Do we know it all? - Thoracic

University of Vermont

Vermont Lung CenterUniversity of Vermont

Charlie Irvin PhD, FRES

March, 2015

Revisiting Mechanics in Obstructive Lung Disease

Do we know it all?

TSANZ Annual Meeting

No conflicts to disclose

other than the fact that physiology is everything.

Actual Quote

“ …smooth muscle contraction and airway narrowing and that is the fundamental problem in asthma”

Unnamed Accomplished Immunologist from a prestigious East Coast Ivy League University

Nadel JA In Asthma Eds KF Austen & L M Lichtenstein Academic Press 1973

Asthma Theory : 1970s

Inflammatory Theory of Asthma: 1980s

altered airway function

THE REDUCTIONISM OF ASTHMA

THE cell

THE mediatorThe DRUG

The gene

altered airway function

Magic ??

Courtesy J Lee

Animal Models of Asthma

• Guinea-pigs• Rats (Brown Norway)• Dogs• Sheep• Horse• Cat• Rabbit• Nonhuman primates• Coatimundi

Thrilling Days of Yesteryear

Measurement of Peripheral Resistance (Rp) or collateral ventilation

Mitzner. In: The Lung 1997

Paleophysiology

Peripheral Airway Resistance

Wagner, ARRD 151:548 1990

Flow (ml/min)100 200 300 400 500

Pb(cm H20)

Asthmatics (90%)

Normals (103%)

Peripheral Airway Resistance Correlates with Methacholine PC20

1/Rp(ml/cm H20-min)

Log MTC PC20

r=0.81 w/o outlierr=0.38 w/ outlier

Wagner, ARRD 151:548 1990

Kaminsky et al AJRCCM 152:1784 1995

Changes in Lung Volumes following dry gas Hyperpnea

Pressure-volume Characteristics Suggest Airway Closure

Control Non-NocturnalAsthma

NocturnalAsthma

Rp (cmH2O/ml/min)

p = < 0.0001* † :

4 PM4 AM

Kraft et al AJRCCM 163: 1551 2001

Seeing is believing

University of Virginia

Exercise

FEV1 103% FEV1 40%

Before Post exercise

Samee et al J Allergy Clin Immunol 2003; 111:1205-1211

Long-term

Baseline 38 Days 412 Days

Baseline 13 Days 70 Days

de Lange et al, Radiology 250:267 2009

Airway closure on imaging relates to AHR to MCh

Farrow et al, 2012, JAP

r = 0.56p = 0.04

AHR(DRS (log % fall FEV1/µmol

Simulation:

• increased airway narrowing compared to controls

Wagers et al J Appl Physiol 96:2016 2004

ControlControl

InflamedInflamed

Simulation:

• same airway narrowing as controls

• airway lining increased by 20 m

•Closure radius increased to 45 m

•Open airway radii limited to > 67.5 m

Methacholine

Lundblad et al AJRCCM 175:768 2007

Changes in FEV1 due to narrowing

Airway Narrowing = (FEV1/FVC)

Changes in FEV1 due to closure

Airway Closure = FVC

Brown et al J Appl Physiol 101:30 2006

0 1 2 3 4 50

r2=0.67p<0.0001

Admission FEV1

Admission FVC

UVM Emergency Department Asthma Study

Airway Closure during MCh

Asthma (62)Control (16)

0.4 0.5 0.6 0.7 0.8 0.9 1.0-10

FEV1/FVC

Chapman et al, ERJ, 2008

• Airway Closure was predicted by airway narrowing, baseline airway calibre and BMI (r2adj = 0.17, p<0.0001)– Explained very little variation in propensity to airway

closure

• AHR(DRslope) was predicted by airway closure, airway narrowing and baseline airway calibre(r2adj = 0.35, p<0.0001)

Airway closure correlates with AHR

-5 0 5 10 15 20 25 30-2

Increased propensity to airway closure in obese non-asthmatics

Asthma Control Obese non-A

FEV1 (% fall)

p=0.001

□ Closure = FVC∆ Narrowing = FEV1/FVC

Dose of methacholine (µmol)

FEV1FEV1

Chapman DG, Farah CS. Salud (i) Ciencia. 2013; 19(6):549)

Reduction in AHR is due to Reduction in Closure

p = 0.47 p = 0.035

Airway narrowing Airway Closure

Chapman et al Respirology 2014

Al-Alwan et al AJRCCM 189: 1494 2014

Improvement in AHR is Not Related to Lung Volume

Importance of Airway Closure

• In asthmatics, ↑ closure is associated with:–↑ risk of severe exacerbation

–↑ severity & ↓ spirometry

– oral steroid treatment

– symptoms

The Big Questions

• Why do airways close?

• What is in the lumen of the airway and how does that contribute to closure?

• What is the biophysical role of surfactant?

• How do we best target the airway obstruction?

Asthma is Like an Oreo Cookie

Acknowledgements:● Denver:

● Sally Wenzel● Juno Pak● Monica Kraft● Richard Martin

Supported by the NIH K08HL04499, R01HL084200, & P20RR155557

● Vermont:● David Kaminsky● Scott Wagers● David Chapman● Jason Bates● Anne Dixon

● U Virginia● Edward de Lange

• To determine whether – airway closure was altered by bariatric

surgery in obese asthmatic subjects

– the reduction in airway closure was associated with improvements in asthma symptoms.

Study design

13 obese asthmatics underwent methacholine challenge before and 12 months following bariatric surgery

Responsiveness to closure is reduced by weight loss in TH2-low

Airway Narrowing Airway Closure

* p < 0.05 vs pre-surgery

Chapman et al, Respirology 2014

Al-Alwan et al AJRCCM 189: 1494 2014

P < 0.03 NS

Frequency (HZ)

Weight Lost is associated with decreased airway inhomogeneity

TH2-high (n = 5) TH2-low (n = 8)

Pre-surgery

Post-surgery

Pre-post change

Pre-surgery

Post-surgery

Pre-post change

Weight loss

p-value

interaction p-value

BMI (kg/m2)

50.9 32.4 18.4 50.7 38.7 11.9 < 0.0001 0.07

(% pred)86.2 97.0 -10.8 80.1 91.2 -11.8 < 0.0001 0.86

FVC(% pred)

89.2 99.8 -10.6 82.1 91.0 -8.9 0.001 0.70

FEV1/FVC 79.2 79.6 -0.4 79.0 80.6 -1.5 0.35 0.58PEF (% pred)

91.2 85.4 -3.4 94.7 103.1 -10.2 0.28 0.17

Weight loss improves airway closure

Changes in FEV1 due to closure

Airway Closure = FVC

Changes in FEV1 due to narrowing

Airway Narrowing = (FEV1/FVC)

Fall in FEV1 due to airway closure

* p < 0.05 vs pre-surgery

Chapman et al, Respirology 2014

Airway Closure in Obesity

• Increased airway closure is associated with increased symptoms (Yoo et al, 2007)

• Obesity may increase airway closure – Decreased FRC

– Tidal breathing may occur at or below closing capacity

Region of Interest from micro-CT

Lundblad et al AJRCCM 175:768 2007

FVC/FEV1, V2 - V1

-1.0 -0.5 0.5 1.0 1.5

r2=0.65p=0.0002

Delta FEV1

Frey & Suki Lancet 2008

Severe Asthma Exhibits Avalanche Behavior

The Signal is the Noise

Mechanical effects of obesity

Beuther, AJRCCM 2006

Conclusions“What’s Going on Down There”

• AHR can be caused by many mechanisms

• The principle defect is heterogeneous airway

closure

• The most sensitive and specific tests are those that

assess peripheral airway closure (Rp, RV)

• Enhanced airway closure could explain AHR

• Its all about lung volume

Acknowledgements

– David Kaminsky– Lennart Lundblad– Lisa Rinaldi– Ryan Norton– Burton E Sobel– Jason H T Bates– Scott Wagers

NCRR- Center of Biomedical Excellence

National Jewish Center

– Juno Pak– Sally Wenzel– Monica Kraft

Acknowledgements

– David Kaminsky– Lennart Lundblad– Lisa Rinaldi– Ryan Norton– Burton E Sobel– Jason H T Bates– Scott Wagers

NCRR- Center of Biomedical Excellence

National Jewish Center

– Juno Pak– Sally Wenzel– Monica Kraft

Airway Closure is reduced following weight loss

Chapman, Irvin, Dixon, unpublished

r = 0.60 p = 0.04

0.60 0.65 0.70 0.75 0.80 0.85 0.90

What predicts Airway Closure?

Asthma Control Obese

Baseline FER, ∆FER, BMI (r2adj = 0.17, p<0.0001)

Is Increased Airway Closure in Obese a Mechanical Effect?

Sri Mahadev, unpublished

Closure at FRC

Asthma in the Elderly

• Increased age is associated with worse asthma control (Molimard et al, 2008)

• Aging leads to– Decreased lung function (Hankinson, 1999)

– Decreased lung elastic recoil (Turner, 1968)

– Altered inflammatory expression (Meyer, 1998)

• Aging may increase airway closure thus

Baseline Gas Trapping predicts AHR in the elderly

Age Group

Predictor β Coefficient (SE) Partial r2 Model r2 P Value

Young FEV1/FVC, % pred −0.018 (0.005) 0.32 … …

FENO, ppb 0.658 (0.18) 0.12 … …

Scond/L 5.352 (1.86) 0.07 0.51 < .0001

Old RV, % pred 0.008 (0.004) 0.33 … …

Sacin/L 1.932 (0.002) 0.19 … …

FEV1, % pred −0.009 (0.62) 0.05 0.57 < .0001

Hardaker et al, 2011, Chest

Acute/Fatal Asthma: All Airways

Airway closure correlates with AHR

Farrow et al, in press, JAP

Log DRS (% fall FEV1/µmole MCh + 3)

r = 0.56p = 0.04

Summary

• Increased airway closure is associated with adverse clinical outcomes

• Increased airway closure correlates with AHR measured by spirometry and imaging

• Does alterations in airway closure play a role in clinical phenotypes of asthma?– Elderly

Asthma in the Elderly

• Increased age is associated with worse asthma control (Molimard et al, 2008)

• Aging leads to– Decreased lung function (Hankinson, 1999)

– Decreased lung elastic recoil (Turner, 1968)

– Altered inflammatory expression (Meyer, 1998)

• Aging may increase airway closure thus

J Clin Invest 114:104-111, 2004

Case Presentation

• 46 yro female• Asthma since 18-19 yro• Smoker < 20 pk/yr• Poorly controlled• GERD, Sinusitis, Cohns Disease (2004)• Prednisone, LABA/ICS, albuterol nebs,montelukast, etc

FEV1 (%Pred) 1.58 L (54%)Post BD FEV1: 1.66 L (57%)

Baseline Gas Trapping predicts AHR in the elderly

Age Group

Predictor β Coefficient (SE) Partial r2 Model r2 P Value

Young FEV1/FVC, % pred −0.018 (0.005) 0.32 … …

FENO, ppb 0.658 (0.18) 0.12 … …

Scond/L 5.352 (1.86) 0.07 0.51 < .0001

Old RV, % pred 0.008 (0.004) 0.33 … …

Sacin/L 1.932 (0.002) 0.19 … …

FEV1, % pred −0.009 (0.62) 0.05 0.57 < .0001

Hardaker et al, 2011, Chest

Airway Closure in Obesity

• Increased airway closure is associated with increased symptoms (Yoo et al, 2007)

• Obesity may increase airway closure – Decreased FRC

– Tidal breathing may occur at or below closing capacity

Case Presentation

• 46 yro female• Asthma since 18-19 yro• Smoker < 20 pk/yr• Poorly controlled• GERD, Sinusitis, Cohns Disease (2004)• Prednisone, LABA/ICS, albuterol nebs,montelukast, etc

-5 0 5 10 15 20 25 30-2

Increased propensity to airway closure in obese non-

asthmatics Asthma Control Obese non-A

FEV1 (% fall)

p=0.001

0.60 0.65 0.70 0.75 0.80 0.85 0.90

What predicts Airway Closure?

Asthma Control Obese

Baseline FER, ∆FER, BMI (r2adj = 0.17, p<0.0001)

□ Closure = FVC∆ Narrowing = FEV1/FVC

Dose of methacholine (µmol)

FEV1FEV1

Is Increased Airway Closure in Obese a Mechanical Effect?

Sri Mahadev, unpublished

Closure at FRC

The Role of Airway Closure in AHR

• AHR in mice can be attributed to an increased susceptibility to small airway closure (Lundblad et al, 2007)

• Does increased airway closure contribute to AHR in human asthma?

• To determine whether – airway closure was altered by bariatric

surgery in obese asthmatic subjects

– the reduction in airway closure was associated with improvements in asthma symptoms.Study design

13 obese asthmatics underwent methacholine challenge before and 12 months following bariatric surgery

Subject CharacteristicsPre-surgery Post-surgery p-value

BMI (kg/m2) 50.7 ± 6.4 36.3 ± 5.4 <0.0001

ACQ 1.47 ± 0.8 0.60 ± 0.5 0.02

FEV1 (% pred) 82.4 ± 6.0 93.5 ± 5.1 <0.0001

FVC (% pred) 84.8 ± 6.0 94.4 ± 6.7 <0.001

FEV1/FVC 79.1 ± 3.3 80.2 ± 3.3 0.26

PEF (% pred) 91.1 ± 7.8 98.0 ± 8.4 0.04

TLC (% pred) 87.9 ± 10.9 93.8 ± 15.5 0.13

FRC (% pred) 58.0 ± 10.0 79.0 ± 30.1 0.07

ERV (mL) * 0.19 [0.133 – 0.37] 0.78 [0.44 – 1.20] 0.004

RV (% pred) 83.9 ± 12.8 83.9 ± 32.3 1.0

RV/TLC * 0.30 [0.28 – 0.33] 0.32 [0.18 – 0.34] 0.95

Rrs 5Hz (cmH20/L/s) 6.96 ± 1.07 6.16 ± 1.48 0.1

Rrs 5Hz-20Hz (cmH20/L/s)

1.61 [0.79 – 2.39] 0.82 [0.17 – 1.56] 0.21

Xrs 5Hz (cmH20/L/s) * -2.23 [-3.25 ̶ -1.89] -1.39 [-1.75 ̶ -1.03] < 0.001

sGrs 5Hz (cmH20/L/s) * 0.10 [0.06 – 0.12] 0.09 [0.07 – 0.17] 0.74

All data are presented as mean ± 95% CI unless otherwise stated.* Median [IQR]

Subject CharacteristicsPre-surgery Post-surgery p-value

BMI (kg/m2) 50.7 ± 6.4 36.3 ± 5.4 <0.0001

ACQ 1.47 ± 0.8 0.60 ± 0.5 0.02

FEV1 (% pred) 82.4 ± 6.0 93.5 ± 5.1 <0.0001

FVC (% pred) 84.8 ± 6.0 94.4 ± 6.7 <0.001

FEV1/FVC 79.1 ± 3.3 80.2 ± 3.3 0.26

PEF (% pred) 91.1 ± 7.8 98.0 ± 8.4 0.04

TLC (% pred) 87.9 ± 10.9 93.8 ± 15.5 0.13

FRC (% pred) 58.0 ± 10.0 79.0 ± 30.1 0.07

ERV (mL) * 0.19 [0.133 – 0.37] 0.78 [0.44 – 1.20] 0.004

RV (% pred) 83.9 ± 12.8 83.9 ± 32.3 1.0

RV/TLC * 0.30 [0.28 – 0.33] 0.32 [0.18 – 0.34] 0.95

Rrs 5Hz (cmH20/L/s) 6.96 ± 1.07 6.16 ± 1.48 0.1

Rrs 5Hz-20Hz (cmH20/L/s)

1.61 [0.79 – 2.39] 0.82 [0.17 – 1.56] 0.21

Xrs 5Hz (cmH20/L/s) * -2.23 [-3.25 ̶ -1.89] -1.39 [-1.75 ̶ -1.03] < 0.001

sGrs 5Hz (cmH20/L/s) * 0.10 [0.06 – 0.12] 0.09 [0.07 – 0.17] 0.74

All data are presented as mean ± 95% CI unless otherwise stated.* Median [IQR]

A/J: increased smooth muscle

0 50 100 1500.0

Time (s)

4 experimental control

A/J miceBALBc

Wagers J Appl Physiol 102:221 2007

0 50 100 1500.0

Time (s)

4 simulated experimental

• Increased fractional narrowing

• Airway closure threshold– 38 microns

0 50 100 1500.0

Time (s)

4 simulated experimental

• Increased fractional narrowing

• Airway closure threshold– 28 microns

Measuring airway closure with Spirometry

2 3 4 5 6

Time (sec)

Change in FEV1 reflectsClosure = FVCNarrowing = (FEV1/FVC)

Airway Narrowing

Airway Closure

Airway Closure is reduced following weight loss

r = 0.60 p = 0.04

Reduction in AHR is due to Reduction in Closure

p = 0.47 p = 0.035

Airway narrowing Airway Closure

Extra slides on Obesity study

Subject CharacteristicsObese Non-Asthmatic Obese Asthmatic p-value

N (female) 8 (8) 25 (22)Age (years) 41.1 ± 7.4 43.9 ± 4.0 0.47BMI (kg/m2) 48.6 [42.7 – 57.6] 49.9 [42.6 – 55.1] 0.83

FEV1 (% pred) 87.8 ± 9.7 81.5 ± 4.8 0.22FVC (% pred) 91.1 ± 10.4 84.2 ± 4.7 0.19

FEV1/FVC 77.5 ± 5.1 78.4 ± 2.2 0.70

PEF (% pred) 86.1 [76.5 – 90.4] 92.5 [80.8 – 98.3] 0.20

TLC (% pred) 86.0 ± 11.6 84.6 ± 5.7 0.80

FRC (% pred) 52 ± 9.6 62.3 ± 7.2 0.06

ERV (mL) * 0.28 [0.18 – 0.43] 0.33 [0.16 – 0.58] 0.65

RV (% pred) 70.5 ± 13.6 76.2 ± 16.1 0.54

RV/TLC * 0.28 [0.25 – 0.30] 0.28 [0.24 – 0.34] 0.55

Rrs 5Hz (cmH20/L/s) 7.0 ± 3.2 7.0 ± 0.8 0.98

Rrs 5Hz (% pred) 203.4 ± 99.2 180.1 ± 24.8 0.56

Rrs 5Hz-20Hz (cmH20/L/s) 5.1 ± 1.1 5.1 ± 0.6 0.86

Xrs 5Hz (cmH20/L/s) -2.2 [-3.3 ̶ -1.7] -2.3 [-3.7 ̶ -1.8] 0.37

Xrs 5Hz (% pred) 175 [150 – 353] 214 [154 – 315] 0.90

sGrs 5Hz (cmH20/L/s) 0.10 [0.08 – 0.15] 0.09 [0.06 – 0.10] 0.24

DRS (% fall FEV1/µmol MCh) $ 3.8 [3.0 – 3.8] 21.7 [10.3 – 45.8] 0.001

All data are presented as mean ±95% CI unless otherwise stated.* Median [IQR] $ geometric mean ± 95 % CI

Increased Airway Closure in the obese is not exacerbated by asthma

Non‐obese, non‐A (0.54)Non‐obese, Asthma (0.60)Obese, non‐A (0.72)Chapman, 2008

Lean Lean

ObeseObese

Bariatric surgery

Non‐asthma Asthma

Proportion of Airway Closure NS

Extra slides on Obesity study

Subject CharacteristicsObese Non-Asthmatic Obese Asthmatic p-value

N (female) 8 (8) 25 (22)Age (years) 41.1 ± 7.4 43.9 ± 4.0 0.47BMI (kg/m2) 48.6 [42.7 – 57.6] 49.9 [42.6 – 55.1] 0.83

FEV1 (% pred) 87.8 ± 9.7 81.5 ± 4.8 0.22FVC (% pred) 91.1 ± 10.4 84.2 ± 4.7 0.19

FEV1/FVC 77.5 ± 5.1 78.4 ± 2.2 0.70

PEF (% pred) 86.1 [76.5 – 90.4] 92.5 [80.8 – 98.3] 0.20

TLC (% pred) 86.0 ± 11.6 84.6 ± 5.7 0.80

FRC (% pred) 52 ± 9.6 62.3 ± 7.2 0.06

ERV (mL) * 0.28 [0.18 – 0.43] 0.33 [0.16 – 0.58] 0.65

RV (% pred) 70.5 ± 13.6 76.2 ± 16.1 0.54

RV/TLC * 0.28 [0.25 – 0.30] 0.28 [0.24 – 0.34] 0.55

Rrs 5Hz (cmH20/L/s) 7.0 ± 3.2 7.0 ± 0.8 0.98

Rrs 5Hz (% pred) 203.4 ± 99.2 180.1 ± 24.8 0.56

Rrs 5Hz-20Hz (cmH20/L/s) 5.1 ± 1.1 5.1 ± 0.6 0.86

Xrs 5Hz (cmH20/L/s) -2.2 [-3.3 ̶ -1.7] -2.3 [-3.7 ̶ -1.8] 0.37

Xrs 5Hz (% pred) 175 [150 – 353] 214 [154 – 315] 0.90

sGrs 5Hz (cmH20/L/s) 0.10 [0.08 – 0.15] 0.09 [0.06 – 0.10] 0.24

DRS (% fall FEV1/µmol MCh) $ 3.8 [3.0 – 3.8] 21.7 [10.3 – 45.8] 0.001

All data are presented as mean ±95% CI unless otherwise stated.* Median [IQR] $ geometric mean ± 95 % CI

Increased Airway Closure in the obese is not exacerbated by asthma

Non‐obese, non‐A (0.54)Non‐obese, Asthma (0.60)Obese, non‐A (0.72)Chapman, 2008

Lean Lean

ObeseObese

Bariatric surgery

Non‐asthma Asthma

Proportion of Airway Closure NS

2.7 2.8 2.9 3 3.1 3.2 3.3 3.4 3.5 3.6

Luminal area large airways (natural log, post-alb, at TLC)

(p=0.0124, R2=0.39)

The site of the increased resistance to expiratory flow in asthma (when smooth muscle tone eliminated) was due to a narrowing of the lumen of the large airways

-1.0 -0.5 0.5 1.0 1.5

r2=0.52p=0.002

Delta BD FEV1

U Vermont/ Mc Gill ED Asthma Study

Resoltion visit

Loring, S. H. et al. J Appl Physiol 102: 841-846 2007;

Transpulmonary pressure (PL)-lung volume (VL) curves after GI and GE

Loring, S. H. et al. J Appl Physiol 102: 841-846 2007;

Lung volumes after glossopharyngeal insufflation (GI) and GE

Healthy subjects

MildIntermittent

MildPersistent

ModeratePersistent

SeverePersistent

0.480.58

n = 13n = 13

n = 20

n = 12

n = 18

asthmatics

de Lange et al, CHEST 2006;130:1055-1062

Bates et al. Am J Respir Crit Care Med 177: 261-8, 2008

Synergy!

Methacholine concentration (mg/ml)

Baseline 1.25 3.125 12.5 50

Naive PLL(33 g) Ova PLL(33 g)+Ova

------ PLL(100 g) + Ova

Effect of bariatric surgery on airway hyperreactivity &

inflammation

Study Questions1) Obese asthmatic patients would have

evidence of increased markers of asthmatic inflammation compared with obese nonasthmatic patients.

2) Bariatric (weight-loss) surgery would lead to improved airways hyperesponisveness, asthma control, and reduced makers of inflammation.

Dixon et al J. Allergy Clin. Allergy 2011

Bariatric Surgery

Normal N= 21

Asthmatics N= 23

Months from Surgery

3 6 9 12

V V V VV

Study Design

1) Cross sectional2) Parallel Group Intervention

Inclusion Criteria

• Asthmatics– PC20 < 16 mg/ml or Increase FEV1 or FVC > 12 %

200 ml

– Doctor diagnosis

– Asthma Rx prescription

• Normal– No diagnosis of asthma

– PC20 > 16 mg/ml or negative bronchodilator responDixon et al J. Allergy Clin. Allergy 2011

Exclusion Criteria

• Asthmatics and/or normals– Smoking > 20 pack years

– Smoking in last 6 months

– FEV1 < 60%

– Significant other disease

– Thiazolidinedione • (antidiabetic med that effects adipokines)

CONSORT Diagram

Co-morbidities in bariatric surgery

Condition BMI

n = 2559 40-50 50-60 >60

Hypertension (%) 51.7 58.3 58.8

Sleep apnea (%) 41.5 53.7 67.6

Diabetes (%) 31 34.2 41.8

Asthma (%) 21.2 26 32.7

DVT/PE (%) 3 4.4 8.5

Congestive heart failure 1.4 3.6 5.7

Belle et al Surg Obes Relat Dis. 2008;4(4):474-480

Does obesity alter the phenotype of asthma?

When compared to obese controls, asthmatics show:

1) No difference in sleep apnea, GERD or rhinitis

2) Worse lung function

3) While serum adiponectin trends lower, leptin levels were not differentDixon et al J. Allergy Clin. Allergy 2011

Response to Treatment in Obese Asthmatics

Post Surgical Change in BMI

-3 0 3 6 9 12 15

months post surgery

p < 0.0001

Post Surgical Asthma Control

months post surgery

0 3 6 9 12

p < 0.0001

Effect of Weight loss on AHR

P < 0.03

Airway hyperreactivity inversely proportional to BMI

3.4 3.6 3.8 4 4.2 4.4

Log Body Mass Index

P=0.04, rho= -

P < 0.001 NS

Question:

Does the improvement of AHR in the non-atopic subject relate to changes in “systemic inflammation”?

Visceral fat expression levels

Sideleva et AJRCCM accepted

0 .2 .4 .6Visceral Fat Leptin Expression

Relationship between visceral fat leptin expression and AHR

Subcutaneous fat expression levels

Summary

• Increased airway closure is associated with adverse clinical outcomes

• Increased airway closure correlates with AHR measured by spirometry and imaging

• Does alterations in airway closure play a role in clinical phenotypes of asthma?– Elderly

– Obesity

Case Presentation

• 46 yro female• Asthma since 18-19 yro• Smoker < 20 pk/yr• Poorly controlled• GERD, Sinusitis, Crohns Disease (2004)• Prednisone, LABA/ICS, albuterol nebs, montelukast, etc

What is the pathophysiological causeof the low FEV1?

Kaminsky et al AJRCCM 162: 179 2000

Peripheral Resistance (Rp) vs. Plateau Pressure (Pp)

Kaminsky et al AJRCCM 162: 179 2000

Residual Volume vs Rp

4 pm4am

.10 .20 .30

mean Rp (cmH2O/ml/min)

r = 0.59p = 0.03

r = 0.71p = 0.004

Kraft et al AJRCCM 163: 1551 2001

Interim ConclusionInterim Conclusion

The principle response of the asthmatic lung appears not to be airway narrowing, but airway closure.

Evidence for lung de-recruitmentEvidence for lung de-recruitment

• Lack of acute pressure drops indicative of airway narrowing.

• Parallel changes in peripheral lung compliance

• In severe asthma(NA), Rp losses flow dependence

• Sudden falls in Rp when flow(pressure) is increased.

• Correlation of Rp with RV

• Increased PV hysteresis

• Polarized helium or Technigas : ventilatory defects

ParadoxParadoxHow does airway closure and lung derecruitment lead to airways hyperresponsiveness ??

0 30 60 90 120 150 1800

ControlInflamed

Time (s)

Methacholine 12.5 mg/ml

0 30 60 90 120 150 1800

Time (s)

ControlInflamedGti

0 30 60 90 120 150 1800

Time (s)

ControlInflamed

Anatomy Based Computational Model

• Lung cast

• Impedance for each airway

Gomes, Respir Physiol Neurobiol 130 (3): 317-25, 2002.

The Role of Airway Closure in AHR

• AHR in mice can be attributed to an increased susceptibility to small airway closure (Wagers et al 2004, Lundblad et al, 2007)

• Does increased airway closure contribute to AHR in human asthma?

0 1 2 3 4 50

r2=0.71p<0.0001

“Resolution” FEV1

“Resolution”FVC

H3He MRI1H MRI

H3He ventilation images

Mild intermittentasthmatic

FEV1 96% pred

Moderate persistentasthmatic

FEV1 69% pred

Severe persistent asthmatic

FEV1 81% pred

H3He MR of asthma

de Lange et al, CHEST 2006;130:1055-1062

Case Presentation

• 46 yro female• Asthma since 18-19 yro• Smoker < 20 pk/yr• Poorly controlled• GERD, Sinusitis, Crohns Disease (2004)• Prednisone, LABA/ICS, albuterol nebs, montelukast, etc

Why is the FEV1 low?Why is her post BD FEV1 still low?What other tests should be conducted?

Do we know it all? - Thoracic

Documents

Thoracic Surgery Intake Form, Sandeep J. Khandhar, MD, FACSvirginiacancerspecialists.com/wp-content/uploads/... · Thoracic Surgery Intake Form, Sandeep J. Khandhar, MD, FACS. Do

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The Earthquake Dont Know And Do Know

Do You Know

Do you know their jobs? Do you know any other jobs?

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Know Understand Do

How do you know what you know? How do you know it? What don’t you know? Why don’t you know it?

Do you know what I know?

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Axioms in Thoracic Spine Thoracic Spine Assessment · Thoracic Spine Orthopedics DX 611 ... Axioms in Thoracic Spine Assessment ... Exercises to maintain present thoracic kyphosis;

Thoracic Outlet Syndrome - Tallahassee, FL€¦ · THORACIC OUTLET SYNDROME John Broussard, DO Sports Medicine Fellow . Institute for Non -Surgical Orthopedics . Larkin Community

What do you know about degrees? What do you know about Radians?

Treatment: What do we know works? Treatment: What do we know works?

The Thorax. The Thorax – what is in it and what do you need to know? Thoracic wall and diaphragm Surface anatomy Thoracic cavity Mediastinum Heart Lungs

How Do We Know What We Know?

Thoracic Surgery By Mike Poullis. Overview What is it ? What do you need to know as a nurse on the ward ?

DO YOU KNOW ????

What Do We Know? And How Do We Know It?