Korean Edition
1400ызМыкЕьЭШ ып╕ъ╡н
COPD эЩШьЮРъ░А ьзДыЛиы░ЫьзА
ык╗эХШъ│а ьЮИыЛд
About 14 Million
Americans Have
Undiagnosed COPD
BY BRUCE JANCIN
IMNG Medical News
NEW ORLEANS тАУ The most
likely place to look for missed
cases of chronic obstructive pulmonary disease тАУ and they exist
in abundance тАУ is among
women younger than age 65.
COPD, the fourth leading
cause of death in the United
States, is far and away the most
widely underdiagnosed serious
illness. The best available prevalence data on COPD come from
the NHANES III (National
Health and Nutrition Examination Survey III), which included
spirometric testing in a proportionate sample of the U.S. population.
ROUGHLY A THIRD OF
UNDIAGNOSED
INDIVIDUALS HAVE
CLINICALLY RELEVANT
COPD WARRANTING
APPLICATION OF
TREATMENT GUIDELINES.
Extrapolating from those
data, roughly 12 million Americans carry the diagnosis of
COPD, and another 12 million
have evidence of impaired lung
function consistent with COPD
but remain undiagnosed. Of
those 12 million undiagnosed
individuals, NHANES III data
indicate that roughly a third
have clinically relevant COPD
warranting application of treat-
ment guidelines, according to
Dr. Fernando J. Martinez,
FCCP, professor of internal
medicine and director of pulmonary diagnostic services at
the University of Michigan, Ann
Arbor.
He added that the latest data
from NHANES IV, now under
review, bump those estimates
up to roughly 14 million patients with diagnosed COPD,
and an equal number with undiagnosed COPD.
The NHANES III data
showed that 70% of individuals
with undiagnosed COPD are
younger than age 65. Other
studies point to a marked sex
discrepancy in misdiagnosis. In
one landmark study, investigators presented American and
Canadian primary care physicians with a classic clinical scenario for COPD (that is, a patient with a strong smoking
history, progressive shortness
of breath, and chronic cough
with morning sputum production). Half the time, investigators identified this hypothetical
patient as male, the other half
female. Physicians diagnosed
COPD 58% of the time when
the patient was male, but in
only 42% of cases when the otherwise identical hypothetical patient
wasfemale
(Chest
2001;119:1691-5).
This sex discrepancy in
COPD diagnosis has been replicated in similar studies conducted in Spain and Israel, Dr. Martinez added.
See Undiagnosed ┬╖ page 2
CHEST PHYSICIAN
Elsevier Korea LLC, 4FL, Chunwoo Bldg,
534 Itaewon-dong, Yongsan-gu, Seoul 140-861,
S. Korea
V OL . 1 / N O . 2 / D ECEMBER 2012
C O N T E N T S
PULMONARY MEDICINE
1400ызМыкЕьЭШ ып╕ъ╡н COPD эЩШьЮРъ░А ьзДыЛиы░ЫьзА ык╗эХШъ│а ьЮИыЛд
Mometasone/Formoterol ы│╡эХйьаЬ, COPD ь╣ШыгМьЭШ ыШР ыЛдые╕ ь╣ШыгМ ьШ╡ьЕШ
Carboplatinъ│╝ Pemetrexed ы│СэХйьЪФы▓Х: ECOG2, IIIB/IV эЩШьЮРьЧРьДЬ ьГЭьб┤ъ╕░ъ░Д эЦеьГБ ьжЭыкЕ
FDG-PETьЭД ьЭ┤ьЪйэХЬ ьаЬ 1ъ╕░ ы╣ДьЖМьД╕эПмэПРьХФ ьзДыЛи ьЬаьЪйьД▒ ыВоьХД
Delamanid, MDR TB ь╣ШыгМьЧР эХЬыЛиъ│Д ьЧЕъ╖╕ыаИьЭ┤ыУЬ
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CRITICAL CARE MEDICINE
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PEDIATRIC CHEST MEDICINE
ьаАьЬДэЧШ ьЖМьХДь▓ЬьЛЭ эЩШьЮРьЧРьДЬ ыздьЭ╝ ICS ьЪФы▓ХьЭШ эХДьЪФьД▒ьЭА ыЦиьЦ┤ьа╕
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PULMONARY PERSPECTIVES
COPDьЧР ыМАэХЬ ьГЭым╝эСЬьзАьЮР
14
ьЭМьХЕь╣╝ыЯ╝
15
Mometasone/Formoterol ы│╡эХйьаЬ,
COPD ь╣ШыгМьЭШ ыШР ыЛдые╕ ь╣ШыгМ ьШ╡ьЕШ
Combination Provides Another
Option for COPD
BY MIRIAM E. TUCKER
IMNG Medical News
ORLANDO тАУ A combination
of fixed-dose mometasone
furoate and formoterol fumarate improved lung function in patients with moderate
to very severe chronic obstructive pulmonary disease.
The finding came from a 26week, phase III, multicenter,
double-blind, placebo-controlled study of 1,055 adults
who were current or former
smokers and had a prebronchodilator forced expiratory
volume in 1 second (FEV1)/
forced vital capacity ratio of
0.70 or less. Currently, three
combinations of inhaled corticosteroid plus long-acting beta
agonists are available for the
treatment of COPD, but not
this particular combination of
mometasone furoate with formoterol fumarate administered with a metered-dose in-
haler, which is licensed for
asthma treatment in the United States under the name
Dulera, Dr. Edward Kerwin
said at the annual meeting of
the American Academy of Allergy, Asthma, and Immunology.
The patients were randomized to one of five twice-daily
metered-dose inhaler treatment
arms: mometasone furoate 400
See Combination ┬╖ page 2
PULMONARY MEDICINE
Undiagnosed COPD
See Undiagnosed ┬╖ from page 1
Interestingly, the first diagnostic test most participating primary care physicians indicated they would
order for this hypothetical patient was a chest x-ray,
which Dr. Martinez dismissed as a тАЬterribleтАЭ tool for
diagnosing COPD. Spirometry, which is in fact the diagnostic test for COPD, would have been ordered initially by only 22% of the physicians.
The pulmonologist stressed that even though spirometry is the diagnostic test for airflow obstruction, three
major sets of guidelines released within the past year
uniformly emphasize that its use should be restricted
to patients with respiratory symptoms. The recent
guidelines he referred to are the latest update from the
Global Initiative for Chronic Obstructive Lung Disease,
which Dr. Martinez coauthored; the joint American
College of Physicians/American College of Chest
Physicians/American Thoracic Society/European Respiratory Society guidelines (Ann. Intern. Med.
2011;155:179-91); and the U.K. National Institute for
Health and Clinical Excellence guideline.
Vitalunderutilized
Signs
in
Spirometry continues to be greatly
IMNG M EDICAL M EDIA
primary care medicine, perhaps in part because some
insurers are unwilling to pay for the test in the office
setting, insisting instead that it be performed in a specialized pulmonary clinic. That policy is destined for
the scrap heap, Dr. Martinez predicted.
In the study that identified sex bias in COPD diagnosis, classic COPD symptoms in women were misdiagnosed most frequently as asthma. ThatтАЩs a crucial
mistake, because the first-choice treatments for these
two common respiratory diseases are тАЬdiametrically
opposite,тАЭ Dr. Martinez said at the annual meeting of
the American College of Physicians.
тАЬIn asthma, you use inhaled corticosteroids up front
as first-line therapy. ThatтАЩs not the case in COPD. In
COPD you use a long-acting bronchodilator up front,
and you add an inhaled corticosteroid to reduce the
exacerbation rate in people83278.CH.graphic
at increased risk based on
a history of two or more exacerbations in the past
CH91
year,тАЭ he explained.
All of the latest guidelines emphasize exacerbation
reduction as a key component of COPD management.
Exacerbations accelerate
disease progression by
D A T A
W A T C H
worsening lung function
and symptoms, and they
Cost of COPD and Asthma 51% Higher for Women
drive up costs as well.
The National Heart,
Heart disease
Lung, and Blood Institute
Cancer
is interested in developing
Mental disorders
a novel, practical means
of screening the general
Trauma-related disorders
population for COPD in
$26.8 bn
Osteoarthritis
primary care physiciansтАЩ
COPD, asthma
offices. Toward that end,
$17.7 bn
the institute recently
Hypertension
awarded a large research
Women
Diabetes
grant to a team of investiBack problems
Men
gators that includes Dr.
Hyperlipidemia
Martinez. He said that
while he and his cowork0
$10
$20
$30
$40
$50
ers are still in the brainBillions
storming stage, they are
Note: Based on data for adults from the Medical Expenditure Panel Survey, 2008.
drawn to a staged apSource: Agency for Healthcare Research and Quality statistical brief 331 (July 2011)
proach involving a very
Another Option for COPD
See Combination ┬╖ from page 1
VITALS
mcg/formoterol 10 mcg (MF400/
F10), mometasone furoate 200 mcg/formoterol 10 mcg (MF200/F10), mometasone furoate 400 mcg alone (MF400), formoterol 10 mcg alone (F10), or placebo.
A total of 840 of the 1,055 randomized
patients completed the treatment period.
About 80% of the patients were male,
with a mean age of 59 years, and about
three-quarters were white. Nearly half
were current smokers, and all had
smoked at one point in time, with an average of 40 pack-years.
The findings of this study also were
published online in the International
Journal of Chronic Obstructive Pulmonary Disease (Int. J. Chron. Obstruct.
Pulmon. Dis. 2012;7:43-55).
One of the two coprimary end points,
the contribution of F10 to the MF400/
F10 combination at week 13, was
reached with a statistically significant
109-mL difference in FEV1 area
under the curve, compared with MF 400
alone. The overall effect size was a 163mL difference for MF400/F10 over
placebo at 13 weeks. A comparison of
MF 400/F10 with MF 400 monotherapy
also demonstrated a statistically significant effect of the F10, with an improvement of 69 mL, reported Dr. Kerwin, of
the Clinical Research Institute of Southern Oregon, Medford.
The other coprimary end point, the
Major Finding: The contribution of F10 to the MF400/F10 combination at
week 13 was shown by a statistically significant 109-mL difference in FEV1
area under the curve, compared with MF400 alone. The mean change from
baseline in morning predose FEV1 at the week 13 end point showed the contribution of the MF400 component, with a statistically significant difference
of 111 mL between MF400/F10 and F10 alone.
Data Source: Data are from a 26-week, phase III, multicenter, double-blind,
placebo-controlled study of 1,055 adults with moderate to very severe COPD.
Disclosures: The study was sponsored by Merck Sharp & Dohme. Dr. Kerwin disclosed receiving consulting fees and/or speaking fees from Dey Laboratories, GlaxoSmithKline, MAP Pharma (AstraZeneca), Merck, Teva, and Sepracor.
SUMMARY
CHEST Physician тАв December 2012
ып╕ъ╡н 4ь░и ъ╡нып╝ъ▒┤ъ░ХьШБьЦСьб░ьВмьЭШ ь╡ЬьЛа ъ▓░ъ│╝ьЧР ыФ░ые┤ый┤ ып╕ъ╡ньЭ╕ ьдС
1400ызМыкЕ ьаХыПДъ░А COPDъ░А ьЮИьЭМьЧРыПД ьзДыЛиы░ЫьзА ык╗эХШъ│а ьЮИыКФыН░
ьЭ┤ые╝ эХ┤ъ▓░эХШъ╕░ ьЬДэХ┤ьДЬ эЪиъ│╝ьаБьЭ╕ COPD screening testьЭШ
ъ░Ьы░ЬьЭ┤ ьаИьЛдэЮИ ьЪФъ╡мыРШъ│а ьЮИыЛд
brief questionnaire, in-office measurement of peak expiratory flow via a pocket spirometer, followed by diagnostic-quality spirometry when indicated.
Polls of busy general internists and family physicians
indicate that if this screening questionnaire is more
than four questions long, they wonтАЩt use it. So, hypothetically, Dr. Martinez said, a three-item questionnaire
might consist of something along these lines: How old
are you? (Epidemiologic data indicate COPD risk rises
at about age 40.) How much do you smoke? (COPD
risk begins climbing with a lifetime history of just 100
cigarettes, a mere five packs.) And, do you have symptoms?
Dr. Martinez said that he would like to incorporate
in-office peak expiratory flow measurement using a
pocket spirometer into the future screening tool in
light of the findings of a recent study in which he was
a principal investigator.
This study of 5,761 patients demonstrated that itтАЩs
rare to find severe airflow obstruction in an individual
whose FEV1 is at least 60% of the predicted value
(Chest 2011 Dec. 22 [Epub ahead of print; PMID
22194590]).тАЬA peak flow measurement has very good
negative predictive value. That could be a useful part
of a screening instrument thatтАЩs going to need to be
very practical,тАЭ he observed.
The use of peak expiratory flow meters for this use
in COPD is currentlyWomen
still under investigation.
Dr. Martinez reported that he serves as a consultant
to Actelion, Almirall, AstraZeneca, Bayer, Forest, GlaxoSmithKline, Ikaria,Men
MedImmune, Merck, Novartis,
Nycomed, Pearl, and Pfizer.
COMMENTARY
2
Dr. Darcy Marciniuk, FCCP, comments: It is
clear that spirometry is underutilized and COPD
is underdiagnosed. COPD is both treatable and
preventable, and utilizing spirometry to appropriately diagnosis COPD in symptomatic patients is the first step in achieving those goals. ItтАЩs
time to spread the word!
mean change from baseline in morning
predose FEV1 at the week 13 end point,
showed the contribution of the MF component. It was statistically significant for
MF400/F10 over F10 alone, at 111 mL,
and for MF200/F10 over F10 alone, at
Continued on following page
Korean Edition
Editor-in-Chief
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Editors
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PULMONARY MEDICINE
December 2012
The proportion of COPD symptomтАУ
free nights improved by 0.15 with
MF400/F10, compared with 0.06 for
placebo, a significant difference over the
26-week period. However, there was no
treatment difference between MF400/F10
and placebo in the proportion of patients
with partly stable COPD at 26 weeks,
with percentages ranging from 38% to
46% across treatment groups.
Time to first COPD exacerbation significantly improved with MF400/F10
over F10 alone; an analysis excluding
mild exacerbations showed that moderate to severe exacerbations were significantly more frequent with placebo than
with MF400/F10 (16.5% vs. 8.8%), he
said.
58 mL. An overall effect size of 128 mL
was seen for MF400/F10 over placebo.
Among the secondary efficacy variables, the MF 400/F10 group exceeded
the 4-point minimum clinically important difference on the St. GeorgeтАЩs Respiratory Questionnaire, compared with
placebo, with a significant effect size of
4.56 points at week 26. Statistically significant improvements in questionnaire
total score for MF400/F10 over placebo
were demonstrated at weeks 4, 13, and
26. However, the MF200/F10 dosage
did not achieve the minimum clinically
important difference, with only a 2.82
reduction, compared with placebo.
with
Treatment
MF400/F10 was well tolDr. Darcy Marciniuk, FCCP,
erated, and the proporcomments: This registration
tion of patients reporting
study confirms prior findings
treatment-emergent adwith other similar agen-ts.
verse events during the
Co-mbination ICS/LABA
26-week
treatment
therapy once again led to eanperiod was similar beingful improvement in lung
tween treatment groups,
function, quality of life, and
ranging from 26% in the
exacerbations in this cohort
MF400/F10 group to
of patients with moderate to
33% in the F10 alone
very severe COPD.
group. The most common of these were
headache, upper respiratory tract infec- dence of oral candidiasis was low, occurtion, cough, COPD, and hypertension. ring in no more than 2.4% of any group
Pneumonia did not occur in more than (five of the MF 400 alone patients), he re1% of any treatment group. The inci- ported.
COMMENTARY
Continued from previous page
3
Carboplatinъ│╝ Pemetrexed ы│СэХйьЪФы▓Х: ECOG2, IIIB/IV эЩШьЮРьЧРьДЬ
ьГЭьб┤ъ╕░ъ░Д эЦеьГБ ьжЭыкЕ NSCLCьЧРьДЬ ьГЭьб┤ъ╕░ъ░Д 12ъ░ЬьЫФ
Survival Boosted With Carboplatin Plus Pemetrexed
More NSCLC patients alive at 1 year.
B Y PAT R I C E W E N D L I N G
IMNG Medical News
PATRICE W ENDLING /IMNG M EDICAL M EDIA
CHICAGO тАУ Coupling carboplatin
chemotherapy with pemetrexed significantly improved survival in the subset
of hard-to-treat patients with advanced
nonтАУsmall cell lung cancer and an Eastern Cooperative Oncology Group performance status of 2.
Progression-free survival increased
from a median of 3.0 months to 5.9
months (hazard ratio, 0.46; P less than
Overall survival increased from 5.6 to
9.1 months, Dr. Rogerio Lilenbaum said.
.001), and overall survival from 5.6
months to 9.1 months (HR, 0.57; P =
.001) with the addition of carboplatin to
pemetrexed (Alimta), according to final
results of a phase III trial.
This represents a 43% reduction in
the risk of death, with 43% of patients
on the combination alive at 12 months
vs. 18% on pemetrexed alone. None of
the patients had received prior
chemotherapy.
The results can be generalized to patients of all histologic subtypes who have
an ECOG performance status of 2, Dr.
Rogerio Lilenbaum said at the annual
meeting of the American Society of Clinical Oncology.
тАЬAlthough carboplatin plus pemetrexed may be a particularly suitable regimen in this population because of its
safety profile, we do not think these
results are unique to this regimen or
nonsquamous patients,тАЭ he said.
тАЬGiven the magnitude of the benefit
seen in this study, and the immediate
applicability of these data to clinical
practice, we urge the appropriate organizations to revise their guidelines,
which to this date, by and large, still
recommend single-agent therapy for
these patients.тАЭ
Patients with nonтАУsmall cell lung cancer (NSCLC) and an ECOG performance
status (PS) of 2 are ambulatory and can
care for themselves, but are unable to
work. The optimal management strategy for these patients remains unresolved
in the wake of mixed results from several
phase III trials, including the IFCT-0501
(Intergroupe Francophone de Cancerologie Thoracique 1501) trial of carboplatin and paclitaxel vs. vinorelbine
or gemcitabine (Gemzar) monotherapy
(Lancet 2011;378:1079-88) and the U.S.
Oncology trial of gemcitabine plus carboplatin vs. gemcitabine (J. Clin. Oncol.
2009;27:5808-15).
In contrast, the current results were
so robust that one audience member
asked whether they were тАЬcontaminatedтАЭ with patients with better performance status.
Discussant Dr. Gregory P. Kalemkerian, codirector of thoracic oncology at
the University of Michigan in Ann Arbor,
said the results clearly demonstrate тАУ as
other trials have suggested тАУ that twodrug regimens can improve response
rate and survival, and should be an option in PS 2 patients. He applauded the
investigators for choosing a tolerable
regimen and avoiding the тАЬcult of cisplatin,тАЭ but went on to say that PS 2 denotes a very heterogeneous population.
Thus, single-agent therapy should remain an option for very elderly patients,
those with excessive comorbidities, and
those who do not tolerate a two-drug
therapy.
Investigators at eight centers in Brazil
and one in the United States stratified
203 chemotherapy-naive patients with
stage IIIB or IV advanced NSCLC by
stage, age, and weight loss, and then
randomly assigned them to pemetrexed
500 mg/m2 or the same pemetrexed
dose plus carboplatin AUC (area under
the curve) 5 every 3 weeks for four cycles. All patients received folic acid, vitamin B12, and dexamethasone. The protocol was amended in May 2009 to
exclude patients with squamous cell histology, for which pemetrexed is not indicated.
Median follow-up was 6.1 months in
all patients. Their median age was 65
years, 95% had stage IV disease, twothirds were former smokers, and 81%
had adenocarcinoma histology. Squamous cell histology was slightly imbalanced at 11% of the single-agent and 3%
of the pemetrexed/carboplatin arm, but
the difference was not significant.
The overall response rate was 24%
with the combination vs. 10.5% with
pemetrexed alone (P less than .029), despite the fact that 33.3% and 23.3% of
patients, respectively, did not reach the
point of a formal response assessment,
said Dr. Lilenbaum, chair of solid tumor
oncology at the Cleveland Clinic Florida
in Weston.
The investigators repeated the survival
analysis excluding patients with squa-
mous cell or unknown histology, and
the hazard ratios were nearly identical
to the intent-to-treat population for both
progression-free and overall survival
(HR, 0.45 and 0.59, respectively).
Subgroup analyses revealed a significant reduction in the risk of death with
pemetrexed plus carboplatin in elderly
patients (HR, 0.49; P less than .015) and
never smokers (HR, 0.47; P less than
.035).
The use of second-line therapy was
similar, at 31% in the pemetrexed arm
and 29.5% in the combination arm. Docetaxel was most commonly used
among the pemetrexed-plus-carboplatin
patients (30% vs. 19%), whereas carboplatin was more common in the singleagent pemetrexed arm (31% vs. 15%).
Toxicity was mild, although the combination arm had slightly more grade
3/4 anemia (11.7% vs. 3.9%) and neutropenia (5.8% vs. 1%). Nonhematologic
toxicity was largely absent.
There were four treatment-related
deaths in the combination arm and none
in the pemetrexed alone arm (P = .121).
Dr. Lilenbaum disclosed research
funding from Eli Lilly, and a coauthor
reported serving as a consultant for Lilly.
Dr. Kalemkerian reported research funding from Lilly.
PULMONARY MEDICINE
4
CHEST Physician тАв December 2012
FDG-PETьЭД ьЭ┤ьЪйэХЬ ьаЬ 1ъ╕░ ы╣ДьЖМьД╕эПм эПРьХФ ьзДыЛи ьЬаьЪйьД▒ ыВоьХД
FDG-PET Performs Poorly in Lung Cancer Diagnosis
Results generalizable to clinical practice.
B Y PAT R I C E W E N D L I N G
IMNG Medical News
COMMENTARY
CHICAGO тАУ The diagnostic accuracy
of FDG-PET in lung cancer performed
below previous reports and varied widely among U.S. centers in a secondary
analysis of a large phase III clinical trial.
тАЬFDG-PET performed poorly for diagnosing nonтАУsmall cell lung cancer in a
national sample of clinical stage 1 patients,тАЭ Dr. Eric L. Grogan, FCCP, said
at the annual meeting of the American
Society of Clinical Oncology.
The current National Comprehensive
Cancer Network guidelines recommend
fluorodeoxyglucose positron-emission
tomography (FDG-PET) for the diagnosis of NSCLC based on studies showing
Dr. Lary Robinson, FCCP, comments: Although this report stems
from a secondary analysis of the
PET scan data obtained from an
ACOSOG (Z4031) clinical trial on using proteomic profiling to diagnose lung cancer,
nevertheless this analysis
of PET scan results
is quite useful and,
frankly, its results are expected. Current FDGPET scans have a large
number of false-positives and falsenegatives, especially in evaluating
smaller nodules and in areas where
fungal diseases are endemic. These
results reinforce my own experience
with PET scanning in lung cancer:
1) A PET scan is not a тАЬcancerтАЭ scan,
but rather itтАЩs a scan for metabolic
a high degree of accuracy for this diagnostic tool, notably a sensitivity of 94%
and a median specificity of 83% in a
meta-analysis of 40 studies (JAMA
2001;285:914-24).
Others have reported, however, that
FDG-PET performs poorly at single institutions in regions of endemic fungal
lung diseases (Ann. Thor. Surg.
2011;92:428-32 and Lung Cancer
2002;36:297-301), observed Dr. Grogan,
of Vanderbilt-Ingram Cancer Center in
Nashville, Tenn.
Among 682 patients in the American
College of Surgeons Oncology Group
(ACOSOG) Z4031 trial, the overall accuracy of FDG-PET was 73%, the sensitivity 82%, and the specificity only 31%.
The series is the largest to date evaluating the accuracy of FDG-PET in patients
activity (benign inflammatory lesions may well be strongly positive);
2) Do not assume an equivocally
sized PET-positive lymph node or
other distant area contains
cancer unless it is histologically confirmed (low specificity rates in PET); and 3)
There is a significant variability of the effectiveness
of the PET scan hardware
and the radiographic interpretation of scans based on
frequency of use and geographic location. PET scans are a
quite useful adjunct to lung cancer
diagnosis and staging, but the clinician must factor in the high falsenegative rate (in bronchioloalveolar
carcinomas, for example) and high
false-positive rate in their decision
making.
with known or suspected clinical stage 1
NSCLC. In addition, it is generalizable
to clinical practice because multiple
FDG-PET scanners were used and the
scans were performed in community
and academic centers and interpreted
by multiple radiologists, Dr. Grogan said.
тАЬResults of PET scans in this population should be interpreted cautiously,
and reasons for the poor test performance should be explored in other studies,тАЭ he said.
Discussant Dr. Tetsuya Mitsudomi,
chief of thoracic surgery at Aichi Cancer
Center Hospital in Nagoya, Japan, said
FDG-PET shows reasonable sensitivity
but very low specificity, compared with
previous studies.
тАЬI think this reflects the real world,тАЭ
he said. тАЬSo, the lung cancer diagnosis
cannot be made on the basis of PET
positivity alone.тАЭ
Investigators at 51 sites in 39 cities enrolled 969 patients with known or clinically suspicious stage 1 lesions between
2004 and 2006 to evaluate the value of
proteomic analysis in diagnosing NSCLC
(the results were presented at ASCO
2010). FDG-PET scans were available
for 682 patients. All underwent surgical
resection. Analyses were performed for
all patients and for sites with more than
25 patients.
PET avidity was determined by the
radiologistтАЩs description of lesion activity
or by the reported maximum standard
uptake value (SUV). Avidity was classified in four categories: category 1 was
no avidity/not cancer (SUV = 0), category 2 was low avidity/not likely cancer
(SUV 0 to less than 2.5), category 3 was
avidity/possibly cancer (SUV 2.5 to less
than 5.0), and category 4 was high avidity/likely cancer (SUV 5.0 or more).
Among the 682 patients, there were
566 cancers and 116 benign cases. In all,
82% of the cancerous lesions were PET
avid, and тАЬsurprisingly, 69% of the benign lesions were avid,тАЭ Dr. Grogan said.
Patients with cancer were significantly
older (67 vs. 61 years; P less than .001)
and had larger lesions (26 mm vs. 20
mm; P less than .001).
The positive predictive value of FDGPET was 85% and negative predictive
value 26%. This translates into 80 false
positives and 101 false negatives. The
majority of false positives were granulomas (69%), he observed. Eleven of the
false negatives were 10 mm or less.
Not surprising, FDG-PET accuracy
improved with lesion size, Dr. Grogan
said. The accuracy was less than 50%
for lesions less than 20 mm, but greater
than 80% for lesions larger than 30 mm.
тАЬAbove 30 mm, the accuracy did not
seem to improve,тАЭ he observed.
In the eight cities with more than 25
patients, the sensitivity varied significantly, from a low of 67% in Los Angeles
to a high of 91% in Durham, N.C. (P =
.03), Dr. Grogan said, without explanation. Specificity ranged from 15% in
Birmingham, Ala., to 46% in Philadelphia, but this did not reach statistical
significance because of the small number
of benign cases at each institution (P =
.72).
Dr. Mitsudomi said he could not explain the reason for the heterogeneity,
especially in terms of the specificity, between centers.
тАЬItтАЩs not possible to remove all the
false positives if you use FDG, but newer
tracers are being developed and they
may increase the specificity rate,тАЭ he
added.
Dr. Grogan reported no disclosures.
Dr. Mitsudomi reported having a consulting/advisory role with Boehringer
Ingelheim, Kyowa Hakko Kirin, Lilly,
and Pfizer, and receiving honoraria from
AstraZeneca, Chugai Pharma, Lilly, and
Roche.
Delamanid, MDR TB ь╣ШыгМьЧР эХЬыЛиъ│Д ьЧЕъ╖╕ыаИьЭ┤ыУЬ
Delamanid Boosts Treatment Punch in Resistant TB
BY MICHELE G. SULLIVAN
IMNG Medical News
C
ombining the investigational drug delamanid
with standard tuberculosis treatment significantly increased sputum-culture conversion
rates in multidrug-resistant tuberculosis, an international study showed.
The results could be particularly good news for China, which now has one-quarter of the worldтАЩs cases of
MDR TB, according to a second study.
In the delamanid study, the conversion proportion
was 45% after 2 months of treatment among those
who received the new drug plus standard therapy,
compared with a 30% rate for standard therapy alone,
Dr. Maria T. Gler and her coauthors reported.
тАЬIt is important to learn more about the use of delamanid in combination with other new and existing
antimycobacterial agents to develop better regimens
for multidrug-resistant tuberculosis,тАЭ wrote Dr. Gler,
of Makati Medical Center and the Tropical Disease
Foundation, Makati City, Philippines, and her colleagues (N. Engl. J. Med. 2012;366:2151-60).
Delamanid, which inhibits mycolic acid synthesis,
has shown effectiveness against drug-susceptible and
drug-resistant strains of Mycobacterium tuberculosis
in preclinical tests.
The team investigated the drugтАЩs effect at 200
mg/day and 400 mg/day, plus a background treatment
regimen approved by the World Health Organization
for MDR TB. A placebo group received only the background treatment тАУ the current standard of care. The
2-month study was carried out in nine countries: China,
Egypt, Estonia, Japan, Korea, Latvia, Peru, the Philippines, and the United States.
The study group included 481 patients with sputum
cultureтАУproven MDR tuberculosis infections. The patientsтАЩ mean age was 35 years. More than 90% of the
group had received prior treatment for tuberculosis,
including 50% who had already taken only first-line
antitubercular agents and 40% who had received a
second- or third-line agent. Only four of the patients
were coinfected with HIV.
By the end of 2 months, both groups receiving delamanid had significantly higher proportions of sputumculture conversion than the placebo groups. Similar
conversion proportions occurred in both active groups:
45% of the 200-mg/day delamanid group, and 42% of
the 400-mg/day group. Conversion in the placebo
group (30%) was significantly less than in both of the
active groups.
The time to conversion also differed significantly
between the active and placebo groups, with conversion proportions beginning to separate by 30 days of
treatment.
There were more adverse events in the delamanid
groups, although the investigators found that only the
incidence of QT prolongation was significantly less in
the placebo group (4%) than in the 200- and 400mg/day delamanid groups (10% and 13%, respectively).
None of the arrhythmias were clinically significant,
Continued on following page
PULMONARY MEDICINE
Continued from previous page
ZVITALS
they noted.
There were no between-group differences in the
rate of hepatotoxicity. One patient died from TB during
the trial.
A longer trial is underway to more closely examine
delamanidтАЩs effect on the hard-to-treat disease in patients taking antiretroviral drugs for HIV infections.
Finding an effective treatment for MDR tuberculosis
is especially important in China, which has the greatest
number of cases in the world, Yanlin Zhao, Ph.D., reported in an accompanying study (N. Engl. J. Med.
2012;366:2161-70).
Dr. Zhao, of the Chinese Center for Disease Control
and Prevention, and colleagues reported on a national
disease survey conducted in 2007. The survey showed
that about 110,000 MDR cases were reported that
year, and that 8,200 showed extensive drug resistance
(XDR) тАУ defined as resistance to isoniazid, rifampin,
ofloxacin, and kanamycin.
Major Finding: Delamanid combined with a standard tuberculosis treatment regimen was associated with significantly
greater sputum-culture conversion rates than standard treatment alone (45% vs. 30%) in patients with MDR TB.
Data Source: This was a 2-month placebo-controlled trial of
481 patients with MDR TB.
Disclosures: Otsuka Novel Products sponsored the study. Dr.
Gler reported that she has received consulting fees from the
company.
ChinaтАЩs prevalence rate of multidrug resistance
among new cases of tuberculosis was 3.5 times greater
than the global median, and nearly twice the global
average.
тАЬWith the use of the World Health Organization estimate of multidrug-resistant tuberculosis in various
countries as a reference, China has the highest annual
number of cases of MDR tuberculosis in the world тАУ a
quarter of the cases worldwide,тАЭ the authors wrote.
A number of factors were linked to drug-resistant
disease. Patients with multiple previous treatments тАУ
with the most recent taken in a tuberculosis hospital тАУ
were at the highest risk.
Poor compliance also influenced drug resistance. In
a subanalysis of 226 patients who had received prior
treatment, 44% had not completed their prior regimen.
Among the 127 patients who had completed treatment,
115 had relapsed TB, and 62% had received that last
treatment in the Chinese Center for Disease Control
(CDC) system.
тАЬThis finding points to the need for interventions
that will increase the continuity of treatment and reduce
the rate of treatment default, especially among patients
treated within the hospital system,тАЭ the authors noted.
Because national facilities provide limited followup, the Chinese Ministry of Health has strengthened
the hospitalsтАЩ follow-up capabilities, they added.
More needs to be done, however, they noted. ChinaтАЩs CDC system, which is responsible for monitoring
patients with tuberculosis in the community, could
COMMENTARY
December 2012
5
Dr. Marcos Restrepo,
FCCP, comments: There
is a great need for finding
new alternatives to treat
patients with multidrugresistant tuberculosis, and
it seems that delamanid
may have efficacy in addition to the standard tuberculous medications.
Although the results are encouraging for countries like China, where higher rates of MDR
tuberculosis are a major public health problem,
the agentтАЩs higher rate of QT prolongation
may need further evaluation regarding patient
safety.
test new approaches to improving adherence to treatment, such as mobile-phone text messaging, and expand such approaches if they prove to be effective.
Improvements are imperative, the study authors cautioned, as the future does not bode well. About 11% of
new cases and 16% of previously treated cases are already resistant to either isoniazid or rifampin, тАЬplacing
them one step away from having MDR tuberculosis.тАЭ
In addition, in patients with MDR but not XDR tuberculosis, more than one-third of cases were resistant
to either ofloxacin or kanamycin тАУ leaving those patients also just one step away from XDR tuberculosis.
Afatinib: EGFR mutated lung cancerьЧРьДЬ
Pemetrexed/Cisplatinы│┤ыЛд ым┤ьзДэЦЙ ьГЭьб┤ъ╕░ъ░Д 2ы░░
Afatinib Beats Chemo in EGFR-Positive Lung Cancer
B Y PAT R I C E W E N D L I N G
IMNG Medical News
VITALS
CHICAGO тАУ First-line afatinib delayed progression
for nearly a year in patients with advanced lung cancer
carrying epidermal growth factor mutations, according
to much-anticipated results from the phase III LUXLung 3 trial.
Median progression-free survival reached 11.1 months
with the experimental oral agent, compared with 6.9
months with cisplatin plus pemetrexed (Alimta)
chemotherapy (hazard ratio, 0.58; P = .0004), investigators reported. At 1 year, more than twice as many patients were progression free on afatinib (47% vs. 22%).
The median reached 13.6 months in afatinib-treated
patients who harbored the most common EGFR mutations тАУ exon deletion 19 or exon 21 L858R тАУ which
account for 90% of all EGFR mutations, but stayed at
6.9 months in the control group (HR, 0.47; P less than
.0001). The progression-free survival rate in those with
EGFR mutations was more than twice as high at 1
year with afatinib (51% vs. 21%).
Patients who were treated with the novel, secondgeneration tyrosine kinase inhibitor (TKI) also had
better sustained tumor shrinkage and improved quality
of life than did those treated with standard cisplatin
plus pemetrexed chemotherapy, Dr. James Chih-Hsin
Yang said at the annual meeting of the American SociMajor Finding: Progression-free survival was 11.1
months with afatinib and 6.9 months with cisplatin plus pemetrexed (HR, 0.58; P = .0004).
Data Source: Investigators conducted a phase
III, open-label, randomized trial in 345 patients
with advanced adenocarcinoma harboring EGFRactivating mutations.
Disclosures: Dr. Yang reported serving as a consultant or adviser and receiving honoraria from Boehringer Ingelheim, the
study sponsor. Several coauthors had financial relationships
with firms including Boehringer Ingelheim. Dr. Solomon
reported serving as a consultant or adviser to
AstraZeneca, Boehringer Ingelheim, Clovis
Oncology, Lilly, Pfizer, and Roche.
ety of Clinical Oncology.
Overall survival data, from what was described as
the largest global prospective trial in EGFR mutationтАУ
positive lung cancer to date, are expected in about
18-24 months, he said.
The available data cannot, however, answer questions of how afatinib compares against the first-generation TKIs in this setting, nor whether the increased
efficacy outweighs any additional toxicity, said discussant Benjamin J. Solomon, Ph.D. Notably, the LUXLung 7 trial has begun comparing afatinib 40 mg/day
with gefitinib 250 mg/day in EGFR mutationтАУpositive,
nonтАУsmall cell lung cancer.
In the current trial, the efficacy of afatinib came at a
cost of increased rates of diarrhea, rash, stomatitis, and
paronychia that appear higher than those seen with
the first-generation TKIs, added Dr. Solomon of the
lung cancer service at AustraliaтАЩs Peter MacCallum
Cancer Centre in East Melbourne, Victoria. Still, the
rate of afatinib discontinuation was lower than with
chemotherapy.
LUX-Lung 3 investigators at 133 sites in 25 countries
in North and South America, Europe, and Asia randomized 345 chemotherapy-naive patients with stage
IIIB or IV adenocarcinoma of the lung and EGFR mutations confirmed by central lab testing. In all, 230
were assigned to afatinib 40 mg daily and 115 to intravenous pemetrexed (500 mg/m2) plus cisplatin (75
mg/m2) every 21 days for up to six cycles.
In all, 61% of patients had an ECOG (Eastern Cooperative Oncology Group) performance status of 1, 65%
were women, 72% were Asian, 89% had stage IV disease, 49% had the exon 19 deletion, 40% had the L858R
mutation, and 11% had other mutations. Their median
age was 61 years. Median follow-up was 16.4 months.
The investigators had hypothesized that afatinib
would be stronger than first-generation, reversible
EGFR TKIs because it irreversibly binds to and inhibits
the entire ErbB family of receptors (ErbB1, HER2,
ErbB3, and ErbB4). The ErbB family plays a critical
role in tumor cell growth and is overexpressed or mutated in most cancers, including lung cancers.
In all, 56% of afatinib and 22.6% of the chemotherapy
patients had an objective response by independent review (P less than .001), said Dr. Yang of the National
Taiwan University Hospital in Taipei. The median duration of response was 11.1 months with afatinib vs.
5.5 months with chemotherapy.
There was also a delay in the time to deterioration
of the lung cancerтАУrelated symptoms of cough (HR,
0.60; P = .007), dyspnea (HR, 0.68; P = .015), and pain
(HR, 0.83; P = .19).
A subgroup analysis revealed that the benefit of afatinib on progression extended to most subgroups, including different races and EGFR mutations, neversmokers, and smokers with less than 15 pack-years
who had stopped for at least 1 year, he said. Only current and тАЬotherтАЭ ex-smokers did not benefit.
Quality of life for those treated with afatinib was
better than with cisplatin plus pemetrexed in all five
domains measured on the EORTC (European Organisation for Research and Treatment of Cancer) Quality
of Life QuestionnaireтАУC30 including physical, cognitive,
and social functioning.
The most common grade 3 adverse events with afatinib were diarrhea (14.4%), rash (16.2%), stomatitis/
mucositis (8.3%) and paronychia (11.4%), with one
case of grade 4 stomatitis/mucositis (0.4%). There
were four deaths related to afatinib.
The duration of treatment likely had an impact on
adverse events, as patients received 16 cycles of afatinib
(median, 336 days) vs. just 6 cycles of chemotherapy,
Dr. Yang pointed out. Drug-related adverse events
leading to discontinuation were reported in 7.9% of
patients who were given afatinib and in 11.7% of those
given cisplatin plus pemetrexed chemotherapy.
Finally, Dr. Solomon said that тАЬas impressive as the
progression-free survival seen with afatinib is тАж all
these patients eventually develop acquired resistance.тАЭ
He highlighted a recent study in which the T790M
secondary mutation was implicated as a mechanism of
acquired resistance to second-generation irreversible
TKIs in a clinical case and in an in vitro cell culture
model (Mol. Cancer Ther. 2012;11:784-91).
PULMONARY MEDICINE
6
CHEST Physician тАв December 2012
Erythromycin, ъ╕░ъ┤АьзАэЩХьЮеьжЭьЭШ ьХЕэЩФ ъ░РьЖМьЩА ьжЭьГБ ъ░ЬьДа
Bronchiectasis Responds Well to Erythromycin
IMNG Medical News
VITALS
SAN FRANCISCO тАУ Long-term, low-dose erythromycin
reduces pulmonary exacerbations, sputum production,
and breathing problems in patients with nonтАУcystic fibrosis
bronchiectasis, according to a randomized, placebocontrolled Australian study.
Low-dose erythromycin also may be less likely to induce antibiotic resistance than is azithromycin, the usual
choice for prophylaxis. For these reasons, erythromycin
should be considered for non-CF bronchiectasis, said
lead investigator Dr. David Serisier at an international
conference of the American Thoracic Society.
A total of 59 nonsmoking adults with the disease
were randomized to erythromycin ethylsuccinate 400
mg twice daily and 58 to placebo, for 48 weeks. (The
dosage of the better-tolerated salt is the equivalent of
250 mg of erythromycin b.i.d.) All patients had at
least two infective exacerbations in the preceding
year, said Dr. Serisier, a chest physician and
Major Finding: Non-CF bronchiectasis patients
have almost 40% fewer exacerbations when
treated with low-dose erythromycin, compared
with placebo.
Data Source: Data are from a randomized,
double-blind, placebo-controlled 48-week trial in
117 patients with non-CF bronchiectasis.
Disclosures: Dr. Serisier said he had no relevant disclosures.
associate professor of medicine at the University of tance, according to a randomized Belgian trial that
Queensland in Brisbane.
found a 53.4% increase (P less than .0001) in macrolideThe erythromycin group had almost 40% fewer ex- resistant oral streptococci after just 3 days of treatment
acerbations (odds ratio, 0.64; 95% confidence interval (Lancet 2007;369:482-90).
тАЬWe are not exactly comparing apples with apples,
[CI], 0.48-0.86; P = .02), corresponding to a mean reduction of 0.7 exacerbations per patient per year. About but thereтАЩs a suggestion that this effect is less with erya third of the erythromycin patients (19) and more thromycin,тАЭ even after an entire year of therapy, Dr.
than half (30) of the placebo patients had two or more Serisier said.
exacerbations during the trial (P = .039). One eryEven so, erythromycin тАЬshould be reserved for subthromycin patient was withdrawn for possible QTc jects who have evidence of more severe airway infecprolongation.
tion. I donтАЩt think itтАЩs something we should be throwFEV1 declined slightly in both groups, but more so ing at all non-CF bronchiectasis patients, and not
in the placebo arm, with a treatment effect of 2.02% those who just have a mild, troublesome cough. I
(95% CI, 0.04-4.2; P = .046) in favor of erythromycin. want this drug to be used in patients who really need
Erythromycin patients also produced about 6 g less of it,тАЭ he said.
sputum per day.
By studyтАЩs end, about
36% of oropharyngeal
Dr. Marcos I. Restrepo,
compared with placebo.
streptococci isolates in the
FCCP, comments: This
However, despite no diferythromycin group were
study provides more eviferences in QT prolongresistant vs. about 5% in
dence suggesting that
ation, the higher rate of
the placebo group (P less
macrolides (e.g., eryerythromcyin-resistant
than .0001). тАЬErythromycin
thromycin) used as impathogens in the eryresulted in a very substanmunomodulators imthromycin-treated group is
tial increase in the proporproved outcomes in
cause for concern. Clinition of macrolide-resistant
non-CF bronchiectasis.
cians should be cautious in
streptococci,тАЭ Dr. Serisier
Erythromycin reduced
generalizing this informsaid.
the number and frequency of exac- ation and assessing the clinical benefit
Azithromycin, howeverbations and resulted in less decline with the risk of adverse events and
er, appears to be a more
in FEV1 and less sputum production, antimicrobial resistance.
potent inducer of resis-
COMMENTARY
BY M. ALEXANDER OTTO
ы░▒ьЭ╝эХ┤ьЭШ ьЬаэЦЙ: ы░▒ьЛаьЭ┤ ьЬаьЭ╝эХЬ ыМАьХИ
Whooping Cough Epidemic: Vaccination Is Key
B Y E L I Z A B E T H M E C H C AT I E
IMNG Medical News
T
he current pertussis epidemic in
Washington state and increased
rates being seen nationwide underline the critical importance of pertussis
vaccination in pregnant women and
other adults who are in contact with babies, Dr. Anne Schuchat said during a
Centers for Disease Control and Prevention telebriefing.
Reports of pertussis have been increasing in infants, as well as among children
aged 10, 13, and 14 years in Washington
and nationwide, making the recommended Tdap booster vaccine
essential for children, said Dr. Schuchat,
director of the National Center for Immunization and Respiratory Diseases at
the CDC in Atlanta.
Pertussis vaccination тАЬremains the single most effective approach to preventing infection,тАЭ she said, noting that unvaccinated children are at an eightfold
greater risk of getting pertussis than are
those who have been fully vaccinated
with DTaP. And vaccinated children
who do contract pertussis typically have
milder cases.
In 2010, only 8% of adults had any
history of having ever received a Tdap
booster, she said.
In addition to encouraging patients
to get vaccinated, clinicians are being
urged to consider pertussis as a possible diagnosis in their patients who
have a persistent cough, she
said.
Since the middle
of 2011, cases of
pertussis have
been increasing in Washington state,
and in April
2012, a pertussis epidemic was
declared after 640 cases
had been reported. As of
June 16, 2,520
cases had been reported in 2012, a
1,300% increase from the
same time period the year before,
and the highest number of cases reported
since the early 1940s (MMWR 2012;
61:517-22).
To date, nine babies in the United
States have died of whooping cough
(one more than reported in the
MMWR), Dr. Schuchat reported.
A higher-than-expected number of cases also have been reported in other
states, with similar trends in the age
groups affected, тАЬand there may be many
more coming,тАЭ Dr. Schuchat said. In
2010, more than 27,000 cases were reported nationally, with 27 deaths (25 in
infants).
Pertussis outbreaks occur in
waves, with peaks every
3-5 years.
During this current wave, the
women and adults who are around babies are being urged to get vaccinated,
she said.
The rates of pertussis have started to
increase after late childhood, with a higher rate in 10-year-olds. Although the rate
decreases in 11- to 12-year-olds, it subsequently increases again among 13-yearolds, Dr. Schuchat said. These trends
also point to the importance of the recommended Tdap booster vaccine in
those aged 11 and 12 years.
The increase in pertussis cases reported in adolescents aged 13-14 in
Washington state and nationThe number of
ally is a concern, and possible
pertussis cases is
causes are being studied furthe highest since
ther. A contributing factor
the early 1940s
could be the switch from the
(gram-stained
whole cell to the acellular
photomicrograph at
vaccine, which may have an
left depicts the
effect on how long immunity
Bordetella pertussis persists. тАЬWaning of protecbacteria, the
tion over time may be part of
etiologic pathogen
the story,тАЭ she said. Howevfor pertussis).
er, she pointed out that unvaccinated people are not
highest rates have been thought to be driving this current
in infants under 1 year of wave of infection.
age, with over half in babies under
Dr. Schuchat said that the increase in
3 months. These children are too pertussis cases goes beyond Washington
young to be protected by the vaccine state.
that is first administered at age 2
тАЬWe really think the disease is spreadmonths, so they are dependent on the ing around the country. тАжWeтАЩre in for
immunity of people around them. This a tough year and a tough couple of
gap in immunity is why pregnant years,тАЭ she said.
C OURTESY CDC
Pertussis cases have increased 1,300% from the
same time period last year.
PULMONARY MEDICINE
December 2012
7
ьЮЕьЫРэЩШьЮР ыМАьГБ эФДыбЬэЖаь╜Ь ъ░ЬьДаьЬ╝ыбЬ ыПЕъ░РьШИы░йьаСьвЕыеа эЦеьГБ ъ░АыКе
Inpatient Protocols Can Up Flu Vax Rates
┬йC ATHERINE L ANE / I S TOCKPHOTO . COM
cines while you have them there,тАЭ to protect them
against influenza, and also pneumococcal disease, he
said.
Inpatient
But itтАЩs not always an easy thing to do, Dr. Talbot
influenza
said.
immunization
тАЬIt is challenging to implement an inpatient vaccinabecame a
tion program,тАЭ he said. тАЬDuring a hospitalization, you
Joint
are trying to get the patient supported for the illness
Commission
that brought them into the hospital. You donтАЩt want
core measure
to do anything that may interrupt that care plan,тАЭ he
set for hospital
said.
accreditation
тАЬI think the places that have seemed to hard-wire [a
programs in
vaccination program] have locked it into a nurse-diJanuary 2012.
rected order set that may be implemented upon discharge, along with education. Or, [it] may be impleBY HEIDI SPLETE
mented a few days into the hospitalization so as to
IMNG Medical News
avoid that first 48 hours when a lot of activity is happening around the acute illness,тАЭ Dr. Talbot said. This
tтАЩs late October, and a 70-year-old woman with a approach helps ensure that vaccination doesnтАЩt fall off
medical history of type 2 diabetes and hypothy- the radar, and allows time to get the vaccine as well as
roidism, as well as a remote history of laryngeal educate patients, he said.
cancer, presents with a COPD exacerbation. The
тАЬOne of the challenges with this type of program is
records say she hasnтАЩt had a flu shot. Would she get making sure that the patientтАЩs outpatient provider is
one at your center?
aware that they have received immunizations,тАЭ Dr.
Experience says if thereтАЩs a protocol in place designed Talbot added. тАЬWe donтАЩt want individuals to get an
for people like her, sheтАЩs in luck. But if thereтАЩs not тАж unnecessary additional flu shot or pneumococcal vacher case points to room for quality improvement.
cination.тАЭ Documentation and communication are key
тАЬThe reason vaccinating patients has become a safety factors, as is having a mechanism in the health care fameasure is that we have found that many patients will cility or hospital to track vaccinations so a returning
encounter health care by being seen in an emergency patient does not receive a second vaccine unnecessarily,
department, being admitted to a hospital, or being he said.
seen by their physician, and not receive the recomAnother challenge to implementing inpatient immended vaccines, and later go on to develop illnesses munization is the concern that some sick patients who
that might be quite serious,тАЭ said Dr. Thomas Talbot, receive a flu vaccine wonтАЩt mount the same immune
author of the Society for Healthcare EpidemiologyтАЩs response as they would while healthy, Dr. Talbot said.
vaccination guidelines and chief hospital epidemiologist
тАЬIn particular populations, such as those immediately
at Vanderbilt University Medical Center in Nashville, post transplant, where we know that the immune reTenn.
sponse would not be robust, immunization should be
тАЬThese are missed opportunities when we have had deferred,тАЭ he emphasized.
patients in our health care system and havenтАЩt taken
тАЬHowever, there is no evidence to suggest that
advantage of the opportunity to vaccinate them,тАЭ Dr. giving a vaccine during a hospitalization will adversely
Talbot said.
impact the course of most illnesses for which people
тАЬThat has been the impetus for a lot of new quality are admitted,тАЭ he said.
measures for those patients who are admitted to the
Dr. Talbot also emphasized the importance of vachospital. Once their acute issue has been cared for and cination for health care workers. (See box below.)
they are getting ready to go home, get them their vacIn developing its Hospital Inpatient Quality measures, the Joint Commission looked to a 2006 National Quality Forum
workgroup recommendammunization. ItтАЩs not just for pa- formation about barriers to successful
tion that тАЬinfluenza and
flu vaccine programs along with
tients anymore. But was it ever?
pneumococcal vaccinaтАЬIt is extremely important for strategies for overcoming them. The
tion measures should aphealth care workers to get vaccinated Centers for Disease Control and Preply to all patients regardevery year,тАЭ said Dr. Talbot. Health vention has also weighed in, recomless of diagnosis.тАЭ
care workers are diligent by nature, mending flu vaccination for all health
As of August 2012, a
and they often come to work when care personnel, based on the advice
proposal from the Centers
they are sick, he said. Also, healthy of the Advisory Committee on Imfor Medicare and Medicadults often shed the flu virus before munization Practices and the Hospital
aid Services requiring certhey are infected, and they might Infection Control Practices Advisory
tain Medicare providers
attribute a runny nose or early flu Committee.
and suppliers to offer all
According to the CDC, health care
symptoms to a cold, he added.
eligible and consenting paSafety issues aside, some hospitals facilities should offer easy-access vactients flu vaccination durand organizations have made immu- cination sites and тАЬtargeted education
ing flu season had not
nization a condition of employment, about the disease, including disease
been approved, and flu
Dr. Talbot said. тАЬIt is now being seen risk among HCP and patients, and
vaccination policies and
as a professional responsibility,тАЭ he about the vaccine.тАЭ
practices vary among hosтАЬYou have to really try to address
said. The Joint Commission made staff
pitals.
immunization a core measure for hos- the misconceptions of the vaccine and
However, inpatient imthere are things that are not proven
pitals in July of this year.
munization is becoming a
Dr. Talbot served on the review by science,тАЭ Dr. Talbot said.
quality measure for hosFlu immunization programs for
panel for тАЬStrategies for Implementpitals, and it will be necing Successful Influenza Immuniza- health care workers are more likely to
essary for reaccreditation,
tion Programs for Health Care Per- succeed if they are presented in a nonaccording to the Joint
sonnel Project.тАЭ A 10-month effort adversarial way, with an emphasis on
Commission. Starting on
completed in 2009, the Joint Com- improving safety for patients, Dr. TalJan. 1, 2012, inpatient inmission project sought to provide in- bot added.
fluenza immunization officially became a core
I
Stopping the Flu Starts With You
I
measure set for hospital accreditation programs, and
will be phased in over time for different programs.
Polishing a Protocol
An inpatient immunization program is working in
Boston at Beth Israel Deaconess Medical Center.
BIDMC first initiated an inpatient flu immunization
protocol in 2006, and it has been refined over time, according to Dr. Alexander Carbo, a hospitalist in the division of general medicine and primary care at BIDMC;
Jaime Levash, project administrator for QI and professional development; and Margie Serrano, RN, who
work together as part of the medical centerтАЩs Influenza
Inpatient Immunization Initiative. They described the
BIDMC protocol as follows:
тЦ╢ When adult patients (aged 18 years and older) are
admitted to BIDMC, the online medical record automatically checks to see when patients have been immunized (or have contraindications such as an allergy).
тЦ╢ If the patientтАЩs vaccine status is unknown in the
BIDMC system, or if the patient previously refused
vaccine, upon admission the ordering providers are
prompted to write for the influenza vaccine protocol,
or to provide a reason for not initiating the protocol
(such as a prior immunization, or allergy).
тЦ╢ If the protocol is initiated, the nursing staff screens
the patient for appropriateness for vaccine and then either provides vaccine (with documentation) or documents the contraindication in the online medical
record.
тЦ╢ During subsequent admissions, providers will be
reprompted to write for the vaccine protocol if the patient previously refused vaccine or if vaccine was not
given (for a reason other than listed contraindications);
otherwise, the prompt will not appear (the computer
system tracks prior immunizations and contraindications, so as not to revaccinate patients or reprompt for
patients with contraindications during the same influenza season).
The BIDMC team has tweaked the protocol over
time to make it more effective at the 650-bed center.
For example, тАЬwe have added a hard stop at discharge
to ensure that each patientтАЩs immunization status is
accounted for during their admission,тАЭ Dr. Carbo said.
Plans for the 2012-2013 flu season are similar to last
yearтАЩs protocols, but will incorporate some of the
newer CDC guidelines for immunizing patients with
egg allergies, Dr. Carbo said.
In addition, тАЬBIDMC mandates immunization for
all employees in patient care areas (allowing exceptions for previously noted contraindications) and
strongly encourages vaccination for all other staff,тАЭ
he noted.
Dr. CarboтАЩs advice to physicians about how to succeed in inpatient immunizations: тАЬWork with a multidisciplinary team,тАЭ he said. тАЬWhen we started in 2006,
I did this in collaboration with one of the nursing leaders. Now we have a multidisciplinary team that includes
representatives from the nursing staff, the pharmacy
staff, information systems, and communications,тАЭ he
said.
Read the Sign
The 566-bed University of Wisconsin Hospital Center
(UWHC) in Madison is also harnessing the power of
protocol.
тАЬWe realized that, as one of our quality control
measures, we were monitoring what proportion of
our patient population was being vaccinated against
pneumonia and influenza and we werenтАЩt doing as
well as we would have liked,тАЭ said Dr. Nasia Safdar,
hospital epidemiologist for the UWHC.
Immunizing inpatients was a top choice among
UWHCтАЩs efforts to optimize vaccination, but тАЬit turned
out quickly that it was easier said than done,тАЭ Dr.
Continued on following page
8
PULMONARY MEDICINE
Continued from previous page
Safdar said.
The Wisconsin hospital faced the challenge with a
protocol similar to the one used at BIDMC. тАЬIt took a
lot of the repeated questioning and thinking out of the
equation because everyone is familiar with the protocol,тАЭ Dr. Safdar said. тАЬIf a patient meets the criteria,
they will be vaccinated.тАЭ
CHEST Physician тАв December 2012
Status is checked upon admission, and barring any
specific objection or event, eligible patients get the
vaccine at some point during their relationship with
the Wisconsin hospital. For example, a transplant patient would not receive a vaccine at the time of the
hospital stay for the transplant, but could be vaccinated
at a follow-up visit 6 months later, she
explained.
тАЬAnother thing we have done is to put notices on
patientsтАЩ doors that say,
тАШEligible for Vaccination Before Discharge,тАЩ and the
pharmacist, who is typically involved in the discharge
medication process, knows right away that this is a patient who needs to be vaccinated,тАЭ she said. тАЬIt is a visible marker of something that needs to be done,тАЭ Dr.
Safdar said.
Dr. Talbot, Dr. Carbo, and Dr. Safdar reported having no financial conflicts to disclose.
Pemetrexed ьЬаьзАьЪФы▓ХьЭ┤ ы╣ДьЖМьД╕эПмэПРьХФ эЩШьЮРьЭШ
ьГЭьб┤ьЬиьЭД ъ░ЬьДаьЛЬэВм ьИШ ьЮИыЛд
B Y PAT R I C E W E N D L I N G
IMNG Medical News
COMMENTARY
CHICAGO тАУ Final results of the phase
III PARAMOUNT trial support continued use of pemetrexed after pemetrexedplus-cisplatin induction therapy for advanced, nonsquamous nonтАУsmall cell
lung cancer.
More patients on pemetrexed (Alimta)
maintenance were alive at 1 year (58%
vs. 45% of the control group) and 2 years
(32% vs. 21%), Dr. Luis Paz-Ares said at
the annual meeting of the American Society of Clinical Oncology. With nearly
all patients off study treatment, median
overall survival from randomization was
13.9 months with pemetrexed maintenance plus best supportive care (BSC)
vs. 11.0 months with BSC plus placebo.
This translates into a 22% reduction
in the risk of death (hazard ratio [HR],
0.78; log-rank P = .0195). An analysis of
overall survival from the start of inducDr. Jeana OтАЩBrien, FCCP,
comments: This phase III trial
of different chemotherapeutic
regimens for patients with
advanced
nonsquam o u s
NSCLC
showed a
small improvement
in median
survival.
Additional
investigation is warranted to determine overall benefit.
tion yielded the same risk reduction,
with the median reaching 16.9 months
in patients maintained on pemetrexed
vs. 14.0 months in the control group
(HR 0.78; log-rank P = .0191).
The benefit of pemetrexed maintenance was consistent across all subgroups, including patients with a complete or partial response (HR 0.81) and
those with stable disease (HR 0.76) after
induction therapy, Dr. Paz-Ares said.
тАЬThis is the first study to show that
continuation maintenance had a clear
impact on the natural courseтАЭ of advanced NSCLC, including an improvement in progression-free survival and
overall survival, and тАЬmay support a
change in the treatment paradigm in
this clinical setting,тАЭ said Dr. Paz-Ares
of University Hospital Virgen del Rocio
in Seville, Spain.
тАЬI think we should share with our patients the information about the role of
maintenance treatment, but it doesnтАЩt
mean that every single patient should
be treated in this way,тАЭ he said.
At last yearтАЩs ASCO meeting, the investigators reported that pemetrexed
maintenance significantly reduced the
studyтАЩs primary end point, the risk of
disease progression (HR 0.62) (Lancet
Oncol. 2012;13:247-55).
The overall survival data were not
mature at the time, leaving some clinicians to question the overall efficacy of
pemetrexed maintenance and whether
the delay in progression was enough to
justify the potential increased toxicity
with continued therapy.
In the PARAMOUNT trial, 939
chemotherapy-naive patients with advanced nonsquamous NSCLC, at least
one measurable lesion, and an ECOG
PATRICE W ENDLING /IMNG M EDICAL M EDIA
Pemetrexed Maintenance May Up Survival in NSCLC
The results of this study тАЬmay support a change in the treatment paradigm,тАЭ Dr.
Luis Paz-Ares said.
performance status of 0 or 1 received four
cycles of induction pemetrexed 500
mg/m2 plus cisplatin 75 mg/m2 on day 1
of a 21-day cycle. The 539 patients who
responded were stratified by disease stage,
performance status, and induction response and randomly assigned to maintenance with pemetrexed 500 mg/m2 every
21 days plus BSC or to BSC and placebo.
The median age was 61 years, about
90% of patients had stage IV disease,
86%-89% had adenocarcinoma histology, and 42%-44% had a complete or
partial response to induction therapy.
The mean number of maintenance cycles was 7.9 (range 1-44) for the 359
pemetrexed patients and 5 cycles for the
180 placebo patients (range 1-38). Median follow-up for all patients was 12.5
months, and reached 24.3 months
among all patients still alive.
Reassessment of progression-free survival at final analysis once again favored
pemetrexed (HR 0.60), confirming the
robustness of the results, Dr. Paz-Ares
said.
The pemetrexed maintenance arm
had more grade 3/4 events than did the
placebo arm, notably fatigue (4.7% vs.
1.1%), anemia (6.4% vs. 0.6%), and neutropenia (5.8% vs. 0%).
In all, 64% of the pemetrexed arm and
72% of the placebo arm received postdiscontinuation therapy, mainly erlotinib
(40% of the pemetrexed arm and 43% of
the control group). Only docetaxel usage
differed significantly between arms (32%
vs. 43%; P = .013), he said.
тАЬWe have very few drugs that are active in nonтАУsmall cell lung cancer and
we have to be able to squeeze most of
the benefit from each of them, and this
is why IтАЩm really in favor of this maintenance kind of treatment,тАЭ he added.
PARAMOUNT was supported by Eli
Lilly. Dr. Paz-Ares disclosed ties with
Bayer, Lilly, Pfizer, and Roche. Coauthors include employees of Eli Lilly.
PULMONARY MEDICINE
December 2012
9
Genomic project, Lung squamous cell cancerьЭШ
ьГИыбЬьЪ┤ ь╣ШыгМэСЬьаБ ъ░Ьы░ЬьЧР ыПДьЫА
Genomics Project Begins to Unravel Lung Cancer
B Y PAT R I C E W E N D L I N G
IMNG Medical News
CHICAGO тАУ Researchers are beginning to unravel the genomics of lung
squamous cell carcinoma, revealing a
disease characterized by complex
genomes with frequent and unique rearrangements.
Exome and RNA sequence analyses
of 178 patients identified 48,690 nonsilent
mutations in total, Dr. Ramaswamy
Govindan reported at the annual meeting of the American Society of Clinical
Oncology.
тАЬThis is not a disease like CML [chronic myeloid leukemia] with one mutation,тАЭ he said. тАЬThis is a tobacco-related
lung cancer with an average of 228 nonsilent mutations per tumor.тАЭ
Lung squamous cell carcinoma
(LSCC) was found to have 8.3 somatic
mutations/megabase, far surpassing, for
example, the 0.5 mutations/megabase
found in acute myeloid leukemia. The
average number of mutations was 360
per tumor.
тАЬItтАЩs quite significant the amount of
mutational burden,тАЭ Dr. Govindan said.
тАЬMany of them are passenger muta-
tions, but still itтАЩs a fairly disordered
genome.тАЭ
Dr. Govindan and his fellow researchers with The Cancer Genome Atlas (TCGA) Lung Cancer Project are
attempting to characterize the poorly
understood genomic and epigenomic
landscape of LSCC and to identify potential therapeutic targets. No molecularly targeted therapy has been approved for use in LSCC, which accounts
for roughly 30% of lung cancer deaths
or 45,000 deaths/year in the United
States.
The researchers hope to sequence
about 1,000 lung cancers in the next
year, with data presented on 178 LSCC
patients, most of whom smoked (96%),
were male (74%), and had early stage
I/II disease (76%). Their median age
was 68 years.
The tumor protein 53 (TP53) gene
was almost universally altered in the
cohort, along with frequent loss of cyclin-dependent kinase inhibitor 2A
(CDKN2A) function, said Dr. Govindan, an oncologist/hematologist and
professor of medicine at Washington
University in St. Louis. Other significantly mutated genes were phos-
phatase and tensin homolog (PTEN),
Kelch-like ECH-associated protein 1
(KEAP1), nuclear factor-erythroid 2 related factor 2 (NFE2L2), human leukocyte antigenтАУA (HLA-A), and phosphoinositide-3-kinase catalytic alpha
(PIK3CA).
Therapeutic targets were identified in
127 patients or roughly three-fourths of
patients with LSCC. тАЬSo itтАЩs really rich
in targets,тАЭ he said.
Most of the samples had distinct genes
that are significant in terms of therapy
and that are altered in a mutually exclusive fashion. Targets include the fibroblast growth factor receptors (FGFR),
phosphoinositide-3 (PI3) kinase pathway
(47%), epidermal growth factor receptor
(EGFR)/erythroblastic leukemia viral
oncogene homolog 2 (ErbB-2), and the
cyclin-cyclin dependant kinase complexes.
The researchers also conducted whole
genome sequencing on 19 tumors, detecting an average of 165 rearrangements/tumor. This is far more than has
been seen in the TCGA database for
breast or colon cancer, Dr. Govindan
said.
mRNA expression profiling confirmed
a recent report that LSCC is composed
of four biologically distinct mRNA expression subtypes, suggesting the need
for different therapies (Clin. Cancer Res.
2010;16:4864-75).
Pathway alterations in LSCC fell into
two major categories. Not surprisingly,
the squamous differentiation pathway
was altered in 44% of patients, but the
oxidative stress response was also found
to be altered in 34% of patients and 62%
of those with the classic mRNA subtype.
Oxidative stress has a role in chemotherapy resistance.
Finally, Dr. Govindan said the lung
cancer community is witnessing a revolution. тАЬWe are at the dawn of a new
era. тАж We used to see the alterations in
the cancer genes through a key hole,
and now we can actually have this
panoramic view.тАЭ
The full paper on the TCGA Lung
Cancer Project findings is expected to be
published shortly and will be deposited
in a public database, Dr. Govindan said.
The Cancer Genome Atlas is supported by the National Institutes of Health.
Dr. Govindan reported ties to Bayer,
Boehringer Ingelheim, and Merck
Serono.
H3N2ы│АьвЕ ыПЕъ░РьЭШ ъ╕ЙьЖНэХЬ ы░ЬьГЭ ьжЭъ░А
H3N2v Flu Infections Take a Big Jump
In early August, the CDC provided guidance to state
laboratories and is now allowing states to confirm
their own H3N2v cases, prior to laboratory confirmanfections due to the influenza A(H3N2) variant tion at CDC. тАЬCases that were positive at the state
virus have soared to 276 cases as of Aug. 24, ac- level were overwhelmingly being confirmed also at
cording to the Centers for Disease Control and CDC,тАЭ said Dr. Bresee, who is a medical epidemiologist
with the CDCтАЩs influenza division.
Prevention.
тАЬGiven this, and in the context of an outbreak situaтАЬThis increase is partly based on the change in reporting requirements тАж but in fact, the increase reflects tion, with very little seasonal influenza circulating, we
accurately what is going on in these outbreaks,тАЭ Dr. felt that it was appropriate for states to begin reporting
Joseph Bresee said during a telephone press conference their positives as confirmed cases rather than waiting
for CDC confirmation,тАЭ he said. тАЬWe anticipate that
held by the CDC.
The 276 confirmed cases of Influenza A(H3N2) vari- the change in reporting requirements will provide for
ant infection include 113 cases in Indiana, 56 cases in a more real-time indication of how these outbreaks
Ohio, 12 in Maryland, and 6 in Wisconsin.
are evolving.тАЭ
Positive samples will
still be forwarded to the
Dr. Vera DePalo, FCCP, comments: of influenza A variant virus
CDC, where these will
Normally swine flu viruses do not (H3N2v) cases may pose diagnostic
be confirmed using gedifficulties for the cliniinfect humans. But sponetic sequencing.
cian. If suspected, tests
radic human infections
тАЬThe severity of huof respiratory speciwith influenza viruses
man illness associated
mens should be perthat normally circulate
with this virus continues
formed at state health
in swine have occurred,
to resemble that of seadepartment labs as
the CDC notes. When
sonal flu. Most of the casrapid influenza diagnosthis happens, these
es are mild, self-limited,
tic tests may not detect
viruses are called тАЬvariand resolve on their
H3N2v virus. The CDC
ant virusesтАЭ and are deown,тАЭ Dr. Bresee said.
confirms the diagnosis.
noted by adding the letThe CDC has not reIt should be suspected
ter тАЬvтАЭ to the end of the
ceived any reports of
in those who had convirus subtype designadeaths associated with
tion. With the approach of flu sea- tact with or exposure to swine prior
the virus and only two
son, the rapid rise in the number to illness onset.
hospitalizations.
Importantly, there is
COMMENTARY
I
SUMMARY
BY KERRI WACHTER
IMNG Medical News
H3N2ы│АьвЕ ыПЕъ░Р ъ░РьЧ╝ьЭ┤ ып╕ъ╡н ьаДьЧньЧРьДЬ ь╡Ьъ╖╝ 276ыбАъ░А ы░ЬьГЭэХШ
ьШАыЛдъ│а ып╕ъ╡ньзИы│СэЖ╡ьаЬьШИы░йьД╝эД░(CDC)ьЧРьДЬ ы░ЬэСЬэХШьШАыЛд. H3N2
ы│АьвЕ ыПЕъ░РьЭА ьВмыЮМ ьВмьЭ┤ьЭШ ьаДьЧ╝ьЭА ыРШьзА ьХКьХД ы▓ФьЬаэЦЙьЭА ыРШьзА ьХК
ыКФ ьГБэЩйьЭ┤ъ│а ьЮДьГБ ьЦСьГБьЭ┤ ъ│ДьаИьД▒ ыПЕъ░Ръ│╝ ьЬаьВмэХШый░ ьВмызЭыбАыКФ
ы│┤ъ│аыРШьзА ьХКъ│а ьЮИыЛд.
no evidence of sustained human-to-human spread in
the community. тАЬThis is not a pandemic situation,тАЭ
Dr. Bresee said. However, тАЬthese viruses are all the
same. TheyтАЩre not completely genetically identical,
but theyтАЩre very close to being so. All of the viruses
that weтАЩre seeing so far, in this latest increase in cases,
are the viruses with the M gene.тАЭ The M gene may
confer increased transmissibility to and among humans.
Most of the cases have involved contact or exposure
to swine prior to illness onset, and many have been associated with state agricultural fairs, where swine were
present.
Signs and symptoms of H3N2v virus infection
are similar to those of seasonal influenza virus
infection. If H3N2v virus infection is suspected
because of recent exposure to pigs, testing of respiratory specimens should be performed at a state
health department; rapid influenza diagnostic
tests may not detect H3N2v virus in human respiratory specimens, resulting in false-negative results.
Two antivirals тАУ oseltamivir (Tamiflu) and zanamivir
(Relenza) тАУ are expected to be effective for treating
H3N2v illness. Antiviral treatment is most effective
when started as soon as possible after illness onset, according to the CDC.
CRITICAL CARE MEDICINE
10
CHEST Physician тАв December 2012
эМиэШИьжЭ эЩШьЮРьЧРьДЬ Hydroxyethyl StarchыКФ ьВмызЭыеаьЭД ьжЭъ░АьЛЬэВиыЛд
Sepsis Deaths Increased With Hydroxyethyl Starch
IMNG Medical News
H
ydroxyethyl starch 130/0.4,
widely used for fluid resuscitation in hypovolemia due to severe sepsis, raises the risk of death within
90 days, compared with RingerтАЩs acetate,
according to a report published online
in the New England Journal of Medicine.
The low-molecular-weight hydrox-
yethyl starch (HES) is a colloid solution
thought to afford more rapid and lasting
circulatory stabilization, compared with
standard IV fluids such as RingerтАЩs acetate. HES 130/0.4 has been widely
adopted in ICUs around the world, even
though data about its effectiveness are
limited and several trials have raised
concerns about its safety, said Dr. Anders
Perner of the department of intensive
care, Copenhagen University Hospital,
and his associates.
Their Scandinavian Starch for Severe
Sepsis/Septic Shock study was an international trial to compare the effects of
HES 130/0.4 against RingerтАЩs acetate on
the composite outcome of death or endstage kidney failure within 90 days of
treatment. The study population comprised 800 septic shock patients treated
at 13 university-affiliated ICUs and 13
nonacademic general ICUs in Denmark,
Norway, Finland, and Iceland between
December 2009 and November 2011.
When their physicians decided that
volume expansion was required, the
study participants were randomly assigned in equal numbers to receive fluid
resuscitation with either HES 130/0.4
or RingerтАЩs acetate in a manner that concealed treatment assignment from patients, clinicians, research staff, and study
committee members. The median cumulative volume of fluid administered
was 3,000 mL.
The primary outcome measure (a
composite of death or dependence on
dialysis), occurred in 51% of patients
who received the starch, compared with
43% of those who received RingerтАЩs solution. When the two outcomes were
analyzed separately, this difference was
found to be entirely due to an increased
risk of death in the starch group, the investigators said (N. Engl. J. Med. 2012
July 27 [doi:10.1056/NEJMoa1204242]).
In multiple further analyses of the
data, including logistic regression and
per-protocol analyses, these results persisted. The separation of the survival
curves indicated that HES 130/0.4 tends
to induce death late in the course of
hospitalization, Dr. Perner and his colleagues said.
In addition, more patients in the starch
group than in the RingerтАЩs group required renal replacement therapy (61%
vs. 44%) or developed bleeding complications (10% vs. 6%).
Previous studies suggested that a high
proportion of HES тАЬis taken up and deposited in tissues, where it cannot be
metabolized and it acts as a foreign body.
Long-term toxic effects of HES deposition have been described in the kidney,
liver, and bone marrow.
тАЬTogether, all these negative effects
of HES may have caused the late deaths
observed in our trialтАЭ and in previous
studies, the researchers noted.
This study also raises the question of
whether HES 130/0.4 is actually more
potent than crystalloids in patients with
severe sepsis. тАЬWe did not observe significant differences in trial fluid volumes
between the study groups,тАЭ a result that
has been reported in a previous study,
they added.
The study findings should be applicable to other populations because this
trial had broad inclusion criteria and
very few exclusion criteria. It even included patients who had acute kidney
injury at baseline, the authors said.
VITALS
BY MARY ANN MOON
Major Finding: Death or kidney
failure occurred within 90 days in
51% of sepsis patients treated
with colloidal HES 130/0.4,
compared with 43% of those
treated with RingerтАЩs acetate.
Data Source: A 2-year, blinded,
randomized international clinical
trial compared outcomes between
400 ICU patients with severe
sepsis who received HES 130/0.4
vs. 400 who received RingerтАЩs
acetate for hypovolemia.
Disclosures: This study was supported by
the Danish Research Council, the Rigshospitalet Research Council, and the Scandinavian Society of Anesthesiology and
Intensive Care Medicine. Dr. Perner reported
receiving grant support from Fresenius Kabi.
CRITICAL CARE MEDICINE
December 2012
11
Enoxaparin ьШИы░йь╣ШыгМьЧРыПД ьЮЕьЫРэЩШьЮР ьВмызЭыеаьЧФ ы│АэЩФьЧЖьЦ┤
Inpatient Mortality Unchanged by Enoxaparin Prophylaxis
BY M. ALEXANDER OTTO
IMNG Medical News
VITALS
SAN FRANCISCO тАУ Thromboprophylaxis with enoxaparin did not reduce
mortality in acutely ill medical inpatients
in a trial funded by the maker of the lowmolecular-weight heparin, Sanofi-Aventis.
Among 4,171 patients randomized to
enoxaparin (Lovenox) 40 mg subcutaneously for 10 ┬▒ 4 days, all-cause 30-day
mortality was 4.9%; among 4,136 randomized to placebo for the same amount
of time, it was 4.8% (relative risk, 1.0;
95% CI, 0.8-1.2; P = .83).
The major bleeding rate was below a
half percent in both groups and not statistically different. Minor bleeding was
seen in 1.8% with enoxaparin and 1.1%
with placebo, a statistically significant
difference, Dr. Samuel Goldhaber,
FCCP, said at an international conference of the American Thoracic Society.
Commenting on the study, New England Journal of Medicine editor Dr. Jeffrey Drazen, FCCP, noted that, in the
United States, the reflex has been to use
prophylaxis on even low-risk patients
for VTE. тАЬThe reason we published
these data was that maybe we should
rethink this. Maybe we should be making decisions about who should be receiving pharmacologic prophylaxis based
on factors other than the fact that they
are in the hospital for an acute medical
illness,тАЭ he said.
Patients were hospitalized for acute
decompensated heart failure, severe systemic infections, or active cancer. No
mortality benefit was found for enoxaparin on subgroup analysis. Both groups
wore knee-high elastic graduated com-
Major Finding: Among 4,171 acutely ill hospitalized medical patients randomized to enoxaparin 40 mg subcutaneously for 10
┬▒ 4 days, all-cause 30-day mortality was 4.9%; among 4,136 randomized to
placebo for the same amount of time, it was 4.8%.
Data Source: Data were taken from a randomized, blinded, placebo-controlled trial.
Disclosures: The trial was funded by Sanofi-Aventis, the maker of enoxaparin. The presenter of the
findings, also an investigator, disclosed that he is a paid consultant for Sanofi-Aventis, Boehringer
Ingelheim, Bristol Myers Squibb, Merck, and several other companies. Dr. Goldhaber disclosed that
he is a paid consultant for Sanofi-Aventis, Boehringer Ingelheim, Bristol Myers Squibb, Merck, and
several other companies. Dr. Drazen reported having no disclosures.
pression stockings during the treatment
phase of the trial (N. Engl. J. Med.
тАШWe were quite
surprisedтАЩ that
the all-cause
1-90 day
mortality curves
тАШwere absolutely
superimposable.тАЩ
DR. GOLDHABER
2011;365:2463-72).
The all-cause 1-90 day mortality
curves for the two groups тАЬwere absolutely superimposable. We were quite
surprised by the results,тАЭ said Dr. Goldhaber, professor of medicine at Harvard
Medical School and director of the venous thromboembolism research group
at Brigham and WomenтАЩs Hospital, both
in Boston.
They were surprised because enoxaparin has been shown to reduce VTE in
both surgical and medical patients, and
to reduce the incidence of fatal PE and
all-cause mortality in surgical patients.
There was a presumption it would save
medical patientsтАЩ lives, too, although
they have a lower PE rate. Current
U.S. treatment guidelines recommend
pharmacologic prophylaxis in both sur-
gical and acutely ill medical inpatients.
The study was conducted in China,
India, Korea, Malaysia, Mexico, the
Philippines, and Tunisia because, in
those places, enoxaparin prophylaxis for
medical patients is тАЬstill considered an
open question,тАЭ Dr. Goldhaber said.
About 88% of the subjects were Asian,
and 63% were men. Their average age
was 65 years. There were no statistically
significant baseline differences between
the placebo and enoxaparin groups.
Perhaps enoxaparin didnтАЩt cut mortality in the trial because тАЬthe natural
history of deep vein thrombosis differs
between medical and surgical patients.тАЭ
ItтАЩs been assumed that тАЬthe natural history would be the same. This assumption may be incorrect,тАЭ Dr. Goldhaber
said.
ItтАЩs also possible that the elastic stockings used in the trial were enough to
prevent fatal PE in the Asian subjects, a
group known to have a lower PE risk
than Westerners. Just one patient in each
group died from a PE in the study; infections were the main cause of death.
Dr. Goldhaber said he still tends to
prophylaxis low-risk medical inpatients.
тАЬIn our world, the quality measures are
in place, but IтАЩd be thinking to myselfтАЭ
that they are probably not going to develop a PE, he said.
ыеШызИэЛ░ьКд ъ┤АьаИьЧ╝ эЩШьЮРьЧРьДЬ
ьаХызеэШИьаДьГЙьаДьжЭьЭШ ы░ЬьГЭьЬДэЧШьЭ┤ ьжЭъ░А
VTE Risk Heightened in Rheumatoid Arthritis
VITALS
BERLIN тАУ Rheumatoid arthritis patients
face a moderately elevated risk of venous thromboembolism that continues
unabated for many years, according to
findings from two large studies that
were presented at the European Congress of Rheumatology.
Dr. Seoyoung C. Kim offered a retrospective cohort study involving 22,143
patients with rheumatoid arthritis (RA)
and 88,572 age- and sex-matched controls. None of the subjects had a baseline history of malignancy or venous
Major Finding: The risk of venous
thromboembolism was 40%
greater in RA patients than controls in one 2-year study, whereas
a second study found the risk of
pulmonary embolism to be 80%100% higher in RA patients than
controls who were followed for as
long as 15 years.
Data Source: The U.S. retrospective cohort study included
more than 22,000 RA patients,
whereas the Swedish prospective
cohort study involved 8,077.
Disclosures: Neither study had commercial
sponsorship. Dr. Holmqvist and Dr. Kim reported having no financial conflicts.
thromboembolism (VTE). The data
came from a large U.S. commercial insurance plan.
During a mean follow-up of 2 years
(starting when the RA patients received
their first prescription for a diseasemodifying antirheumatic drug), deep
vein thrombosis or pulmonary embolism occurred in 1.2% of RA patients
and 0.5% of controls. The incidence
among RA patients was 6.1 cases per
1,000 person-years, a rate 2.4-fold
greater than in controls. The pulmonary
embolism rate was 2.7 times higher
than in controls, whereas the deep vein
thrombosis rate was 2.2-fold higher, according to Dr. Kim of Brigham and
WomenтАЩs Hospital, Boston, where she
is a rheumatologist.
After adjustment for known risk factors for VTE, including surgery, hospitalization, and cardiovascular disease,
the VTE risk associated with having
RA remained moderately elevated, with
a 40% increase compared with controls.
The mechanism underlying this
increased risk is believed to hinge
upon the systemic inflammation
that is a central feature of RA.
This inflammation is thought to
predispose to thrombus formation,
up-regulation of procoagulants,
down-regulation of anticoagu-
lants, and suppression of fibrinolysis, Dr. Kim noted.
Dr. Marie Holmqvist presented a
prospective population-based cohort
study including 8,077 patients who were
newly diagnosed with RA during 19972009, as well as 203,329 controls.
In all, 84 RA patients were diagnosed
with a pulmonary embolism during
43,178 person-years of prospective follow-up. That translated to an incidence
of 1.9 cases per 1,000 person-years, compared with 1.1 cases per 1,000 personyears among controls.
The increased risk of pulmonary
embolism was evident 1 year after diagnosis of RA and remained unchanged thereafter. In the period 1-4
years after diagnosis of RA, the RA
group had a 1.8-fold greater risk of
pulmonary embolism than did controls drawn from the general population. During years 5-9, the risk was
increased 2.0-fold, and in years 10-15
the risk of pulmonary embolism in
RA patients was 1.9-fold greater than
in controls, although only a small
number of subjects were followed that
long.
Control subjects who were hospitalized for any reason had a 5.4-fold increased risk of pulmonary embolism
for the next year, compared with non-
hospitalized controls. The risk of pulmonary embolism in hospitalized RA
patients was elevated for the next year
to the same extent as in hospitalized
controls. In other words, having RA
didnтАЩt pile on additional risk beyond
hospitalization itself, according to Dr.
Holmqvist of the Karolinska Institute,
Stockholm.
COMMENTARY
BY BRUCE JANCIN
IMNG Medical News
Dr. Jun Chiong, FCCP, comments: Rheumatoid arthritis is
not generally considered to be a
risk factor for VTE, although
abnormalities of coagulation factors have
been found
in patients
with RA.
T h e s e
studies suggest that
RA
patients may
have higher rates of VTE and raise our
awareness of the risks to lower
the threshold for VTE prophylaxis as well as evaluation of patients suspected for possible
VTE or PE.
12
CRITICAL CARE MEDICINE
CHEST Physician тАв December 2012
COMMENTARY
ьЮЕьЫРьЛЬ ы░ЬьГЭэХШыКФ ьДмызЭьЭШ ьЭ┤эХ┤ьЧР ьГИыбЬьЪ┤ ыПДьХ╜
New Steps in In-Hospital Delirium
expect that [insert patient
name here] will have a
BY STEPHEN J.
hospital stay measured in
BEKANICH, M.D.
a period of days. During that
time we will do our best to
prevent complications of hospitalization, which include things such as blood clots and infections. We
will also do our best to quickly recognize and treat
other complications such as confusion or pain.тАЭ This
is a conversation I have with most patientsтАЩ families
when their medically complicated loved one is hospitalized.
I was certain that one gentleman, who had esophageal
cancer with metastasis to the spine causing cord compression, would suffer from delirium during his hospital
stay. His advanced age, multiple comorbidities, urgent
surgery, ICU stay, and pain medications (which initially
included a fentanyl PCA [patient-controlled analgesia]
later augmented by a ketamine infusion) all seemed to
put him at high risk for delirium. Yet, even during his
time on our ketamine protocol, he had clear and appropriate conversations with our team.
Another elderly woman, with previously undiagnosed dementia, was living at home with family assistance until coming to the hospital after a fall. During
her hospital stay, she experienced side effects of pain
medications and developed a urinary tract infection.
COMMENTARY
тАЬI
Dr. Carl Kaplan, FCCP, comments: It is one
thing to successfully treat a disease and another to make an early
diagnosis, but it is the
most rewarding if you
can identify a focused
vulnerable population at
risk and provide the resources to prevent the
occurrence of the disease
altogether. This material
expands our knowledge
and understanding of delirium in the ICU,
which is a common problem.
The delirium that ensued was severe. She required
ICU admission because of the intense nursing supervision she needed to keep her out of physical restraints.
After 2 weeks, she was discharged to a skilled nursing
facility rather than home because of persistent cognitive
problems.
Delirium in hospitalized patients is a common problem. Its presence is often partnered with extended
lengths of stay, escalation of care, and poorer outcomes.
Once it occurs, we turn to screening tools and treatment protocols that evidence has shown to be useful.
Therefore, it should come as no surprise that a hospitalтАЩs approach to delirium management is now recognized as a quality-of-care marker.
Two new studies highlight the impact of delirium
and provide a new tool for predicting this condition.
They expand our body of knowledge, and one may
even allow us to head off delirium before it occurs.
The first study is a prospective cohort enrolled between 1991 and 2006 into a patient registry for
AlzheimerтАЩs disease (AD). The 771 participants were
over the age of 65 years with a clinical diagnosis of AD
in this community setting. Databases identified those
who were hospitalized, experienced delirium, died, or
were institutionalized. Cognitive decline was also evaluated and based upon a validated test score (Ann. Intern. Med. 2012;156:848-56).
A total of 367 patients (48%) were hospitalized, and
194 (25%) developed delirium. Patients who did not
experience delirium in the hospital had an increased
risk of death or institutionalization (relative risks of
4.7 and 6.9, respectively), but an even more dramatic
increase in risk was noted in those with delirium (RRs
of 5.4 and 9.3). Delirium was associated with 6% of
deaths, 15% of institutionalizations, and 21% of cognitive declines in hospitalized patients with AD.
This is the first time the relative contributions of
hospitalizations and episodes of delirium to adverse
outcomes for AD patients have been evaluated. The
results clearly showed that hospitalization is a danger
to this patient population and that the outcomes are
worse for those with delirium. This clinical cohort
was created by merging multiple databases, so incomplete medical records were a limitation. Two other as-
pects of the study are worth noting. As this study was
nonrandomized, the hospitalized patients had lower
baseline cognitive function than those who avoided
admission. Also, ethnic minorities made up only 5% of
the study population.
The second work is a multicenter observational
study that entailed the development of the Prediction
of Delirium in ICU Patients (PRE-DELIRIC) model in
a prospective cohort of 1,613 patients (see story below).
The PRE-DELIRIC model contains 10 risk factors
(see graphic below). The main outcome measured was
development of delirium within the ICU. The modelтАЩs
ability to predict delirium was compared with the ability of ICU physicians and nurses to independently predict delirium within 24 hours of admission.
The modelтАЩs area under receiver operating characteristics curve (AUROC) was 0.85 pooled across three
cohorts. The AUROC for both physiciansтАЩ and nursesтАЩ
predictions of delirium was 0.59. ProvidersтАЩ predictive
accuracy did not differ by level of clinical experience.
PRE-DELIRIC is the first predictive model published
for the ICU population experiencing delirium. The
model clearly outperformed the physicians and nurses,
who were equally inferior when it came to predicting
delirium, and more experienced clinicians fared no
better than their greener colleagues. Limitations included a varied case mix from multiple specialties and
inclusion of risk factors that were not based on the authorsтАЩ systematic review for factors associated with
delirium.
Both of these studies move us forward. The first
should heighten our level of awareness that hospitalization with delirium is a major marker for adverse
outcomes. It also should prompt proactive communication with our AD patientsтАЩ families about expectations in this scenario. The second study should help
create a mindset of predicting and preventing delirium
rather than our current model, which is to screen and
then treat.
DR. BEKANICH is an internist and medical director of
palliative care at Seton Healthcare in Austin, Tex.
ьД▒ьЭ╕ ьдСэЩШьЮР ьДмызЭ ы░ЬьГЭ ьШИь╕бьЭД эЦеьГБьЛЬэВдыКФ ыПДъ╡м
Tool Boosts Power to Predict Delirium in Adult ICU
A
recently developed tool could help
doctors stay ahead of the game in
preventing delirium in ICU patients.
Dutch researchers say their delirium
prediction model was significantly more
successful than doctors and nurses at
predicting delirium in ICU patients.
Preventive measures for delirium can
limit its incidence, severity, and duration.
While several assessment tools exist for
other populations of hospitalized patients, тАЬno evidence-based prediction
model for general intensive care patients
is available,тАЭ Mark van den Boogaard,
Ph.D., of Radboud University Nijmegen
(Netherlands) Medical Centre and his
colleagues said (BMJ 2012;344:e420 [doi:
10.1136/bmj.e420]).
For PRE-DELIRIC (Prediction of
Delirium in ICU Patients), the authors
defined 10 risk factors that can be assessed within 24 hours of admission (see
graphic).
тАЬThe use of the PRE-DELIRIC model
to identify and consequently preventively treat high-risk patients could offer an
important contribution to intensive care
practice and ensure efficient use of research resources to study only high-risk
patients,тАЭ the researchers said.
Clinically, the model may improve
the use of nondrug measures to prevent
delirium in high-risk patients, the researchers added. Such measures include
cognitive stimulation, early mobilization,
and listening to music, they said. PREDELIRIC also could inform the choice
to use prophylactic haloperidol in ICU
patients, the authors said.
After testing their model for temporal
validation, the researchers conducted an
Continued on following page
Formula for PRE-DELIRIC Model
Risk of Delirium = 1/(1 + exp тАУ (тАУ6.31 + all applicable risk factors below)
0.04 ├Ч age
0.06 ├Ч APACHE-II score
1.05 for infection
0.29 for metabolic acidosis
0 for
0.31
1.13
1.38
Admission category
surgical
for medical
for trauma
for neurology/neurosurgical
0 for
0.41
0.13
0.51
Morphine use
none
for 0.01-7.1 mg/24h
for 7.2-18.6 mg/24h
for >18.6 mg/24h
1.39 for use of sedatives
0.03 ├Ч urea concentration (mmol/L)
0.40 for urgent admission
0 for
0.55
2.70
2.84
Coma
non-coma
for drug-induced coma
for miscellaneous coma
for combination coma
Note: Model was developed with data for
1,613 consecutive patients from one hospital ICU.
Source: BMJ 2012;344:e420
(doi:10.1136/bmj.e420)
IMNG M EDICAL M EDIA
BY HEIDI SPLETE
IMNG Medical News
PEDIATRIC CHEST MEDICINE
December 2012
13
ьаАьЬДэЧШ ьЖМьХДь▓ЬьЛЭ эЩШьЮРьЧРьДЬ ыздьЭ╝ ICS ьЪФы▓ХьЭШ эХДьЪФьД▒ьЭА ыЦиьЦ┤ьа╕
Low-Risk Kids With Asthma May Not Need Daily ICS
IMNG Medical News
VITALS
SAN FRANCISCO тАУ Children aged 12
years and older may be less likely to
have asthma exacerbations than are
younger children, according a 44-week
trial in 288 children with mild, persistent
asthma.
Girls also may be less likely to have
asthma exacerbations than are boys. The
lower risk in girls and older children
means that these patients probably donтАЩt
need inhaled corticosteroids (ICS) daily,
but only for symptoms or rescue, said
Dr. Joseph Gerald of the University of
Major Finding: Over 44 weeks, almost 30% of boys but only 15%
of girls with mild, persistent asthma had more than two exacerbations requiring oral corticosteroids.
Data Source: This was a randomized, placebo-controlled trial of
288 children with mild, persistent asthma.
Disclosures: The investigators said they
have no relevant disclosures.
Arizona, Tucson.
тАЬItтАЩs a reasonableтАЭ approach that limits
impaired growth and other potential ICS
side effects when тАЬthe benefit to be gained
from daily inhaled steroids is not that
great,тАЭ he said at an international conference of the American Thoracic Society.
The researchers randomized 72 children to daily ICS, 71 to rescue ICS
only, 71 to combined treatment with
ICS and inhaled albuterol, and 74 to
placebo. The daily ICS regimen consisted of one 40-mcg puff of beclomethasone twice daily; combined
treatment consisted of one 40-mcg puff
of beclomethasone with each albuterol
puff used for symptom relief. Dummy
inhalers were used as needed to maintain blinding. The participants were 618 years old.
Compared with placebo, all three ICS
regimens reduced treatment failures (defined as more than two exacerbations
requiring oral corticosteroids) in boys,
in children 6-11 years old, and in children
with allergic forms of the disease as indicated by eczema, positive skin tests,
methacholine PC20 (a provocative concentration of methacholine causing a
CRITICAL CARE MEDICINE
Continued from previous page
external validation study of data from patients admitted to four
Dutch ICUs between Jan. 1 and Sept. 1, 2009. The pooled data included information from 3,056 patients aged 18 years and older.
The researchers compared the predictions of patient delirium
made using their model to predictions made by doctors and nurses
in the hospital, using a convenience sample of 124 patients.
The pooled area under the receiver operation charactertics curve
(AUROC) for the PRE-DELIRIC model (0.85) was significantly
higher than that for the doctors and nurses (0.59).
No significant differences were seen in the predictions of ICU
nurses, student ICU nurses, intensivists, fellow-intensivists, and residents, the researchers said.
The findings were limited by the static nature of the model,
which does not account for changes in health status that might
affect the development of delirium.
The researchers reported having no financial conflicts of interest.
THE INVESTIGATORS WERE
UNABLE TO SHOW A
SIGNIFICANT BENEFIT FOR ANY
ICS STRATEGY IN GIRLS.
The investigators were unable to
show a statistically significant benefit
for any ICS strategy in girls, in children
12-18 years old, and in those with higher
methacholine PC20 levels, lower IgE
levels, negative skin tests, and no
eczema.
ThatтАЩs probably not because inhaled
steroids work better in boys and other
responders, but rather because nonresponders had lower exacerbation rates
in general, making it harder to detect a
benefit, Dr. Gerald said.
For example, although almost 30% of
boys in the placebo group failed treatment, only 15.2% of girls (5 of 33) in the
placebo group failed. Similarly, 26% of
children aged 6-11 years (13 of 50) failed
treatment in the placebo arm, but only
16.7% of children aged 12-18 years (4 of
24) did so.
тАЬWe think the baseline [exacerbation]
risk is what we are detecting here. [Nonresponders] started from a lower risk
and just didnтАЩt benefit as much,тАЭ Dr.
Gerald said. The study did not determine the best ICS regimen among responders.
Dr. Burt Lesnick, FCCP, comments: At CHEST 2012, on Oct.
23 at 4:30 p.m., a pro/con session
is dedicated to this topic. Dr.
Leonard
Bacharier
will present
the тАЬproтАЭ
position in
favor of
using intermittent ICS
in
mild
asthma.
Dr. Craig
Schramm will present the тАЬconтАЭ
position. We encourage those
interested to attend what should
be a lively discussion.
ъ░ДьаСэЭбьЧ░ьЭ┤ ьЖМьХДьЭШ ы░йъ┤С ъ╕░ыКеьЧР
ым╕ьаЬые╝ ъ░Аьа╕ьШм ьИШ ьЮИьЦ┤
Secondhand Smoke May
Harm KidsтАЩ Bladders
BY MICHELE G. SULLIVAN
IMNG Medical News
ATLANTA тАУ Children exposed to secondhand tobacco smoke have an increased risk
of urinary urgency, frequency, and incontinence, prospective data showed.
Among children with these bladder
symptoms, 28% were exposed to tobacco
smoke on a daily basis тАУ 13% higher than
the overall child exposure rate in New Jersey, Dr. Kelly Johnson said at the annual
meeting of the American Urological Association.
In addition to irritating a childтАЩs bladder,
childhood exposure to tobacco smoke is directly linked to the development of bladder
cancer as an adult, she said in a press briefing.
Dr. Johnson, chief urology resident at the
Robert Wood Johnson University Hospital,
New Brunswick, N.J., presented prospective data on 45 children, aged 4-17 years,
who presented with irritative bladder
symptoms тАУ frequency, urgency, and incontinence.
About half of the group (21) had very mild
or mild symptoms, while the rest had moderate or severe symptoms.
COMMENT
BY M. ALEXANDER OTTO
20% fall in forced expiratory volume in
1 second) at or below 12.5 mg/dL, and
IgE levels at or above 185 kU/L. For instance, 29.3% of boys (12 of 41) in the
placebo group failed treatment, but only
2.4% of boys (1 of 42) in the daily ICS
group did so.
COMMENTARY
Older children (those aged 12-18 years) did not
benefit from daily ICS.
Dr. Susan Millard, FCCP, comments:
Now we have more information to
tell parents who pollute their homes
and cars with secondhand smoke.
None of the children with mild scores were
exposed to secondhand smoke on a daily
basis, and none had mothers who smoked.
However, 23% of those with moderate to severe scores had mothers who smoked, and
50% were exposed to smoke in a car on a regular basis.
тАЬOn our measures of environmental tobacco smoke exposure, children with greater
exposure had significantly higher symptom
severity scores than children who werenтАЩt
exposed,тАЭ Dr. Johnson said. тАЬThis relationship
was particularly striking for the younger children aged 4-10 years old.тАЭ
Physicians who see children with bladder
dysfunction should ask parents about
smoke exposure, she advised. тАЬItтАЩs a teachable momentтАЭ that can have a long-lasting
positive impact on both the child and the
parent.
Dr. Johnson said that she had no relevant
financial disclosures.
14
PULMONARY PERSPECTIVES
CHEST Physician тАв December 2012
COPDьЧР ыМАэХЬ ьГЭым╝эСЬьзАьЮР
Biomarkers in COPD
Chest Imaging as Biomarkers in COPD
biomarker discovery because the primary
site of disease in COPD is the airways.
To facilitate this research, international
guidelines have been developed to
promote standardization of methods
for sputum collection and processing
to ensure comparability of results
across centers and between studies
(Efthimiadis et al. Eur Respir J Suppl.
2002;37:19s). The most promising data
have been generated with the cellular
components of induced sputum.
Sputum eosinophilia, for instance,
defined as eosinophil counts 3% in the
sputum, which affects about 25% of
patients with COPD, is associated with
increased clinical responsiveness to
both inhaled and oral corticosteroids
(Brightling et al. Lancet.
2000;356[9240]:1480; Brightling et al.
Thorax. 2005;60[3]:193). Sputum
neutrophilia, on the other hand, is
associated with poor therapeutic
responses or no therapeutic responses
to corticosteroids. Sputum cell counts
may also be used to classify etiologies
for exacerbations. For instance, in
approximately 30% of exacerbations,
patients demonstrate a significant
increase in sputum eosinophils, and
these patients may be more responsive
to corticosteroids than those with
тАЬpauciinflammatoryтАЭ features in
sputum (Bafadhel et al. Am J Respir
Crit Care Med. 2011;184[6]:662).
Assessment of proteins or mediators in
induced sputum, on the other hand,
does not appear to provide incremental
information beyond that achieved by
sputum cell differentials (Liesker et al.
Respir Med. 2011;105[12]:1853).
With the advent of high-resolution CT
scans, several studies have evaluated
the possibility of using CT scans to
classify patients by phenotype to assess
health outcomes in COPD. Compared
with spirometry, the use of inspiratory
and expiratory low-dose thoracic CT
scans can provide diagnostic information
regarding COPD with a positive
predictive value of 76% and a negative
predictive value of 79% (corresponding
to a sensitivity of 63% and a specificity
of 88%) in heavy current or ex-smokers
with >16.5 pack-years of smoking
history (Mets et al. JAMA. 2011;306[16]:
1775). Low-dose CT scans can also
provide prognostic information.
For instance, one study (Mohamed
Hoesein et al. Thorax. 2011;66[9]:782)
found that heavy smokers with
evidence of emphysema on baseline
CT scans experienced a rapid fall in
lung function, especially those with
upper lobe predominance. Another
study (Yuan et al. Thorax.
2009;64[11]:944) found that smokers
with emphysema had, on average, 15
to 20 mL/y greater decline in FEV1 on
CT scans than those without emphysema. Moreover, the presence of emphysema on thoracic CT scan is associated
with a two-fold increase in lung cancer
risk compared with thoracic CT scans
which do not demonstrate any
emphysema (Zurawaska et al. Chest.
2012;[5]:). However, to date, there is
little knowledge on whether the
changes from emphysema on CT scans
are modifiable or provide incremental
prognostic or diagnostic information
beyond that achieved with lung
function measurements. Nevertheless,
CT-based measurements are being
used as surrogate endpoints for therapeutic evaluation of alpha1-antitrypsin
augmentation therapies for emphysema related to alpha1-antitrypsin
deficiency (Stockley et al. Respir Res.
2010;11:136).
1999
Sputum Parameters as
Biomarkers in COPD
Sputum is an attractive source of
Table 1. Candidate Plasma or Serum Biomarkers Associated
With Important Health Outcomes Reported in ECLIPSE
Study and Lung Health Study
Exacerbation
Yes
No data
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Possibly
No data
ACRP-30 = adipocyte complement-related protein of 30
25 kDa
PARC/CCL-18 = pulmonary and activation-regulated chemokine/chemokine (C-C motif)
ligand 18
Note: Adapted from Vestbo et al. N Engl J Med 2011;365[13]:1184; Sin et al. Am J
Respir Crit Care Med 2011;183[9]:1187; Hurst et al. N Engl J Med
2010;363[12]:1128; Yoon H. et al. Chest Dec. 29, 2011 [doi:10.1378/chest.11-2173].
2003
899
Other Sources of Biomarkers
Various investigators have interrogated
other sources for potential biomarkers.
These include exhaled volatile gases
Continued on following page
Figure 1. Number of Publications in PubMed Identified
Using the Search Terms тАШBiomarkerтАЩ and тАШCOPDтАЩ
FEV1 Decline
Yes
Possibly
No
No
No
No data
No data
No
No
No
No
200
Number of Publications
Mortality
No
Yes
Yes
Yes
175
Yes
No data
No data
125
No
Yes
Yes
75
No data
IMNG M EDICAL M EDIA
Biomarker
ACRP-30
Clara cell secretary protein 16
C-reactive protein
Fibrinogen
Interleukin-6
Interferon-inducible protein 10
Matrix metalloproteinase 9
Myeloid progenitor inhibitory factor 1
PARC/CCL-18
Surfactant protein-D
Tumor necrosis factor-infinity
2001
Blood Parameters as
Biomarkers in COPD
The most promising source of
biomarker in blood is plasma or serum.
This area of investigation has ballooned
in recent years with the realization that
COPD is a systemic disorder with
multiple extrapulmonary manifestations
(Rabe et al. Am J Respir Crit Care Med.
2007;176[6]:532). There are several
promising proteins that are candidate
biomarkers in COPD (Table 1). The
most promising are interleukin (IL)-6,
surfactant protein-D, and Clara cell
secretory protein (CC)-16. Of all the
plasma proteins commonly assayed
among patients with COPD, IL-6 has
shown the strongest association with
total mortality (Celli et al. Am J Respir
Crit Care Med. 2012;185[10]:1065).
Lung-predominant proteins, such as
surfactant protein-D and CC-16, have
been associated with mortality and
accelerated decline in lung function,
respectively (Vestbo et al. N Engl J
Med. 2011;365[13]:1184; Hurst et al. N
Engl J Med. 2010;363[12]:1128). Plasma
C-reactive protein (CRP) is a promising
biomarker for diagnosing acute
(bacterial) exacerbations and blood
eosinophilia, defined by a peripheral
blood eosinophil count of 2%, and it
may be a therapeutic biomarker to
predict steroid responsiveness in acute
exacerbations (Bafadhel et al. Am J
Respir Crit Care Med. 2011;184[6]:662).
However, none of these biomarkers
has high enough performance
characteristics to be useful as a clinical
tool. To enrich the pool of candidate
protein biomarkers, some investigators
have used unbiased or multiplex
proteomics platforms. Although several
promising peptides and proteins have
been identified through this process,
none of them are ready for clinical
translation owing to poor performance
characteristics, lack of reproducibility,
or the high cost of assay development.
Other investigators (Bhattacharya et al.
J Clin Bioinforma. 2011;1[1]:12) have
explored the possibility of using gene
expression data as biomarkers in
COPD. While the use
of microarrays has led to the discovery
of many differentially expressed genes
between
COPD and
control 2011
subjects,
2015
2007
2009
limitations, which include lack of
consistent reproducibility of findings
across studies, the large number of
false-positive results (owing to multiple
comparisons), and the variability in the
measurement of gene expression
levels, have precluded the translation
of research findings into clinical practice.
150
100
50
0
1998
2000
2002
2004
2006
Calendar Year
2008
2010
2012
IMNG M EDICAL M EDIA
T
he National Institutes of Health
(NIH) defines biomarkers as тАЬa
characteristic (or variable) that
is objectively measured and evaluated
as an indicator of normal biologic
processes, pathogenic processes, or
pharmacologic responses to a
therapeutic intervention.тАЭ In practical
terms, a biomarker is an objective and
reproducible measurement that reflects
how patients or individuals feel,
function, or survive with the disease in
question. Clinically, biomarkers can be
used for diagnosis, prognosis, severity
assessment, staging of disease, and
monitoring disease activity or clinical
response to therapeutic interventions.
In clinical trials, biomarkers are used as
surrogate endpoints for patient-focused
clinical outcomes such as survival.
In COPD, the US Food and Drug
Administration (FDA) currently
indicates that тАЬwith exception of the
lung function tests, there are no
well-validated biomarkers or surrogate
endpoints that can be used to establish
efficacy of a drug for COPD.тАЭ
Although FEV1 is relatively easy to
obtain, highly reproducible, and tracks
certain health outcomes in COPD, it is
not an ideal biomarker for COPD
because it is hard to modify with
therapies, does not reflect disease
activity, and correlates only loosely
with clinically important health
endpoints such as mortality, hospitalization, and even the quality of life of
patients. Thus, over the past decade,
there has been an explosion of research
activities to identify and discover novel
biomarkers in COPD. A quick search
of PubMed using search terms
тАЬbiomarkerтАЭ and тАЬCOPDтАЭ reveals an
exponential growth in the number of
publications in the literature since 2000
(Fig 1), reflecting the growing interest
in discovering novel biomarkers in
COPD using noninvasive or minimally
invasive procedures. This paper provides
a short synopsis on the current state of
knowledge on COPD biomarkers.
PULMONARY PERSPECTIVES
December 2012
Continued from previous page
SUMMARY
such as nitric oxide, exhaled breath
condensate, bronchoscopic brushings,
and BAL fluid and urine. Although
some interesting findings have been
generated in these studies, there are
major limitations with all of these
sources, including invasiveness of test
FEV1 ьЭ┤ьЩ╕ьЧРыПД ъ░ЭыЛ┤ыВ┤ьЭШ эШ╕ьВ░ъ╡мы╢ДэЪН, эШИьХб
ыВ┤ьЭШ CRP, IL-6, ьВмызЭыеа ыШРыКФ эПРъ╕░ыКе ьХЕэЩФ
ыУ▒ъ│╝ ъ┤Аыаи. ыМАъ╖Ьыки ь╜ФэШ╕эК╕ые╝ ьЭ┤ьЪйэХЬ ьЬаьаД
эХЩьаБ ы╢ДьДЭьаХы│┤ъ░А ьГИыбЬьЪ┤ ьГЭым╝эСЬьзАьЮРыбЬьДЬ
ъ╕░ыМАыРЬыЛд.
in the case of bronchoscopy and lack of
reproducibility of data in the case of other
sources, which preclude their use in
the clinic.
Summary and Future Directions
Research on biomarker discovery in
COPD is progressing at a rapid pace.
There are several promising biomarkers
on the horizon. In the sputum, eosinophilia
is a promising biomarker for COPD
exacerbation and steroid responsiveness.
In the blood, promising plasma proteins
include C-reactive protein (for exacerbation, especially if the levels are >10
mg/L), IL-6 (for predicting total mortality),
and CC-16 (for predicting accelerated
decline in lung function). Additionally,
blood eosinophilia (>2% of total cell
count) may be a good predictor of steroid
responsiveness in acute exacerbations.
Evolving technology in gene sequencing,
micro-RNA interrogation, and robust,
high throughput proteomics, coupled
with large scale cohort studies in COPD
(eg, ECLIPSE [Evaluation of COPD
Longitudinally to Identify Predictive
Surrogate Endpoints], SPIROMICS
[Subpopulations and Intermediate
Outcome Measures in COPD Study],
COPDGene, CanCOLD [Canadian
Cohort of Obstructive Lung Disease])
will enable identification, validation,
and qualification of even better bio-
15
markers in the near future for the
diagnosis, prognosis, and monitoring
of therapeutics in COPD.
Dr. Jin Woo Kim
UBC James Hogg Research Centre
Vancouver, BC, Canada
The Catholic University of Korea
Department of Internal Medicine
Division of Pulmonology
Seoul, Korea
Dr. Don D. Sin, FCCP
UBC James Hogg Research Centre
St. PaulтАЩs Hospital
Department of Medicine
Respiratory Division
Vancouver, BC, Canada
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эЕМ ь╣╕эГАы╣МыаИ>ьЩА эХиъ╗Ш ыЯмьЛЬьХД ьЛдыВ┤ьХЕ ьЮСэТИ ъ░АьЪ┤ыН░ ъ░АьЮе ыЫ░ьЦ┤ыВЬ
ьИШьЮСьЬ╝ыбЬ ы╜СьЭД ьИШ ьЮИыЛд. ьЭ┤ эШДьХЕьВмьдСьг╝ыКФ ъ╖╕ьЭШ ьЮСэТИьД╕ъ│Дъ░А ьЫР
ьИЩэХЬ ьЛЬьаИьЭШ ьВмьдСьг╝ыбЬ ы│┤ыбЬыФШьЭ┤ ъ╖╕ьЭШ ьХДыВ┤ые╝ ьЬДэХ┤ ьЮСъ│бэХЬ ьЮСэТИ
ьЭ┤ыЛд. ьаЬ3ьХЕьЮе ыЕ╣эД┤ьЧРьДЬ ь▓╝ыбЬьЩА ы░ФьЭ┤ьШмыж░ьЭ┤ ы▓Иъ░ИьХД ыУдыадьг╝ыКФ ьДа
ьЬиьЭА ы░ФыбЬ ьЭ┤ ьВмыЮСэХШыКФ ьЧ░ьЭ╕ыУдьЭ┤ ыВШыИДыКФ ыЛмь╜дэХЬ ьВмыЮСьЭ┤ьХ╝ъ╕░ые╝
ъ╖╕ыжмъ│а ьЮИыЛд. ьаДы░ШьаБьЬ╝ыбЬ ыЯмьЛЬьХДьЭШ ьДЬьаХьД▒ьЭ┤ эТНы╢АэХШъ▓М ымШьВмыРШ
ьЦ┤ ьЮИыЛд.
ьаЬ1ьХЕьЮе Allegro moderato ызИь╣Ш ым╝ эЭРые┤ыКФ ыКРыВМьЭШ ьЬаыадэХЬ ьДаьЬи
ыбЬ ъ╖╕ыж░ ьХДыжДыЛ╡ъ│а эИмыкЕэХЬ ьг╝ьаЬъ░А ыЕ╕ыЮШыРШый┤ьДЬ ъ╖╕ ьг╝ы│АьЧР эММыПДьЩА
ъ░ЩьЭА ы░Шьг╝ъ░А ъ│ДьЖНыРЬыЛд. ьЮаьЛЬ эЫД ьХ╜ъ░Д ьЛмьШдэХЬ ы╢ДьЬДъ╕░ьЭШ ьДаьЬиыбЬ
ыДШьЦ┤ъ░Аый┤ьДЬ ъ│ДьЖНыРШыКФ ы░ШьЭМыУдьЧР ьЭШэХ┤ ызИь╣Ш эПнэПмьИШь▓ШыЯ╝ эЭШыЯмыВ┤ыжм
ый┤ьДЬ ьаИьаХьЭД ьЭ┤ыгиъ│а ызИьзАызЙьЧРыКФ ъ│аьЪФэХШъ▓М ьЮФьЮФэХ┤ьзАый░ ызЙьЭД ыВ┤
ыж░ыЛд.
ьаЬ2ьХЕьЮе Scherzo Allegro ьЮмь╣Ш ы░ЬыЮДэХЬ ьДаьЬиыбЬ ы╢ДьЬДъ╕░ъ░А ьаДэЩШ
ыРШый┤ьДЬ ьЛЬьвЕ ы╣аые╕ ыйЬыбЬыФФыбЬ ъ░АыЛдъ░А ьЮмь╣Ш ьЮИъ▓М ьб░ьЪйэЮИ эФ╝ь╣Шь╣┤эЖа
ыбЬ ъ▓░ызРьЭД ыз║ыКФыЛд.
ьаЬ3ьХЕьЮе Nocturne Andante ыЯмьЛЬьХД эПЙьЫРьЭД ъ╖╕ыж░ ыУп ыздьЪ░ ьДЬьаХ
ьаБьЭ┤ъ│а ъ│аьХДэХЬ ьХДыжДыЛдьЫАьЬ╝ыбЬ ъ░АыУЭ ь░м ьДаьЬиыбЬ ъ░АьК┤ьЭД ьЛЬыжмъ▓М эХЬ
ыЛд. 3ы╢А эШХьЛЭьЭ┤ый░ ьЭ┤ ъ░РыПЩьЭА ыНФьЪ▒ ъ╣КьЭА ъ░РыПЩьЬ╝ыбЬ ьаЦьЦ┤ыУдъ▓М эХШ
ый┤ьДЬ ъ╖╕ ьЛЬыж░ ъ░АьК┤ьЭ┤ ъ┐ИьЖНьЭШ ьДаьЬиь▓ШыЯ╝ ь░иы╢ДэХШъ▓М ъ░АыЭ╝ьХЙыКФыЛд.
ьаЬ4ьХЕьЮе Finale Andante-Vivace ьб░ьЪйэХЬ ь▓╝ыбЬ ьЬДыбЬ ы╣аые╕ ъ░СьЮР
ъ╕░ ьДаьЬиьЭШ ы╣ДьШмыЭ╝ъ░А ыУ▒ьЮеэХШый┤ьДЬ ы╢ДьЬДъ╕░ъ░А ьаДэЩШыРЬыЛд. ьХЮ ыЛдэИмьЦ┤
ьДЬыбЬ ы▓Иъ░ИьХДъ░Аый░ ыйЬыбЬыФФые╝ ыЕ╕ыЮШэХШый┤ьДЬ ыйЛьзД эЩФьЭМьЬ╝ыбЬ ъ▓░ызРьЭД
ыз║ыКФыЛд.
ыУдьЭДызМэХЬ ьЭМы░Ш
ы│┤ыбЬыФШ эШДьХЕьВмьдСьг╝ыЛи[Decca, 1962]
ыУЬыбдь╕а эШДьХЕьВмьдСьг╝ыЛи[DG, 1970]
ы│┤ыбЬыФШ эШД
ьХЕьВмьдСьг╝
ыЛи[Melo
diya, 1
982]
, 1994]
ыЛи[Alto
ьг╝
ьдС
ьВм
ы╣Дь╣Ш
ьЗ╝ьКдэГАь╜Ф

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