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IPF Natural History and Prognostic Indicators

IPF Natural History and Prognostic Indicators. Learning Objective: Critically evaluate the prognostic indicators used in clinical practice . Updated. IPF Prognosis. At Time of Diagnosis (Baseline). Follow Up (Dynamic). Clinical Dyspnea Physiologic DL CO 6MWT desaturation A-a gradient

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IPF Natural History and Prognostic Indicators

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  1. IPF Natural History andPrognostic Indicators Learning Objective: Critically evaluate the prognostic indicators used in clinical practice

  2. Updated IPF Prognosis At Time of Diagnosis (Baseline) Follow Up (Dynamic) • Clinical • Dyspnea • Physiologic • DLCO • 6MWT desaturation • A-a gradient • Pulmonary hypertension • Radiologic • HRCT pattern • Clinical • Dyspnea • Physiologic • Forced vital capacity • DLCO

  3. 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.

  4. Mortality According to Baseline Lung Function n= 168 FVC P(A-a)O2 DLco 3 3 35 60 35 14 7 30 30 50 44 25 25 40 67 65 20 33 20 Deaths (%) 30 42 15 16 15 44 31 20 59 10 10 23 10 5 5 21 32 0 0 0 0 30–39 20–29 50–59 40–49 30–39 20–29 10–19 < 10 40–49 10–19 ≥ 50 ≥ 90 80–89 70–79 60–69 50–59 40–49 % Predicted DLCO P(A-a)O2,mm Hg % Predicted FVC King TE, et al. Chest. 2005;127:171-177.

  5. Updated 100 75 Survival (%) P = 0.03 50 25 DLCO > 35% (n = 76) UIP: DLCO < 35% (n = 12) NSIP: DLCO < 35% (n = 16) 0 0 12 24 36 Time (months) Baseline Diffusing Capacity at Presentation and Survival Latsi PI, et al. Am J Respir Crit Care Med. 2003;168:531-537.

  6. Baseline Desaturation on 6MWT Predicts Decreased Survival in IPF 1.0 0.8 P = 0.0018 0.6 N= 83 0.4 Survival Probability 0.2 0.0 0 2 1 3 4 5 Years Nondesaturators (SaO2 > 88%, n = 39) Desaturators (SaO2 ≤ 88%, n = 44) Lama VN, et al. Am J Respir Crit Care Med. 2003;168:1084-1090.

  7. Mean Pulmonary Artery Pressure: A Predictor of Survival in IPF Patients 1.0 No (mPAP ≤ 25 mm Hg) n = 54 0.8 0.6 Cumulative Probability to Survival Yes (mPAP > 25 mm Hg) 0.4 n = 25 P < 0.001 0.2 0.0 7 6 3 4 5 1 2 0 Years to Event Lettieri CJ, et al. Chest. 2006;129:746-752.

  8. Baseline HRCT Appearance Flaherty KR, et al. Thorax. 2003;58:143-148.

  9. Baseline HRCT Findings Updated • 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.

  10. Updated KL-6 ≤ 1000 U/mL KL-6 ≤ 1000 U/mL KL-6 May Predict Survival in IPF Satoh H, et al. Journal of Internal Medicine. 2006;260:429–434.

  11. Baseline Factors Associated With Risk of Mortality in IPF • Diffusing capacity for carbon monoxide (DLCO) • Alveolar-arterial oxygen pressure gradient (P[A-a]O2) • Desaturation during a 6-minute walk test (SpO2 < 88%) • Presence of pulmonary hypertension (mPAP > 25 mm Hg) • Definite IPF pattern on HRCT (fibrosis with honeycomb)

  12. Updated Other Predictors Under Investigation • Number of fibroblastic foci1-3 • Surfactant proteins A and D4 • Duration of symptoms5 • 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. PLoSONE. 2007;2(5): e482:1-11.

  13. Dynamic Predictor: Decline in FVC Predicts Mortality 100 Improved (Increase in % predicted of ≥ 10) 80 Stable (Change in % predicted < 10) n = 9 60 Survival (%) Declined (Decrease in % predicted of ≥ 10) 40 20 • Data collected every 6 months • Similar characteristics were seen in the 12-month follow up n = 22 n = 50 0 0 2 6 12 4 10 8 Years Collard HR, et al. Am J Respir Crit Care Med. 2003;168:538-542.

  14. Dynamic Predictor: Change in Dyspnea Score 100 Improved (Decrease of 2 points or greater) 80 Stable (Change of less than 2 points) n = 15 60 Declined (Increase of 2 points or greater) Survival (%) n = 33 40 Similar characteristics were seen in the 12-month follow up 20 n = 31 0 0 2 4 6 8 10 12 Years Collard HR, et al. Am J Respir Crit Care Med. 2003;168:538-542.

  15. Dynamic Predictor: Change in Diffusing Capacity (DLCO) at 12 Months 100 (P = 0.0005) 75 n = 21 Survival (%) 50 n = 20 Stable/improved DLCO 25 Decline in DLCO 0 0 12 24 36 48 72 60 Time (months) Mortality was substantially higher in patients with decrease in DLCOof more than 15% Latsi PI, et al. Am J Respir Crit Care Med. 2003;168:531-537.

  16. Prognostic Utility

  17. Predicting Disease Progression • While clinical predictors are useful in describing the natural history of IPF, disease progression in individuals remains difficult to predict • Nearly 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.

  18. Clinical Progression of IPF Traditional View: Slow Decline Emerging Paradigm: Heterogeneous Progression Slow Decline Healthy Normal Asymptomatic Early Disease Respiratory Function/Symptoms Lung Function State of Health Late Disease Acute Exacerbation Rapid Decline Sick Low 0 1 2 3 4 Years Time Kim DS, et al. Proc Am Thoracic Soc. 2006;3:285-292.

  19. 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.

  20. Radiograph of Acute Exacerbation Updated Acute Exacerbation Stable Images courtesy of Jeffrey A. Golden, MD.

  21. Low Magnification of AE Shows UIP Updated CL CL HCF Image courtesy of Kirk Jones, MD.

  22. Histopathology of Acute Exacerbation af Image courtesy of Kirk Jones, MD.

  23. Histopathology of Acute Exacerbation HM Image courtesy of Kirk Jones, MD.

  24. Take Home Messages • Baseline factors associated with an increased risk of mortality • Low DLCO • A-a gradient • Desaturation during a 6MWT (SpO2 < 88%) • Pulmonary arterial hypertension (mPAP > 25 mm Hg) • Honeycombing on HRCT • Dynamic predictors of mortality • FVC • DLCO • Dyspnea • Prognostic indicators do not fully predict the course of disease for an individual patient

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