Outline FEF Reduced FEF25-75 in asthma. What does it mean and what are the clinical implications?

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1 Reduced FEF25-75 in asthma. What does it mean and what are the clinical implications? Fernando Holguin MD MPH Director, Asthma Clinical & Research Program Center for lungs and Breathing University of Colorado Outline What is FEF What does it mean having a reduced FEF What are the potential clinical applications associated with having a reduced FEF25-75 Isolated FEF25-75, a different asthma phenotype? Limitation and future directions FEF Forced expiratory flow averaged over the middle portion of FVC, measured in L/s Historically thought to represent small airways disease Hypothesized to be a marker for peripheral airways obstruction; more sensitive to early involvement Quanjer et al, ERJ 2014; 43:

2 Defining FEF A physiological measure provided with every spirometry, for which everyone has a different opinion on what it measures and on its clinical relevance Unlike FEV1, a physiological measure for which there are no specific guidelines on how it should be interpreted. Mid expiratory flow rates in the flow volume loop 0 25% Effort dependent 25 75% - Effort independent - Reflects flows from more distal lung segments in which at lower lung volumes, elastic recoil and small airway resistances are major determinants of expiratory flow rates Cross sectional analysis of 39 males and 14 females, which had MMF < 80% of predicted and an FEV1 > 80% on two consecutive occasions. (17 smokers) FEV1 % MEFR % MMF % No hx of asthma 86% reported having ever wheezed 68% reported frequent coughing Mc Fadden R, et al Am J Med 1972

3 From reduction in MMF to small airways disease 1. Reductions in MMF could be a normal variant. - Unlikely given that these patients had abnormal physiology 2. Reductions in MMF could be the result of loss of elastic recoil - Unlikely given that static pressure volume curves were within normal range 3. The small peripheral bronchioles explain the reductions in MMF -Supported by data showing: a) Cdyn was frequency dependent b) Reduced conductance of the small airways was low, and c) There were changes in gas exchange. These changes must have been caused by marked time constant discrepancies AND, given that Raw was within normal limits, it is unlikely that larger airway ( 1 4 th generation) are the site of this process. THEREFORE it must be in the peripheral airways. Because, 2mm airway diameters are the site of anatomical involvement in early COPD and the greater site of resistance at low lung volumes, reduced MMF represent obstruction in this site Forced mid expiratory Are more sensitive to detect early changes in asthma & emphysema, Proposed ability to detect changes in more peripheral airways CHEST, VOL. 64, NO. 6, DECEMBER, 1973 In 25 patients who developed bronchiolitis obliterans (BOS) after bilateral lung transplantation, both airway conductance and FEF25-75 were sensitive indicators CHEST/ /JUNE, 1997

4 80 patients with asthma, mild to severe. FEF inversely related to bronchial thickening in major airway segments Niimi A et al, Am J Respir Crit Care Med Vol 162. pp , 2000 FEF25-75, best correlation with air trapping index. Allergy Asthma Immunol Res April;3(2): In asthmatics, FEF25-75% is not associated with measures of distal airway inflammation Sutherland R, J ALLERGY CLIN IMMUNOL VOLUME 113, NUMBER 6, 2004

5 Rao et al, J Asthma 2012 ORs for the association between a 10% reduction in FEF25-75% and long term asthma Persistence at follow up; adjusted for age, sex, body mass index, allergic sensitization, allergic rhinitis, age of asthma onset at baseline, and active smoking ever 337 participants (142 children and 225 adults) with current asthma (asthma attacks or treatment in the past 12 months) recruited to the Epidemiological Study on the Genetics and Environment of Asthma (EGEA1) and followed up at 12 and 20 year surveys Siroux, et al. J ALLERGY CLIN IMMUNOL VOLUME 137, NUMBER 6 Adjusted association (ORs and 95% CIs) between FEF25-75 percent predicted at baseline and subsequent risk for uncontrolled asthma 10 years later. ORs are estimated for an FEF25-75 level reduced by 10% of predicted value.

6 Children with low FEF25 75, have greater bronchodilator responses Children with low FEF25 75 have greater asthma morbidity Age, sex, race matched Purpose: to determine whether FEF is associated with clinical outcomes or markers independent of other spirometric values Utilized uni- and multivariate analysis on patient data from SARP 1-2 Sensitivity analysis of non-obstructed patients (FEV 1 /FVC >LLN) with normal vs decreased FEF Riley et al PLOS One 12, 2015

7 N=829 FEF% quartiles (median, IQR) Greater AA % Q1 88 (74 146) Q2 64 (56 74) Q3 46 (37 55) Q4 27 (9 37) Greater BMI, asthma duration Lower FEV1, and FEV1/FVC Greater levels of T2 biomarkers and BHR Greater morbidity Multivariate analysis 829 patients from SARP with asthma Age >18, smoked <5 pack years FEF % predicted divided into quartiles Logistic regression to compare quartiles: Univariable analysis Adjusted for demographic data (model 2) Adjusted for demographics, FEV 1, FEV 1 /FVC (model 3) Nocturnal and persistent asthma symptoms are greater in patients with lower FEF25-75 Dyspnea Wheeze Tightness Sputum Nocturnal symptoms Persistent symptoms Dyspnea Wheeze Tightness Sputum Nocturnal symptoms Persistent symptoms 2 nd FEF% quartile (63 [IQR:59-68]) 3 rd FEF% quartile (46 [IQR:41-50]) Dyspnea Wheeze Tightness Sputum Nocturnal symptoms Persistent symptoms 4 th FEF% quartile (25 [IQR:20-32]) Odds Ratios and 95% CI Models adjusted for: for age, sex, body mass index, duration of asthma, history of smoking, FEV1 and FEV1/FVC. Error bars represent 95% confidence intervals.

8 FEF 25-75, % predicted Asthmatics in the lowest quartile had an increased OR for ever been admitted to the ICU for asthma Ever ICU admission Ever hospitalized Ever intubated Ever admitted to ED 2 nd FEF% quartile (63 [IQR:59-68]) Ever ICU admission Ever hospitalized Ever intubated Ever admitted to ED Ever ICU admission Ever hospitalized Ever intubated Ever admitted to ED 3 rd FEF% quartile (46 [IQR:41-50]) 4 th FEF% quartile (25 [IQR:20-32]) Odds Ratios and 95% CI Models adjusted for: for age, sex, body mass index, duration of asthma, history of smoking, FEV1 and FEV1/FVC. Error bars represent 95% confidence intervals. Lower FEF25 75 quartiles, are associated with greater T-2 biomarkers And bronchia hyperresponsiveness. Serum IgE Exhaled NO Eosinophils blood Eosinophils sputum Methacholine PC20 Serum IgE Exhaled NO Eosinophils blood Eosinophils sputum Methacholine PC20 Serum IgE Exhaled NO Eosinophils blood Eosinophils sputum Methacholine PC20 2 nd FEF% quartile (63 [IQR:59-68]) 3 rd FEF% quartile (46 [IQR:41-50]) 4 th FEF% quartile (25 [IQR:20-32]) Log-transformed Odds Ratios and 95% CI Models adjusted for: for age, sex, body mass index, duration of asthma, history of smoking, FEV1 and FEV1/FVC. Error bars represent 95% confidence intervals FEV1 % and FEF % predicted linear association FEV1, % predicted FEF % Predicted > LLN FEF % Predicted < LLN

9 FEF25-75% reduced when FEV1 is normal Sensitivity analysis Restricted to non-obstructed patients with FEV 1 /FVC > LLN FEF % >60 vs FEF % <60 Logistic regression to compare: Univariate analysis Adjusted for demographic data Did not adjust for any additional PFT data Sensitivity analysis: symptoms Wheeze SOB Model 1 Model 2 Model 1 Model 2 Reference (N=348) Low/Normal (N=113) 2.80 (1.76, 4.45) 2.36 (1.43, 23.89) 3.41 (1.94, 5.96) 2.46 (1.35, 4.47) Nocturnal Sx Persistent Sx Model 1 Model 2 Model 1 Model 2 Reference (N=348) Low/Normal (N=113) 2.57 (1.66, 3.96) 2.01 (1.26, 3.21) (8.50, 23.40) (5.92, 17.17) Model 1: univariata analysis. Model 2: Multivariate analysis adjusted for age, sex, BMI, duration of asthma, history of smoking. Odds ratios (95% CI).

10 Sensitivity analysis: healthcare utilization and biomarkers Any Daily b-agonist use* Any Systemic CS use* Model 1 Model 2 Model 1 Model 2 Reference (N=348) Low/Normal (N=113) 1.91 (1.24, 2.93) 1.62 (1.01, 2.59) 4.69 (2.42, 9.06) 4.13 (2.02, 8.44) PC20** Model 1 Model 2 Reference (N=348) 1 1 Low/Normal (N=113) (-3.72, -1.28) (-4.19, -1.64) Model 1: univariate analysis. Model 2: Multivariate analysis adjusted for age, sex, BMI, duration of asthma, history of smoking. *Odds ratios (95% CI). **Linear regression beta coefficient (95% CI). Conclusions Independent of FEV 1 and FEV 1 /FVC, FEF is associated with more severe symptoms, greater healthcare utilization, and elevated biomarkers of airway inflammation Decreased FEF in the setting of normal FEV 1 /FVC is similarly associated with greater symptom burden, increased medication use and greater airway reactivity spirometric measurements from 11,654 white males and 11,113 white females, aged 3 94 years, routinely tested in the pulmonary function laboratories of four tertiary hospitals Using Z scores, discordances between FEF25%-75% when FEV1 and FEV1/FVC were normal, only occurred in 3% This is rare and should lead to reviewing whether the FVC maneuver was performed correctly. Quanker P, et al Eur Respir J 2014; 43:

11 Patients with severe asthma have reduced FVC as consequence of air trapping J Appl Physiol 104: , 2008.

12 Expressing FEF25-75% as percent predicted introduces a considerable age bias, and the lower limit of normal expressed as a percentage of the predicted value declines steeply with age. We wonder whether these biases have influenced the results in the study by Riley et al. Using Z scores in the fully adjusted model attenuated the association with the healthcare utilization outcomes. Specifically, when comparing the lowest Z-score quartile to the highest referent quartile, having ever spent the night in the hospital for asthma (OR 1.01 [95% CI ]), ever been admitted to the ICU (OR 1.69 [95% CI 0.58, 4.49]), and bronchial hyperresponsiveness (β= [95% CI -3.60, 1.23]), became nonsignificant. However, the lowest FEF-Z score quartile remained significantly associated with persistent asthma symptoms (OR 5.92 [95% CI 1.62, 21.64]), nocturnal symptoms (OR 2.40 [95% CI 1.02, 5.68]) and blood eosinophils (β=0.13 [95% CI 0.02, 0.24]). Similar results were observed in the sensitivity analyses. Therefore, independently of FEV1 and degree of airway obstruction, FEF identifies a more severe eosinophilic and persistently symptomatic asthma phenotype. Future directions Given the cross-sectional nature of this data, no causal relationship can be implied. This will be longitudinally examined in SARP 3. It remains unknown if FEF represents an earlier marker of airway obstruction or distal airway obstruction The clinical relevance of decreased FEF may represent a more severe asthma phenotype similar to elevated eno