Can We Simplify the Management of Complicated
Pneumonia in Children?
Samir S. Shah, MD, MSCE
Divisions of Infectious Diseases and General PediatricsThe Children’s Hospital of Philadelphia
Departments of Pediatrics and Biostatistics and EpidemiologyUniversity of Pennsylvania School of Medicine
Objectives
Explore the use of administrative data to clarify the changing epidemiology of pneumonia and
complicated pneumonia role of operative vs. non-operative interventions in
the management of children with complicated pneumonia
Background: Pneumonia
Community-acquired pneumonia (CAP) is a common serious bacterial infection in children >600,000 hospitalizations in the U.S. each year
Up to one-third of children hospitalized with CAP have a pleural effusion (complicated pneumonia)
What do we mean by the term complicated pneumonia?
Case
3-year-old boy with cough and fever Evaluated 2 weeks ago
Diagnosed with asthma and clinical pneumonia Treated with albuterol and amoxicillin
Returns with continued cough and fevers to 39.2°C
Case: Chest X-ray
Case: Chest CT
Changing Epidemiology of Invasive Pneumococcal Disease
Licensure of a 7-valent pneumococcal conjugate vaccine in 2000 Decrease in invasive pneumococcal infections Subsequent increase in the rate of infections
caused by penicillin-resistant S. pneumoniae serotypes not included in the current vaccine
Increasing prevalence of infections caused by methicillin-resistant S. aureus
National Hospital Discharges (all ages)
■= Bacteremia of any etiology
▲= Pneumococcal bacteremia
Shah SS, et al. Clin Infect Dis 2006;42:e1-5
Pneumococcal Bacteremia By Serotype Category
♦=vaccine serotype
■=vaccine-related serotype
○=non-vaccine serotype
Steenhoff A, Shah SS, et al. Clin Infect Dis 2006;42:907-914
Invasive Disease Caused by Penicillin-Susceptible and Non-susceptible Pneumococci (ages <2)
Kyaw MH, et al N Engl J Med 2006;354:1455-1463
What does this have to do with pneumonia?
Have rates of pneumonia or complicated pneumonia changed
over time?
Datasource: National Hospital Discharge Survey (NHDS)
Created by the National Center for Health Statistics Includes only non-federal US hospitals
All hospitals with >1,000 beds Representative sample of others based on location, size &
specialty Includes ~500 hospitals & 250,000 discharges each year
Weighting of records by hospital size/region allows for calculation of nationally representative estimates
Eligibility
Inclusion Ages 1-18 years Discharged 1993-2006 Diagnosis of community-acquired pneumonia
Exclusion Age <1 to eliminate bronchiolitis Known underlying predisposition to pneumonia
(e.g., malignancy, HIV, cystic fibrosis)
Definitions of Pneumonia
Community-acquired pneumonia (CAP) Pneumonia as 1°diagnosis OR Pneumonia-related symptom as 1° diagnosis
(e.g., cough) & pneumonia as 2° diagnosis OR Empyema or pleurisy as 1° diagnosis and
pneumonia as 2° diagnosis Sensitivity of 89% and specificity of 80%
compared with medical record review
Whittle J, et al. Am J Med Qual 1997;12:187-193
Definitions of Complications
Local Metastatic Systemic
Bronchopleural fistula Endocarditis HUS
Empyema Intracranial abscess Respiratory failure
Lung abscess Mastoiditis Sepsis
Lung resection Meningitis SIRS
Osteomyelitis
Pericarditis
Septic arthritis
Abbreviations: HUS, hemolytic-uremic syndrome; SIRS, systemic inflammatory response syndrome
Challenges
Accuracy of ICD-9 codes to identify conditions of interest Does our definition exclude the sickest patients?
Change in ICD-9 codes over time (e.g., addition of 4th or 5th digits) Review annual ICD-9 addendum
Complex survey statistics (i.e., sample weights) to calculate national estimates May limit accuracy of data for subpopulations
Insufficient data in publicly available dataset to calculate standard errors for some subpopulations
Gorton CP, et al. Pediatrics 2006;117:176-180
Regional Variation in Pediatric CAP Hospitalizations (Pennsylvania)
The epidemiology of pneumonia and complicated pneumonia is complex and
changing
Evolution of Empyema
Exudative Neutrophil migration into pleural space
Fibrinopurulent Fibrin deposition Loculations impair lung expansion
Organizing Fibroblast formation produces an inelastic
membrane or “fibrinous peel”
Management of Empyema
Radiologic assessment CXR (upright & decubitus) Ultrasound CT scan
Management of Empyema
Surgical options Thoracentesis (needle aspiration) Tube thoracostomy (+ fibrinolysis) Video-assisted thoracoscopy* Thoracotomy*
*Require post-procedure thoracostomy tube
Management of Empyema
No consensus on optimal initial drainage strategy Technique? Timing?
Why use administrative data to study complicated pneumonia?
Sonnappa et al. Kurt et al. Avansino et al. Li et al. Shah et al.
Sonnappa et al.
1st randomized study of VATS vs. thoracostomy tube drainage
60 patients enrolled from January 2002 to February 2005
Groups similar in Age & Sex Preadmission symptoms Effusion stage Causative bacteria (mostly S. pneumoniae)
Sonnappa S. Am J Respir Crit Care Med 20006;174:221-227
Sonnappa et al.
Variable Thoracostomy VATS P
(N=30) (N=30)
Median LOS (days) 7 8 0.645
Tube drainage (days) +1 compared to VATS 0.055
Repeat Procedures 17% 13% ?
Kurt BA, et al. Pediatrics 2006;118:e547-e553
Kurt et al.
1st randomized study of VATS vs. thoracostomy tube drainage in U.S.
18 patients enrolled from November 2003-May 2005
Groups similar in Age & sex Preadmission symptoms & antibiotics Effusion size Presence of loculation
Kurt BA, et al. Pediatrics 2006;118:e547-e553
Kurt et al.
Variable Thoracostomy VATS P
(N=8) (N=10)
Mean LOS (days) 13.3 5.8 0.004
Tube drainage (days) 9.6 2.8 <0.001
Oxygen (days) 3.6 1.6 0.965
Narcotic use (days) 7.6 2.2 0.043
Procedures (no.) 2.25 1.0 0.002
Kurt BA, et al. Pediatrics 2006;118:e547-e553
Key Differences
Differences Kurt et al. used substantially larger chest tubes
(16-24 Fr vs. 8-10 Fr) Sonnappa et al. used more aggressive fibrinolysis LOS presented as mean (Kurt) or median
(Sonnappa) Limitations
Single centers Few patients
Can a meta-analysis more address this issue more
definitively?
Avansino et al. Systematic review of therapy for empyema (outcome data
from 3781 children)
Outcome PrimaryOperative
Primary Non-operative
Mortality 0% 3.3%Re-intervention 2.5% 23.5%Duration of hospitalization 10.8 d 20.0 dDuration of TT 4.4 d 10.6 dDuration of antibiotics 12.8 d 21.3 d
Avansino JR. Pediatrics 2005;115:1652-1659
Avansino et al.
In the pooled analysis, primary operative therapy reduced LOS by 45% (199 patients, 4 studies) Repeat procedures by 90% (492 patients, 9 studies) Results biased towards favoring operative therapy
Non-operative group= needle thoracentesis or chest tube drainage
Avansino JR, et al. Pediatrics 2005;115:1652-9
Avansino et al. - Limitations Poor study quality
No randomized studies performed at time of review Inclusion only of small (all <70 patients) observational studies
with heterogeneous study designs
Primary outcome of interest “therapeutic failure” not chosen a priori
Failure to adjust for confounding variables Timing of intervention Chemical fibrinolysis Empiric antibiotic therapy
Where do things stand?
Randomized studies Small & single center Multicenter studies difficult to conduct because
prevailing personal & institutional dogmas Pooled analyses
Few high quality studies Administrative data
Seriously?
Li et al.
2003 Kids’ Inpatient Database Inclusions
Age 0-18 years ICD-9 codes for “empyema” (510.0 & 510.9)
Exclusions Co-morbid illness Transfer from another hospital
Li ST. Arch Pediatr Adolesc Med 2008;162:44-48
Li et al.
1173 patients Primary operative management (POM) vs.
Non-operative management (NM) POM= decortication within 2 days of admission NM= everything else, including decortication 3 or
more days after admission
Li ST. Arch Pediatr Adolesc Med 2008;162:44-48
Li et al.
Procedure LOS Adjusted Change
Overall (n=1173)
NM 13.6 days Reference
POM 9.8 days -4.3 (-6.4 to -2.3)
Empyema as primary diagnosis (n=362)
NM 10.3 days Reference
POM 8.9 days -1.7 (-0.4 to -3.0)
Li ST. Arch Pediatr Adolesc Med 2008;162:44-48
Li et al. - Limitations
ICD-9 codes incomplete Other codes that suggest effusion were not included
511.1 – effusion, with mention of bacterial cause other than tuberculosis
513.0 – abscess of lung Diagnosis of pneumonia not required
Potential for inclusion of effusions not related to pneumonia (e.g., post-op)
NM group heterogeneous For example, those drained early by chest tube may be
different than those drained late by VATS and those never drained
Shah et al.
Pediatric Health Information System (PHIS) Inpatient data from 27 not-for-profit, tertiary care, U.S.
children’s hospitals Inclusions
Age 12 months to 18 years of age Discharged between 2001-2005 ICD-9 codes 510.0, 510,9, 511.1, or 513.0 as primary
diagnosis plus pneumonia (480-486) Pleural fluid drainage within 48 h of hospitalization
Exclusion Co-morbid illness
Shah SS. Arch Pediatr Adolesc Med 2008;162:675-681
Shah et al. - PHIS Study Population
Pneumonia(N=49,574)
Complicated Pneumonia
(N=2,862)
Early Drainage34% (N=961)
Late Drainage29% (N=829)
No Drainage37% (N=1,072)
Shah SS. Arch Pediatr Adolesc Med 2008;162:675-681
Shah et al. - Initial Procedure
Procedure No. (%)
Chest tube 714 (74.3)
VATS 50 (5.2)
Thoracotomy 197 (20.5)
Shah SS. Arch Pediatr Adolesc Med 2008;162:675-681
Shah et al. - Procedure Variation by Hospital
0%
20%
40%
60%
80%
100%
Hospital
%
OF
PROCEDURES
ChestTube
VATS
Thoracotomy
Shah et al. - Variation in LOS by Hospital*
Hospital
MEDIAN
LOS
0
2
4
6
8
10
12
14
16
*7% of patients had a LOS >28 days
Shah et al. - Change in LOS
Variable Adjusted Change in LOS*
P-value
Procedure (baseline=13.29 d)
Chest tube Reference …
VATS -2.66 d 0.006Thoracotomy -1.26 d 0.439
*Also adjusted for race, asthma diagnosis, receipt of systemic corticosteroids, empiric vancomycin therapy, and fibrinolysis
Shah SS. Arch Pediatr Adolesc Med 2008;162:675-681
Shah et al. - Repeat Procedure
Repeat procedure 298 (31%) overall required a repeat procedure Percent requiring repeat procedure
34% with primary chest tube 8% with primary VATS 24% with primary thoracotomy
Shah SS. Arch Pediatr Adolesc Med 2008;162:675-681
Shah et al. - Variation in Repeat Procedures by Hospital
0%
10%
20%
30%
40%
50%
60%
70%
80%
Hospital
REPEAT PROCEDURE
Shah SS. Arch Pediatr Adolesc Med 2008;162:675-681
Shah et al. - Repeat Procedure
Variable Adjusted Odds Ratio (95% CI)*
P-value
Procedure
Chest tube Reference …
VATS 0.16 (0.06- 0.42) <0.001Thoracotomy 0.60 (0.31- 1.16) 0.133
*Also adjusted for race, asthma diagnosis, receipt of systemic corticosteriods, empiric vancomycin therapy, and fibrinolysis
Shah SS. Arch Pediatr Adolesc Med 2008;162:675-681
Shah et al. - Summary
Among the subset of children with complicated pneumonia who undergo early pleural drainage, VATS is associated with 20% shorter LOS Fewer repeat procedural interventions
Shah SS. Arch Pediatr Adolesc Med 2008;162:675-681
But which strategy is more cost-effective?
Background
VATS is more expensive than primary chest tube placement in terms of physician and procedural costs
Are these additional costs are offset by associated reductions in length of stay and repeat procedures?
A recent decision analysis concluded that chest tube with fibrinolysis was the preferred strategy
Shah et al.
Pediatric Health Information System (PHIS) Inpatient data from 27 not-for-profit, tertiary care, U.S.
children’s hospitals Inclusions
Age 12 months to 18 years of age Discharged between 2001-2005 ICD-9 codes 510.0, 510,9, 511.1, or 513.0 as primary
diagnosis plus pneumonia (480-486) Pleural fluid drainage within 48 h of hospitalization
Exclusion Co-morbid illness
Shah SS. Arch Pediatr Adolesc Med 2008;162:675-681
Shah et al. – Resource Utilization (Unadjusted data)
Procedure Total Charges
Pharmacy Charges
Imaging Charges
LOS
Early chest tube $36,618 $5,978 $2,939 10 days
Early VATS $32,136 $4,385 $1,779 7 days
Any late procedure
$48,324 $7,465 $3,634 13 days
Analytic approaches
Children undergoing VATS vs. chest tube likely differ in many respects
How can one handle confounding in an observational study? Restriction Matching Adjustment in a regression model Propensity scores
Propensity Score
Represents the probability of treatment Estimated using logistic regression
Outcome = Treatment (i.e., VATS vs. chest tube) Exposures = Measured characteristics of the
study patients In theory, patients with similar propensity
scores should have a similar distribution of measured covariates
1.) Indications for Propensity Scores
Theoretical advantages Confounding by indication may cause treatment
groups to differ dramatically Comparison of propensity scores in exposed and
unexposed subjects can identify these areas of non-overlap
2.) Indications for Propensity Scores
Useful for matching subjects Matching on propensity score outperforms other
matching strategies with many covariates Balance achieved will mimic randomization (for
measured variables)
3.) Indications for Propensity Scores
Improved estimation with few outcomes Reliable estimates not possible with multivariable
modeling when there are many covariates and few outcomes
4.) Indications for Propensity Scores
Propensity score by treatment interactions Can address possibility that the effectiveness of a
drug may vary according to the strength of the indication for its use
5.) Indications for Propensity Scores
Propensity score calibration to correct for measurement errors A specific (and complicated) method that allows
one to account for multiple unobserved confounders Propensity score 1st created in a subgroup of patients
that have detailed information available This gold-standard propensity score is used to correct
the main study effect of the drug on outcome
Rationale for Analytic Approach
#1 Theoretical advantages Confounding by indication may cause treatment groups to
differ dramatically Comparison of propensity scores in exposed and
unexposed subjects can identify these areas of non-overlap
#2 Useful for matching subjects Matching on propensity score outperforms other matching
strategies with many covariates Balance achieved will mimic randomization (for measured
variables)
Approaches to Propensity Score Analysis Restriction
Restrict analysis to participants with sufficient overlap in scores
Matching A science unto itself
Stratified analysis Stratify analysis by score categories (e.g., quintiles)
Weighting Case weight=score; control weight=inverse of 1 minus their
score then apply sample weights in regression model Regression
Treat propensity score as model covariate with treatment
Approaches to Propensity Score Analysis
All methods should produce similar results What if there are differences?
Figure out why Present the best analysis (i.e., the one perceived
to be most accurate)
Practical Considerations
Determine area under the ROC curve for propensity score Rough rule of thumb, perhaps 0.7-0.9 is ok Very high values suggest non-overlap of
distribution of propensity scores between subjects Visually compare propensity score
distributions
Distribution of Propensity Scores
Propensity Score
Quintile
Chest tube
VATS
1 23% 6%
2 21% 16%
3 27% 24%
4 12% 16%
5 17% 38%
AUC = 0.70
Distribution of Propensity Scores
Propensity Score
Quintile
Chest tube
VATS
1 23% 6%
2 21% 16%
3 27% 24%
4 12% 16%
5 17% 38%
Poor overlap of propensity scores between the 2 groups at the extreme quintiles Restriction Matching Stratified analysis Weighting Regression
Matched vs. Unmatched Example
Covariate All VATS
(N=50)
All TT (N=714)
Matched TT
(N=345)
Winter 42% 38%* 44%**
Spring 36% 22% 35%
Summer 2% 14% 2%
Fall 20% 26% 19%
P-value - 0.02 0.99
Total Hospital Charges: VATS vs. Chest Tube
Method* Coefficient 95% CI P-value
Multivariable -0.14 -0.36 to 0.08 0.225
Restriction -0.18 -0.46 to 0.11 0.217
Matching** 0.004 -0.23 to 0.23 0.972
Regression -0.15 -0.39 to 0.08 0.191
*Multivariable model included age, race, sex, season, asthma, steroids, fibrinolysis, and empiric vancomycin receipt. Propensity score created using all of these variables.
**48 VATS patients matched with 7 patients, 1 matched with 5, 1 matched with 4
Propensity Analysis
Bottom line: VATS does not cost more than chest tube placement despite higher physician charges and additional operating room charges
Can We Simplify the Management of Complicated
Pneumonia in Children?
What we think we know
Early intervention reduces duration of hospitalization
Compared with chest tube placement, VATS Modestly decreases LOS Substantially decreases repeat procedures Does not cost more
Chemical fibrinolysis does not affect key outcomes
What we don’t know
Short-term outcomes Affect of various procedures on frequency of local,
systemic and metastatic complications
Long-term outcomes Correlation with short-term outcomes Impact of Impact of early vs. late intervention Impact of early VATS vs. tube thoracostomy
Impact of changing epidemiology on short- and long-term outcomes
Thank You