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IDIOPATHIC PULMONARY FIBROSIS
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MONITORING THE CLINICAL COURSE OF DISEASE
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IPF Prognosis At Time of Diagnosis (Baseline) Follow Up (Dynamic)
Physiologic Gas exchange Desaturation Pulmonary hemodynamics Radiologic HRCT score HRCT pattern Pathologic Pattern Extent Physiologic Forced vital capacity Gas exchange Dyspnea IPF Prognosis The prognosis of patients with IPF can be evaluated at diagnosis or by assessing changes in parameters over time. Baseline predictors include physiologic variables (eg, gas exchange, desaturation, pulmonary hemodynamics), radiologic variables (eg, HRCT score, HRCT pattern), and pathologic variables (eg, disease pattern or extent). Dynamic physiologic parameters such as FVC, gas exchange, and dyspnea are predictive for IPF outcomes.
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Clinical Predictors IPF
Age: Poorer prognosis Median survival for patients younger than age 50 years was more compared with those between 50–60 years,60-70 years and above 70 years1 Sex : More common in men, but sex differences in survival have been inconsistent 1.Am J Respir Crit Care Med 2001;164:1171–1181.
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Clinical Predictors IPF
Ethnicity: Limited data; earlier study suggested higher mortality of whites compared with blacks Smoking status: Non-smokers had a higher survival rate than former smokers and all smokers (current and former) Am J Respir Crit Care Med 2011;183:431–440.
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Clinical Predictors IPF
Dyspnea: MRC chronic dyspnea score and the CRP dyspnea score at baseline and change in score at 6 and 12 months shown to be significant Physical findings: Digital clubbing significantly associated with reduced survival; BMI has shown an inverse association with survival Impact of comorbidities: pulmonary hypertension, emphysema, bronchogenic carcinoma, gastroesophageal reflux and significant coronary artery disease may also affect outcome in IPF Am J Respir Crit Care Med 2011;183:431–440.
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Physiologic Predictors
Most consistently associated with prognosis are FVC, TLC, and DLCO Confounding by obstructive lung disease, especially emphysema Composite physiologic index : 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 ; may be a more accurate predictor of survival
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Impact of Baseline FVC and DLCO on Risk of Mortality
Forced Vital Capacity Diffusion Capacity for Carbon Monoxide ≥ 50 40–49 30–39 20–29 10–19 5 10 15 20 25 35 30 % Predicted DLCO Deaths in Placebo Groups (%) 35 30 25 20 Deaths in Placebo Groups (%) 15 10 5 Impact of Baseline FVC and DLCO on Risk of Mortality 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: ≥ 90 80–89 70–79 60–69 50–59 40–49 % Predicted FVC King TE, et al. Chest. 2005;127: Retrospective analysis , n= 168 patients who received placebo as part of a randomized trial evaluating the efficacy of interferon -1b among IPF patients with IPF. DLCO was predictive for death, with a progressive increase in deaths as the predicted DLCO decreased. In contrast, predicted FVC at baseline was not predictive for mortality.
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Baseline diffusing capacity at presentation and survival
25 50 75 100 36 Time (months) 12 24 DLCO > 35% (n = 76) IPF: DLCO < 35% (n = 12) NSIP: DLCO < 35% (n = 16) Survival (%) P = 0.03 N= 104 patients with fibrotic idiopathic interstitial pneumonia (UIP = 63; NSIP = 41). Survival was better in patients with a DLCO of more than 35% predicted (n = 76) than patients with DLCO of less than 35% predicted (n = 28). In the latter group, survival did not differ between UIP and NSIP (P = 0.28). Am J Respir Crit Care Med. 2003;168:
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Survival in relation to the magnitude of serial change in FVC
Studies have demonstrated that 6- to 12-month changes in FVC and DLCO are highly predictive of outcome Clinically significant changes in FVC and DLCO have typically been considered greater than 10% and greater than 15%, respectively Even marginal declines in FVC at 6 months (5–10%) are associated with higher risk for mortality
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Survival in relation to the magnitude of serial change in FVC at 6 months
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). 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 Kaplan-Meier survival estimates for 6-month change in FVC % predicted (n = 79).
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Change in Diffusing Capacity (DLCO) at 12 Months: A Dynamic Predictor of Survival
100 (P = ) 75 n = 21 Survival (%) 50 n = 20 25 Stable/improved DLCO Decline in DLCO Change in Diffusing Capacity (DLCO) at 12 Months: A Dynamic Predictor of Survival This study by Latsi and colleagues1 evaluated prognostic factors for survival in 104 patients with fibrotic idiopathic interstitial pneumonia (UIP = 63; NSIP = 41). This graph illustrates the survival in the 41 patients with UIP who remained under follow-up at 12 months relative to serial 12-month changes in total gas transfer (DLCO). Mortality was substantially higher in those with more than 15% deterioration in gas transfer compared with those with stable/improved DLCO (P < ). A similar trend was evident for patients with NSIP. Other studies have found that the change in FVC is a better predictor than DLCO.2 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 ;168: 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. 2003;171: 12 24 36 48 60 72 Time (months) N= 41 patients with UIP who remained under follow-up at 12 months relative to serial 12-month changes in total gas transfer (DLCO). Mortality was substantially higher in patients with a change in DLCO of more than 15% compared with those with stable/improved DLCO (P < ). Latsi PI, et al. Am J Respir Crit Care Med. 2003;168:
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Change in dyspnea score as a dynamic predictor of survival
100 Stable (Change of less than 2 points) Improved (Decrease of 2 points or greater) Declined (Increase of 2 points or greater) 80 n = 15 60 Survival (%) n = 33 40 Similar characteristics were seen in the 12-month follow up 20 n = 31 Change in Dyspnea Score as a Dynamic Predictor of Survival In the same study, changes in dyspnea score were also predictive for survival. Patients were categorized according to the change in dyspnea score over 6 months, with patients 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. Collard HR, King TE Jr, Bartelson BB, et al. Changes in clinical and physiologic variables predict survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2003;168: 2 4 6 8 10 12 Years 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. Am J Respir Crit Care Med. 2003;168:
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Physiologic Predictors: Exercise testing
Both distance walked and desaturation during the 6MWT found to predict mortality, and a composite of the product of distance and desaturation in one study predicted mortality better than either measure alone1 Change in 6MWD is highly predictive of mortality (decline in 6MWD>50 m over 24wk is associated with a fourfold increase in risk of death at 1 year [P , ])2 Abnormal heart rate recovery after 1 minute of rest after the 6MWT may be a novel and powerful predictor of mortality3 1.Respir Med 2006;100:1734–1741. 2.Am J Respir Crit Care Med 2010;181:A1103. 3. Chest 2009;136:841–848.
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Radiographic Predictors
HRCT : overall extent of fibrosis has been consistently shown to correlate with disease severity parameters on pulmonary function tests and prognosis UIP pattern on HRCT: worse prognosis in patients with IPF compared with those with atypical HRCT findings Am J Respir Crit Care Med 2008;177:433–439. Thorax 2003;58:143–148.
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Flaherty KR, et al. Thorax. 2003;58:143-148.
Survival Time Is Influenced by Both Histologic and HRCT Appearance at Presentation HRCT Biopsy Median Survival Definite/probable UIP UIP 2.08 years Indeterminate UIP or definite/probable NSIP 5.76 years Definite/probable NSIP NSIP > 9 years worst prognosis Survival Time Is Influenced by Both Histologic and HRCT Appearance at Presentation In this study, Flaherty and colleagues assessed whether HRCT features add prognostic information to the histologic classification in patients with histologic UIP (n = 73) or histologic NSIP (n = 23). The combination of biopsy and HRCT findings allowed for the most discrete separation of patients into groups with different prognoses. The table in this slide reports median survival by diagnostic category. Patients with both an HRCT and histologic diagnosis of UIP had the shortest median survival (2.08 years). Those with histologic UIP and an HRCT diagnosis of indeterminate UIP or NSIP had an intermediate survival (5.76 years) while those with histologic NSIP and an indeterminate UIP or NSIP diagnosis on HRCT had the best median survival (> 9 years). The authors found that patients with an HRCT UIP diagnosis also had histologic signs of UIP. But patients without HRCT UIP signs could have either histologic UIP or NSIP diagnosis, with different survival rates. Flaherty KR, Thwaite EL, Kazerooni EA, et al. Radiological versus histological diagnosis in UIP and NSIP: survival implications. Thorax. 2003;58: Fibroblastic foci and their quantification has been shown to predict survival Flaherty KR, et al. Thorax. 2003;58:
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Biomarker Predictors Blood
B-type natriuretic peptide was shown to be a better predictor of survival1 Albumin levels negatively correlate with prognosis in many diseases and predict survival2 Circulating fibrocyte levels are elevated in IPF and increase further during acute exacerbations3 Higher Krebs von den Lungen-6 (KL-6 )levels may have reduced survival4 High serum levels of both surfactant proteins A and D (SP-A and SP-D) - increased mortality5 Serum chemokines CCL-18 levels6 1.Respir Med 2009;103:180–186. 2.Chest 2009;135:929–935. 3.Respir Crit Care Med 2009;179:588–594. 4.Respirology 2006;11:164–168. 5.Am J Respir Crit Care Med 1999;160:1843–1850. 6.Am J Respir Crit Care Med 2009;179:717–723.
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Biomarker Predictors BAL fluid
Neutrophilia in BAL at baseline shown to independently predict 1-year mortality1 Matrix metalloproteinases (MMPs- 3, 7, 8, and 9) appear to be elevated in both blood and BAL fluid in patients with IPF2 BAL fluid elevated CCL-2, 17, 22 produced by alveolar macrophages, SP-A and SP-D4 shown to be a strong and independent predictor of mortality3 1.Eur Respir J 2009;33:77–84. 2.Respiration 2009;78:285–292. 3.Chest 2008;133:226–232. 4.Am J Respir Crit CareMed 2000;162:1109–1114.
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Monitoring Patients with IPF
Every 3 to 6 months monitor for : Worsening Symptoms Worsening Oxygenation (Spirometry, DLco , 6 MWT) Progression of Fibrosis from Baseline on HRCT Complications and Comorbidities Presence of any of the following changes is consistent with progressive disease: Progressive dyspnea (objectively assessed) Progressive, sustained decrease from baseline in absolute FVC and/or absolute DLCO (corrected for hemoglobin) Progression of fibrosis from baseline on HRCT Acute exacerbation Death from respiratory failure Monitoring Patients with IPF It is recommended that patients with IPF be routinely evaluated every 3 to 6 months. The evaluation should comprise: spirometry, diffusion testing, a 6MWT, a patient questionnaire to assess dyspnea and QOL, determination of the patient’s O2 requirement, and review of comorbidities. An HRCT is recommended only with a clinical change. Am J Respir Crit Care Med 2011; 183:788–824.
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Individual predictors of survival in IPF
Am J Respir Crit Care Med 2011; 183: 788–824.
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Schematic pathway :clinical management of patients with IPF
Am J Respir Crit Care Med 2011; 183:788–824.
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Summary IPF is a disease of multiple pathways ;combination therapy likely to be most successful. Clinical predictors useful in describing natural history of IPF, however disease progression remains difficult to predict FVC may be the most appropriate single prognostic parameter providing prognostic information Similar to the diagnosis of IPF, prognosis of individual patients will likely best be determined using a multidisciplinary approach
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