC ≥ 90 80 –89 70 –79 60 –69 50 –59 40 –49 0 5 10 15 20 25 35 30 % Predicted FVC Deaths (%) 16 3 33 44 65 7 0 14 42 59 32 21 23 31 67 44 3
  • Baseline Diffusing Capacity at Presentation and Survival Latsi PI, et al. Am J Respir Crit Care Med . 2003;168:531-537. Updated 0 25 50 75 100 0 36 Time (months) 12 24 DL CO > 35% (n = 76) UIP: DL CO < 35% (n = 12) NSIP: DL CO < 35% (n = 16) Survival (%) P = 0.03
  • Baseline Desaturation on 6MWT Predicts Decreased Survival in IPF Lama VN, et al. Am J Respir Crit Care Med . 2003;168:1084-1090. 0 1 2 3 4 5 0.0 0.2 0.4 0.6 0.8 1.0 Years Survival Probability Desaturators (SaO 2 ≤ 88%, n = 44) P = 0.0018 Nondesaturators (SaO 2 > 88%, n = 39) N = 83
  • Mean Pulmonary Artery Pressure: A Predictor of Survival in IPF Patients 7 4 3 1 Lettieri CJ, et al. Chest. 2006;129:746-752. 1.0 0.8 0.6 0.4 0.2 0.0 0 5 P < 0.001 Yes (mPAP > 25 mm Hg) No (mPAP ≤ 25 mm Hg) Years to Event Cumulative Probability to Survival n = 54 n = 25 2 6
  • Baseline HRCT Appearance Flaherty KR, et al. Thorax. 2003;58:143-148. 5.8 years HRCT indeterminate and biopsy UIP 2.1 years HRCT definite UIP and biopsy UIP Survival
  • Baseline HRCT Findings
    • Sumikawa et al
      • 98 cases of IPF
      • Quantified various HRCT findings
      • Traction bronchiectasis and “fibrosis score” associated with survival (HR 1.3 and 1.1, respectively)
    • Best et al
      • 167 cases of IPF (Interferon beta trial)
      • Quantified various HRCT findings
      • Extent of fibrosis (combined reticulation and honeycombing) associated with survival (HR 1.1)
    Sumikawa H, et al. Am J Respir Crit Care Med. 2008;177:433-439. Best AC, et al. Radiology. 2008;246:935-940. Updated
  • KL-6 May Predict Survival in IPF Satoh H, et al. Journal of Internal Medicine. 2006;260:429–434. Updated KL-6 ≤ 1000 U/mL KL-6 ≤ 1000 U/mL
  • Baseline Factors Associated With Risk of Mortality in IPF
    • Diffusing capacity for carbon monoxide (DL CO )
    • Alveolar-arterial oxygen pressure gradient (P[A-a]O 2 )
    • Desaturation during a 6-minute walk test (SpO 2 < 88%)
    • Presence of pulmonary hypertension (mPAP > 25 mm Hg)
    • Definite IPF pattern on HRCT (fibrosis with honeycomb)
  • Other Predictors Under Investigation
    • Number of fibroblastic foci 1-3
    • Surfactant proteins A and D 4
    • Duration of symptoms 5
    • King TE, et al. Am J Respir Crit Care Med. 2001;164:1025-1031.
    • Nicholson AG, et al. Am J Respir Crit Care Med. 2002;166:173-177.
    • Flaherty KR, et al. Am J Respir Crit Care Med. 2001;164:1722-1727.
    • Greene KE, et al. Eur Respir J. 2002;19: 439-446.
    • Selman M, et al . PLoS ONE . 2007;2(5): e482:1-11.
    Updated
  • Dynamic Predictor: Decline in FVC Predicts Mortality Declined (Decrease in % predicted of ≥ 10) Collard HR, et al. Am J Respir Crit Care Med . 2003;168:538-542. Stable (Change in % predicted < 10) Improved (Increase in % predicted of ≥ 10) Years 12 10 8 6 4 2 0 0 20 40 60 80 100 Survival (%)
    • Data collected every 6 months
    • Similar characteristics were seen in the 12-month follow up
    n = 9 n = 50 n = 22
  • Dynamic Predictor: Change in Dyspnea Score Stable (Change of less than 2 points) Improved (Decrease of 2 points or greater ) Declined (Increase of 2 points or greater) Collard HR, et al. Am J Respir Crit Care Med . 2003;168:538-542. Years 12 10 8 6 4 2 0 0 20 40 60 80 100 n = 31 n = 33 n = 15 Similar characteristics were seen in the 12-month follow up Survival (%)
  • Dynamic Predictor: Change in Diffusing Capacity (DL CO ) at 12 Months Stable/improved DL CO 0 25 50 75 100 0 72 12 24 36 48 60 Decline in DL CO Survival (%) Latsi PI, et al. Am J Respir Crit Care Med . 2003;168:531-537. Mortality was substantially higher in patients with decrease in DL CO of more than 15% ( P = 0.0005) n = 21 n = 20 Time (months)
  • Prognostic Utility + + Dyspnea + Pulmonary arterial pressure + + Dynamic (Progression) + HRCT pattern + 6MWT – desaturation (  88%) + A-a gradient + DL CO % FVC % Baseline (Severity)
  • Predicting Disease Progression
    • While clinical predictors are useful in describing the natural history of IPF, disease progression in individuals remains difficult to predict
    • N early half of the deaths in a large prospective randomized trial occurred prior to evidence of disease progression
    Raghu G, et al. N Engl J Med . 2004;350:125-133.
  • Clinical Progression of IPF Traditional View: Slow Decline Emerging Paradigm: Heterogeneous Progression Early Disease Late Disease Asymptomatic State of Health Healthy Sick Time Lung Function Normal Low Years Acute Exacerbation Slow Decline Rapid Decline Kim DS, et al . Proc Am Thoracic Soc . 2006;3:285-292. Respiratory Function/Symptoms 0 1 2 3 4
  • Proposed Definition for Acute Exacerbation of IPF
    • Acute, clinically significant deterioration of unidentifiable cause in a patient with underlying IPF
    • Diagnostic criteria:
      • Previous or concurrent diagnosis of IPF
      • Unexplained worsening or development of dyspnea within 30 days
      • High-resolution computed tomography with new bilateral ground-glass abnormality and/or consolidation superimposed on a background reticular or honeycomb pattern consistent with UIP pattern
      • No evidence of pulmonary infection by endotracheal aspirate or bronchoalveolar lavage
      • Exclusion of alternative causes, including the following:
        • Left heart failure
        • Pulmonary embolism
        • Identifiable cause of acute lung injuryx
    • Patients with idiopathic clinical worsening who fail to meet all five criteria due to missing data should be termed ‘‘suspected acute exacerbations.’’
    Collard HR, et al . Am J Respir Crit Care Med. 2007;176:636–643.
  • Radiograph of Acute Exacerbation Images courtesy of Jeffrey A. Golden, MD. Updated Stable Acute Exacerbation
  • Low Magnification of AE Shows UIP Image courtesy of Kirk Jones, MD. CL HCF CL Updated
  • Histopathology of Acute Exacerbation Image courtesy of Kirk Jones, MD. af
  • Histopathology of Acute Exacerbation Image courtesy of Kirk Jones, MD. HM
  • Take Home Messages
    • Baseline factors associated with an increased risk of mortality
      • Low DL CO
      • A-a gradient
      • Desaturation during a 6MWT (SpO 2 < 88%)
      • Pulmonary arterial hypertension (mPAP > 25 mm Hg)
      • Honeycombing on HRCT
    • Dynamic predictors of mortality
      • FVC
      • DL CO
      • Dyspnea
    • Prognostic indicators do not fully predict the course of disease for an individual patient