pulmonary exacerbations: out of the wilderness
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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) - PowerPoint PPT PresentationTRANSCRIPT
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
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
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
Antibiotics improve FEV1Re
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
Antibiotics improve FEV1Re
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)
Does abundance matter?
Tunney MM et al: Thorax 2011; 66: 579-584
Exacerbation(N = 16)
End of Treatment(N = 16)
9
8
7
6
5
4
3
Total ViablePa Count(log10 CFU/g)
Does abundance matter?
Tunney MM et al: Thorax 2011; 66: 579-584
Exacerbation(N = 16)
End of Treatment(N = 16)
Stable(N = 9)
9
8
7
6
5
4
3
Total ViablePa Count(log10 CFU/g)
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
==
Courtesy of Ben Staudinger and Pradeep Singh
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
Courtesy of Ben Staudinger and Pradeep Singh
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
Courtesy of Ben Staudinger and Pradeep Singh
LDH
rele
ase
P. aeruginosa
Airway epithelia
P. aeruginosa subpopulations
Courtesy of Ben Staudinger and Pradeep Singh
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