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 Stewart
Jacobellis 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
accompanied by…
• An acute decrease in lung function (i.e. FEV1)
A typical definition of a CF pulmonary
exacerbation is …
signs /symptoms
FEV1
better
Worsening of
clinical status
and FEV1
Status
intervene
worse
Time
But, are all exacerbations acute events?
signs /symptoms
FEV1
better
Status
intervene
worse
Time
But, are all exacerbations acute events?
better
encounter
Status
worse
intervention
Time
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
Oral/Inhaled antibiotics
IV Antibiotics
100%
Antibiotic
Treatments
for PEx,
2003-2005
80%
60%
40%
20%
0%
<6
6-12
13-17
18-24
Age group (yrs)
Wagener et al., Ped Pulmonol 2008;S31:359
25+
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 medications
Inhaled plus IV tobramycin
Airway clearance
1 vs. 2 antibiotics for Pseudomonas
Aminoglycosides: once daily v. multidose
Continuous infusion -lactam antibiotics
Duration of antibiotics
Routine synergy testing
Corticosteroids
*Consensus recommendation (see previous guidelines)
Am J Respir Crit Care Med 2009; 180: 802-808
I
B*
I
B*
I
C
I
I
D
I
about
antibiotics
Classical approach to
pulmonary exacerbation management
III. BACTERIA
CAUSE
EXACERBATIONS
IV. ANTIBIOTICS
THEM
Old Testament
CURE
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?
< 18 years old
Patients
Treated
w/IVs
Median
Days
Treated
≥ 18 years old
100%
100%
80%
80%
60%
60%
40%
40%
20%
20%
0%
0%
Care Centers
30
30
20
20
10
10
0
0
Care Centers
CFF Center Director’s Report, 2009
Care Centers
Care Centers
Exacerbations
are associated
with
Has
our collective
vision changed?
impairment of lung function
Mean IV treatments/yr
2.0
Lowest PFT decile
1.6
1.2
0.8
Highest PFT decile
0.4
0
120%
100%
80%
60%
Mean FEV1 % predicted
Goss and Burns, Thorax 2007;62:360-7
40%
Mean FEV1 (% predicted)
Improving FEV1 in the US CF cohort:
1995-2005
100
6-12 yrs
90
13-17 yrs
80
70
18-24 yrs
60
50
1995
>25 yrs
2000
Year
VanDevanter et al., Pediatr Pulmonol 2008; 43:739-44
2005
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…
and
mean 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: 360-367
et al., Pediatr Pulmonol 2008; 43: 739-744
2VanDevanter
Annual IV antibiotic treatment incidence:
US CF cohort 1994 - 2009
40%
R² = 0.1296
38%
Patients treated
36%
at least once
with IVs
for exacerbation 34%
32%
30%
1994
1998
2002
Year
CFF Patient Registries, 1994 - 2009
2006
2010
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?
Antibiotics are a common treatment
for an exacerbation
signs /symptoms
FEV1
better
Status
intervene
worse
Time
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
Killing the bacteria will
solve… which problems?
• 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?
Killing the bacteria will
solve… which problems?
• FEV1
– Antibiotics improve FEV1
historical
exacerbation
definition
better
Status
treatment goal
D
signs /symptoms
FEV1
antibiotics
worse
Time
treatment duration
Sanders DB, et al. Am J Respir Crit Care Med 2010; 182:627–632
Antibiotics improve FEV1
Exacerbating Patients
Relative FEV1 Response
Regelmann et al., N = 8
Time (days)
Regelmann et al., Am Rev Respir Dis 1990;141:914-21
Antibiotics improve FEV1
Exacerbating Patients
Relative FEV1 Response
Regelmann et al., N = 5
Collaco et al., N = 492
VanDevanter et al., N = 50
VanDevanter et al., N = 45
Time (days)
Regelmann et al., Am Rev Respir Dis 1990;141:914-21
Collaco et al., AJRCCM 2010; 182(9):1137-1143
VanDevanter et al., Respir Res, 2010;11:137
Antibiotics improve FEV1
Stable Patients
Relative FEV1 Response
Ramsey et al., N = 262
McCoy et al., N = 135
Time (days)
Ramsey et al., New Eng J Med 1999; 340: 23–30
McCoy et al., Am J Respir Crit Care Med 2008; 178: 921-928
Hypothesized causes of exacerbations
• Bacteria
– New or more bacteria
– Change in virulence
This is the information we are accustomed to:
Does abundance matter?
9
8
Total Viable 7
Pa Count 6
(log10 CFU/g)
5
4
3
Exacerbation
(N = 16)
Tunney MM et al: Thorax 2011; 66: 579-584
Does abundance matter?
9
8
Total Viable 7
Pa Count 6
(log10 CFU/g)
5
4
3
Exacerbation
(N = 16)
Tunney MM et al: Thorax 2011; 66: 579-584
End of Treatment
(N = 16)
Does abundance matter?
9
8
Total Viable 7
Pa Count 6
(log10 CFU/g)
5
4
3
Exacerbation
(N = 16)
Tunney MM et al: Thorax 2011; 66: 579-584
End of Treatment
(N = 16)
Stable
(N = 9)
You all look alike to me
How diverse is the infecting population?
CF Sputum
Culture in lab
Courtesy of Ben Staudinger and Pradeep Singh
Measure
phenotypes
related to
infection
pathogenesis
CF Pseudomonas populations are highly diverse
+ + - - +
- + - + +
50
40
% of 30
total 20
Subpopulation
- = 1
+ = 2
Population diversity based on tests
Rare populations may be very important
10
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Subpopulations
Courtesy of Ben Staudinger and Pradeep Singh
Yet the isolates are genetically-related siblings
LL
Isolates with diverse phenotypes
have the same genetic fingerprint
Courtesy of Ben Staudinger and Pradeep Singh
lab strains
Diversity arises from evolution of the
infecting strain
Genetic variant
arises
*
*
Initial strain
*
*
*
*
*
Diverse
infecting
community
Some subpopulations are more virulent
than others
30
25
LDH release
P. aeruginosa
Airway
epithelia
20
15
10
5
0
1
11
21
31
41
51
61
71
81
P. aeruginosa subpopulations
Courtesy of Ben Staudinger and Pradeep Singh
91
The relative abundance of subpopulations
changes at exacerbation onset
% of
total
Well period
50
40
30
20
10
0
Exacerbation ("sick") period
40
Could increases in these
subpopulations have
caused the flare?
30
% of
total
20
10
0
2
4
6
8
Courtesy of Ben Staudinger and Pradeep Singh
10 12
14
14
18 20
22
24
How would these bacteria move in the airways?
Community structure around exacerbation
Even more on bacterial diversity1, 2
J. LiPuma - unpublished
1Kong
R et al: Abstract 260; 2Planet W et al: Abstract 262
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 encounterbased 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 exacerbation
Exacerbation Prevention Trial
Leidy et al. Value in Health 2010; 13: 965-975
Early intervention in pulmonary exacerbation
-effect of monitored care50
40
Pulmonary
exacerbations
over 6 months
P = 0.19
P = NS
30
20
10
0
Usual
care
Monitored
care
(N = 16)
(N = 19)
Aitken et al., NACFC 2011 Abstract 331: Workshop 08
COPD exacerbation
Acute 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 a
pulmonary 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