Pulmonary Exacerbations: Out of the Wilderness

Pulmonary Exacerbations:Out of the Wilderness

Patrick A. Flume, M.D.Medical University of South Carolina

D. R. VanDevanter, Ph.D.Case Western Reserve University

School of Medicine

MUSC Cystic Fibrosis Team

Dictionary definition of exacerbation

• Exacerbate (transitive verb)– To make more violent, bitter, or severe

• Exacerbation (noun)– A worsening. In medicine, exacerbation may refer

to an increase in the severity of a disease or its signs and symptoms.

Clinician definition of (pulmonary) exacerbation?

“I shall not today attempt further to define [it] … within that

shorthand description; and perhaps I could never succeed in

intelligibly doing so. But I know it when I see it …”

Supreme Court Justice Potter StewartJacobellis v. Ohio, 378 U.S. 184 (1964)

A typical definition of a CF pulmonary exacerbation is…

• An acute worsening of signs and symptoms– Weight loss, cough, increased sputum,

hemoptysis, malaise

• An acute decrease in lung function (i.e. FEV1)

accompanied by…

Status

better

worse

Time

intervene

signs /symptomsFEV1

Worsening ofclinical status

and FEV1

A typical definition of a CF pulmonary exacerbation is …

Status

better

worse

Time

intervene

signs /symptomsFEV1

But, are all exacerbations acute events?

Status

better

worse

Time

But, are all exacerbations acute events?

encounter

intervention

Why are exacerbations important?• Resource-intensive to manage

– Lieu et al., Pediatrics. 1999;103:e72– Ouyang et al., Pediatr Pulmonol. 2009;44:989-96

• Negative effect on patient quality of life– Orenstein et al., Chest. 1990;98:1081-4– Bradley et al., Eur Respir J. 2001;17:712-5– Britto et al., Chest. 2002;121:64–72.

• Associated with decreased survival– Liou et al., Am J Epidemiol. 2001;153:345-52– Mayer-Hamblett et al., AJRCCM 2002;166:1550-5– Emerson et al., Pediatr Pulmonol. 2002;34:91-100– Ellaffi et al., AJRCCM 2005;171:158-64.

Why are exacerbations important?

They occur frequently

PEx treated with IV antibiotics in 2010

Among 26,351 patients in the 2010 CFF Registry

Antibiotic treatments by age group:Epidemiologic Study of Cystic Fibrosis

AntibioticTreatments

for PEx,2003-2005

Wagener et al., Ped Pulmonol 2008;S31:359

Why are exacerbations important?

They occur frequently

PEx treated with IV antibiotics in 2010

PEx treated with any antibiotics (estimated)

Among 26,351 patients in the 2010 CFF Registry

Despite the frequency of these events we still find ourselves wandering in the wilderness

Cystic Fibrosis Pulmonary Guidelines: Treatment of Pulmonary Exacerbations

Site of treatment (home vs. hospital)Chronic medicationsInhaled plus IV tobramycinAirway clearance1 vs. 2 antibiotics for PseudomonasAminoglycosides: once daily v. multidoseContinuous infusion -lactam antibioticsDuration of antibioticsRoutine synergy testingCorticosteroids

IB*I

B*ICIIDI

*Consensus recommendation (see previous guidelines)Am J Respir Crit Care Med 2009; 180: 802-808

aboutantibiotics

Classical approach to pulmonary exacerbation management

III.III. BACTERIA CAUSE BACTERIA CAUSE EXACERBATIONSEXACERBATIONS

IV.IV. ANTIBIOTICS CURE ANTIBIOTICS CURE THEMTHEM

III.III. BACTERIA CAUSE BACTERIA CAUSE EXACERBATIONSEXACERBATIONS

IV.IV. ANTIBIOTICS CURE ANTIBIOTICS CURE THEMTHEM

Old Testament

Matters of faith

• We know an exacerbation when we see it• Antibiotics improve outcomes

Matters of faith

• We know an exacerbation when we see it– Do clinicians share the same “vision”?– Has our collective vision changed?

Do clinicians share the same vision?

CFF Center Director’s Report, 2009

100%

80%

60%

40%

20%

0%

30

20

10

0

< 18 years old ≥ 18 years old

MedianDays

Treated

PatientsTreatedw/IVs

30

20

10

0

100%

80%

60%

40%

20%

0%

Care Centers Care Centers

Care Centers Care Centers

Has our collective vision changed?

Goss and Burns, Thorax 2007;62:360-7

80% 60% 40%100%120%

2.0

1.6

1.2

0.8

0.4

0

Mea

n IV

trea

tmen

ts/y

r

Mean FEV1 % predicted

Highest PFT decile

Lowest PFT decile

Exacerbations are associated with impairment of lung function

Improving FEV1 in the US CF cohort:1995-2005

6-12 yrs

13-17 yrs

18-24 yrs

>25 yrs

Year

Mea

n FE

V 1 (%

pre

dict

ed)

VanDevanter et al., Pediatr Pulmonol 2008; 43:739-44

Reducing risk of exacerbation:an important clinical trial outcome

• Dornase alfa– Fuchs et al., N Engl J Med. 1994;331:637–642– Quan et al., J Pediatr. 2001;139(6):813-820

• Inhaled antibiotics– Ramsey et al., N Engl J Med. 1999;340:23–30– Murphy et al., Pediatr Pulmonol. 2004;38:314–320– McCoy et al., AJRCCM. 2008;178:921-8

• Oral macrolides– Saiman et al., JAMA. 2003;290(13):1749-1756– Clement et al., Thorax 2006;61(10):895-902

• Hydrators– Elkins et al., N Engl J Med. 2006;354:229–240

Has our collective vision changed?

If exacerbation incidence inversely correlates with FEV1 % predicted1…

andmean FEV1 for the US CF cohort has steadily

improved over the past decades2…then

shouldn’t the mean rate of IV treatment for exacerbations be falling?

1Goss and Burns, Thorax 2007; 62: 360-3672VanDevanter et al., Pediatr Pulmonol 2008; 43: 739-744

Annual IV antibiotic treatment incidence:US CF cohort 1994 - 2009

Patients treated at least once

with IVs for exacerbation

CFF Patient Registries, 1994 - 2009

Matters of faith

• We know an exacerbation when we see it– Do clinicians share the same “vision”?– Has our collective vision changed?

• Antibiotics improve outcomes– Which outcomes?– How do we measure them?

Status

better

worse

Time

intervene

signs /symptomsFEV1

Antibiotics are a common treatmentfor an exacerbation

What is the evidence that antibiotics are necessary to treat exacerbation?

Killing the bacteria will solve… which problems?

• Signs and symptoms– Antibiotics improve signs and symptoms– There has never been a demonstration that

antibiotics change the time or magnitude of sign and symptom response


• Signs and symptoms– There has never been a demonstration that

antibiotics change the time or magnitude of sign and symptom response

• FEV1

– Antibiotics improve FEV1

– How is treatment duration related to response?


• FEV1

– Antibiotics improve FEV1

better

worse

Time

antibiotics

signs /symptomsFEV1

Status

treatment duration

treatment goal

historicalexacerbation

definition

Sanders DB, et al. Am J Respir Crit Care Med 2010; 182:627–632

Antibiotics improve FEV1Re

lativ

e FE

V 1 Res

pons

e

Time (days)

Exacerbating Patients

Regelmann et al., N = 8

Regelmann et al., Am Rev Respir Dis 1990;141:914-21


lativ

e FE

V 1 Res

pons

e

Time (days)

Regelmann et al., N = 5

Exacerbating Patients

Collaco et al., N = 492VanDevanter et al., N = 50VanDevanter et al., N = 45

Collaco et al., AJRCCM 2010; 182(9):1137-1143Regelmann et al., Am Rev Respir Dis 1990;141:914-21

VanDevanter et al., Respir Res, 2010;11:137


lativ

e FE

V 1 Res

pons

e

Time (days)

Ramsey et al., N = 262

Stable Patients

McCoy et al., N = 135

McCoy et al., Am J Respir Crit Care Med 2008; 178: 921-928Ramsey et al., New Eng J Med 1999; 340: 23–30

Hypothesized causes of exacerbations

• Bacteria– New or more bacteria– Change in virulence

This is the information we are accustomed to:

Does abundance matter?

Tunney MM et al: Thorax 2011; 66: 579-584

Exacerbation(N = 16)

9

8

7

6

5

4

3

Total ViablePa Count(log10 CFU/g)




End of Treatment(N = 16)

9

8

7

6

5

4

3





End of Treatment(N = 16)

Stable(N = 9)

9

8

7

6

5

4

3


You all look alike to me

How diverse is the infecting population?

Measure phenotypes related to infection

pathogenesis

CF Sputum

Culture in lab

Courtesy of Ben Staudinger and Pradeep Singh

CF Pseudomonas populations are highly diverse

Ceftazidime

Rhamnolipids

Growth w/o AA

Swimming

Tobramycin

Ciprofloxacin

+ + - - + -- + - + + +

Sub-population

12

==


Rare populations may be very important

Subpopulations1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

0

10

20

30

40

50Population diversity based on tests

% of total

Yet the isolates are genetically-related siblings


Isolates with diverse phenotypes have the same genetic fingerprint

lab strains

L L

Initial strain

*

Genetic variant arises

*

*

*

*

*

*

Diverse infecting

community

Diversity arises from evolution of the infecting strain

Some subpopulations are more virulent than others


LDH

rele

ase

P. aeruginosa

Airway epithelia

P. aeruginosa subpopulations


The relative abundance of subpopulations changes at exacerbation onset

01020304050 Well period

% of total

Exacerbation ("sick") period

0

10

20

30

40

% of total

2 4 6 8 10 12 14 18 20 22 2414

Could increases in these subpopulations have

caused the flare?

How would these bacteria move in the airways?

Community structure around exacerbation

J. LiPuma - unpublished1Kong R et al: Abstract 260; 2Planet W et al: Abstract 262

Even more on bacterial diversity1, 2

Microbiology and treatment• The “old ways” of thinking about bacteria and

exacerbation are not helpful– clinical micro doesn’t predict response

• The search for better models of the bacterial role in exacerbation arises in part from recognition of this problem

• Assumption: improved understanding of bacterial role in exacerbation will lead to:– More rationale selection of antibiotics for

treatment– Better treatment outcomes

Hypothesized causes of exacerbations

• Bacteria– New or more bacteria– Change in virulence

• Environmental– Pollution– GERD1

• Viral2-4

• Other (e.g. ABPA)

1Boesche R et al: Abstract 488; 2Flight W et al: Abstract 265; 3Cochrane ER et al: Abstract 319; 4Kong M et al: Abstract 78

Our problem(s)

• Exacerbations are an important clinical problem– Variable treatments must lead to variable outcomes

• We don’t understand the physiology of exacerbation– Room for many theories of “best” management

• Empirical tools to diagnose exacerbation and then to compare responses to different treatments are “underdeveloped”

We can’t improve what we don’t measure

Patient-reported outcomes• Important point of emphasis within FDA

– Clinical Endpoint: “A characteristic or variable that reflects how a patient feels, functions, or survives”

• Historical precedents for PRO in CF– Cystic Fibrosis Questionnaire – Revised (CFQ-R)– Cystic Fibrosis Respiratory Symptom Diary (CFRSD)

• Ideal approach for transition from encounter- based to surveillance-based respiratory management

Kraynack N, presented at NACFC 2010

Standardizing measurement of COPD exacerbations

• EXACT-Pro– Exacerbations of Chronic Pulmonary Disease Tool

(EXACT)– Patient Reported Outcomes (PRO)

• 14-item daily diary– Reliable– Valid– Sensitive to changes during recovery from

exacerbation

Leidy NK et al Am J Respir Crit Care Med 2011; 183: 323-329

COPD exacerbationExacerbation Prevention Trial

Leidy et al. Value in Health 2010; 13: 965-975

Early intervention in pulmonary exacerbation-effect of monitored care-

Aitken et al., NACFC 2011 Abstract 331: Workshop 08

50

40

0

Pulmonaryexacerbationsover 6 months

Usual care

(N = 16)

Monitoredcare

(N = 19)

P = 0.19

30

20

10

P = NS

COPD exacerbationAcute Treatment Trial

Leidy et al. Value in Health 2010; 13: 965-975

Advancing patient reported outcomes in children with cystic fibrosis

• Used CFRSD during 14 day treatment of exacerbations

• N=51, Age 13.2, 87.6% of diaries completed• Conclusion: demonstrates feasibility and

responsiveness

Goss CH et al: Abstract 231

Update on the definition of apulmonary exacerbation

• Working Group– Nancy K Leidy– Christopher Goss– Donald Patrick– Patrick Flume– Nathan Kraynack– Bruce Marshall

• Phase I– Review all CFRSD

development documents– prepare an outline of the

CFRSD briefing document

– prepare a needs assessment

• Phase II– development of the

briefing package– Submit to the FDA

Conclusions• We have presumed that antibiotics are an

important aspect of treatment of a pulmonary exacerbation, but our evidence is weak.

• Antibiotics are clearly effective in the treatment of chronic infection of the CF airways

• Is it likely that many of the “pulmonary exacerbations” were actually progression of disease, and not an acute event?– Our “definition” of a pulmonary exacerbation has

been evolving– We need to improve our definition of pulmonary

exacerbation and it will be a measure of patient reported outcomes.

Conclusions

• Is there yet a role for bacteria as a cause or contributor to pulmonary exacerbations?– Studies of the microbiome are compelling– If we don’t measure response rigorously, how will

we compare/validate different micro models?

• Where do we go from here?

A call to arms

• Pulmonary exacerbation data tracked in PortCF• Pharmacokinetics of inhaled and IV tobramycin1

• eICE study• Prospective monitoring for exacerbations

• NHLBI proposal has been submitted– Pilot and feasibility study of comparative

effectiveness using PortCF as a research tool

1Stenbit A et al: Abstract 376

Peer Review Comments

“With due respect to the eminent committee … I must admit to being quite underwhelmed ... because of the actual paucity of data that is available to us all as clinicians in addressing the very real questions that are posed and addressed by the committee”

Translation:

Flume, presented at NACFC 2009

• We know a little more jack• We know Jack a little better

Thank you

Pulmonary Exacerbations: Out of the Wilderness

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