Do we know it all? - Thoracic

1

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

2

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

3

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

Asthma Theory : 1970s

Inflammatory Theory of Asthma: 1980s

4

altered airway function

THE REDUCTIONISM OF ASTHMA

THE cell

THE mediatorThe DRUG

The gene

altered airway function

Magic ??

Courtesy J Lee

5

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

6

Peripheral Airway Resistance

Wagner, ARRD 151:548 1990

25

20

10

5

0

Flow (ml/min)100 200 300 400 500

Pb(cm H20)

Asthmatics (90%)

Normals (103%)

15

Peripheral Airway Resistance Correlates with Methacholine PC20

0

10

30

20

40

50

0 1 2

1/Rp(ml/cm H20-min)

Log MTC PC20

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

Wagner, ARRD 151:548 1990

7

Kaminsky et al AJRCCM 152:1784 1995

Changes in Lung Volumes following dry gas Hyperpnea


8


Pressure-volume Characteristics Suggest Airway Closure

0

0.03

0.06

0.09

0.12

0.15

Control Non-NocturnalAsthma

NocturnalAsthma

Rp (cmH2O/ml/min)

*†

*

†

*†

p = < 0.0001* † :

4 PM4 AM

Kraft et al AJRCCM 163: 1551 2001

9

Seeing is believing

10

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

11

Airway closure on imaging relates to AHR to MCh

Farrow et al, 2012, JAP

Air

way

Clo

sure

du

rin

g M

Ch

(% o

f lu

ng

volu

me)

r = 0.56p = 0.04

AHR(DRS (log % fall FEV1/µmol

MCh))

Simulation:

• increased airway narrowing compared to controls

Wagers et al J Appl Physiol 96:2016 2004

12

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


13

Methacholine

+ air

Methacholine

+ O2

Lundblad et al AJRCCM 175:768 2007

Changes in FEV1 due to narrowing

Airway Narrowing = (FEV1/FVC)

14

Changes in FEV1 due to closure

Airway Closure = FVC

15

Brown et al J Appl Physiol 101:30 2006

0 1 2 3 4 50

1

2

3

4

5

r2=0.67p<0.0001

Admission FEV1

Admission FVC

UVM Emergency Department Asthma Study

16

Airway Closure during MCh

Asthma (62)Control (16)

0.4 0.5 0.6 0.7 0.8 0.9 1.0-10

0

10

20

30

40

FV

C (

% f

all)

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


17

-5 0 5 10 15 20 25 30-2

0

2

4

6

8

10

12

14

16

Increased propensity to airway closure in obese non-asthmatics

Asthma Control Obese non-A

FV

C (

% f

all)

FEV1 (% fall)

p=0.001


□ Closure = FVC∆ Narrowing = FEV1/FVC

Dose of methacholine (µmol)

Per

cen

t fa

ll in

lun

g fu

nct

ion

FEV1

FEV1

FEV1FEV1

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

18

Reduction in AHR is due to Reduction in Closure

p = 0.47 p = 0.035

Airway narrowing Airway Closure

Chapman et al Respirology 2014

NS

Al-Alwan et al AJRCCM 189: 1494 2014

Improvement in AHR is Not Related to Lung Volume

19

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?

20

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

21

Aim

• 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


22

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

23

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

FEV1

(% 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

24

Changes in FEV1 due to narrowing

Airway Narrowing = (FEV1/FVC)

Fall in FEV1 due to airway closure

Les

s A

irw

ay C

losu

re

* p < 0.05 vs pre-surgery

Chapman et al, Respirology 2014

25

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

26

FVC/FEV1, V2 - V1

-1.0 -0.5 0.5 1.0 1.5

-1.0

-0.5

0.5

1.0

1.5

r2=0.65p=0.0002

Delta FEV1

Del

ta F

VC


Frey & Suki Lancet 2008

Severe Asthma Exhibits Avalanche Behavior

The Signal is the Noise

27

Mechanical effects of obesity

Beuther, AJRCCM 2006

28

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

29

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

30

0.60 0.65 0.70 0.75 0.80 0.85 0.90

0

5

10

15

20

What predicts Airway Closure?

FV

C (

% f

all)

FER

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

Per

cen

t of

TL

C (

% p

red

)

Closure at FRC

31

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

32

Acute/Fatal Asthma: All Airways

Airway closure correlates with AHR

Farrow et al, in press, JAP

Air

way

Clo

sure

du

rin

g M

Ch

(% o

f lu

ng

volu

me)

Log DRS (% fall FEV1/µmole MCh + 3)

r = 0.56p = 0.04

33

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

34

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%)

35

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

36

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

0

2

4

6

8

10

12

14

16

Increased propensity to airway closure in obese non-

asthmatics Asthma Control Obese non-A

FV

C (

% f

all)

FEV1 (% fall)

p=0.001


37

0.60 0.65 0.70 0.75 0.80 0.85 0.90

0

5

10

15

20

What predicts Airway Closure?

FV

C (

% f

all)

FER

Asthma Control Obese


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

□ Closure = FVC∆ Narrowing = FEV1/FVC

Dose of methacholine (µmol)

Per

cen

t fa

ll in

lun

g fu

nct

ion

FEV1

FEV1

FEV1FEV1

38

Is Increased Airway Closure in Obese a Mechanical Effect?

Sri Mahadev, unpublished

Per

cen

t of

TL

C (

% p

red

)

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?

39

Aim

• 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]

40

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

0.4

0.8

1.2

Time (s)

H

0

2

4

G

0

2

4 experimental control

R N

A/J miceBALBc

Wagers J Appl Physiol 102:221 2007

41

0 50 100 1500.0

0.4

0.8

1.2

Time (s)

H

0

2

4

G

0

2

4 simulated experimental

R N

• Increased fractional narrowing

• Airway closure threshold– 38 microns

A/J


A/J

0 50 100 1500.0

0.4

0.8

1.2

Time (s)

H

0

2

4

G

0

2

4 simulated experimental

R N

• Increased fractional narrowing

• Airway closure threshold– 28 microns

A/J


42

Measuring airway closure with Spirometry

4

3

2

1

1

Vo

lum

e (L

)

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

43

Reduction in AHR is due to Reduction in Closure

p = 0.47 p = 0.035

Airway narrowing Airway Closure

Extra slides on Obesity study

44

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

45

Lean Lean

ObeseObese

Bariatric surgery

Non‐asthma Asthma

Proportion of Airway Closure NS

NS

Extra slides on Obesity study

46

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

47

Lean Lean

ObeseObese

Bariatric surgery

Non‐asthma Asthma

Proportion of Airway Closure NS

NS

-.4

-.35

-.3

-.25

-.2

-.15

-.1

-.05

0

.05

FE

V1/

FV

C(n

atur

al lo

g, f

ract

ion

pred

icte

d,

post

-alb

)

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

48

-1.0 -0.5 0.5 1.0 1.5

-1.0

-0.5

0.5

1.0

1.5

r2=0.52p=0.002

Delta BD FEV1

del

ta B

D F

VC

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

49

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

Lung volumes after glossopharyngeal insufflation (GI) and GE


0

1

2

3

4

5

Ven

tila

tio

n d

efec

t sc

ore

Healthy subjects

MildIntermittent

MildPersistent

ModeratePersistent

SeverePersistent

0.480.58

0.99

0.26

1.99

n = 13n = 13

n = 20

n = 12

n = 18

asthmatics

0.69

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

50

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

Synergy!

0

25

50

75

100

125

Methacholine concentration (mg/ml)

Baseline 1.25 3.125 12.5 50

0.0

0.5

1.0

1.5

2.0

2.5

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

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

H (

cmH2

O.s

.ml

-1

)R

(cm

H2O

.s.m

l-1

)

Effect of bariatric surgery on airway hyperreactivity &

inflammation

51

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

52

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)


53

CONSORT Diagram



54


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

55

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

56

Post Surgical Change in BMI

25

30

35

40

45

50

55

60

65

70

75

-3 0 3 6 9 12 15

months post surgery

BM

I

p < 0.0001


Post Surgical Asthma Control

months post surgery

01

23

4

0 3 6 9 12

p < 0.0001

ACQ


57



58

Effect of Weight loss on AHR

0

5

10

15

0 12

P < 0.03

PC20


Airway hyperreactivity inversely proportional to BMI

-10

12

3L

og A

irway

Hyp

erre

activ

ity

3.4 3.6 3.8 4 4.2 4.4

Log Body Mass Index

P=0.04, rho= -

59

P < 0.001 NS



60

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

61

05

10

15

0 .2 .4 .6Visceral Fat Leptin Expression

Relationship between visceral fat leptin expression and AHR

PC20


Subcutaneous fat expression levels


62

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?

63

Kaminsky et al AJRCCM 162: 179 2000

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

Kaminsky et al AJRCCM 162: 179 2000

64

Residual Volume vs Rp

4 pm4am

RV

(L

)

1.0

2.0

3.0

4.0

.10 .20 .30

RV

(L

)

1.0

2.0

3.0

4.0

.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.

65

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 ??

RV

AHR

Rp

?

66

0 30 60 90 120 150 1800

50

100

150

200

250

ControlInflamed

(% c

ha

ng

e fr

om

ba

selin

e)

Time (s)

Rn

Methacholine 12.5 mg/ml

DI

0 30 60 90 120 150 1800

50

100

150

200

Time (s)

(% c

ha

ng

e fr

om

ba

selin

e)

ControlInflamedGti


DI

0 30 60 90 120 150 1800

30

60

90

120

150

Time (s)

ControlInflamed

(% c

ha

ng

e fr

om

ba

selin

e)

Hti


DI


Anatomy Based Computational Model

Anatomy Based Computational Model

• Lung cast

• Impedance for each airway

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

67


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?

68

0 1 2 3 4 50

1

2

3

4

5

r2=0.71p<0.0001

“Resolution” FEV1

“Resolution”FVC



H3He MRI1H MRI

H3He ventilation images

69


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?

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Do we know it all? - Thoracic