PULMONARY, SLEEP, AND

CRITICAL CARE UPDATE

Update in Sepsis and Acute Kidney Injury 2014

Frédérique Schortgen1,2 and Pierre Asfar3,4
1
Réanimation Médicale, Groupe Hospitalier Henri Mondor, AP-HP, Créteil, France; 2INSERM, U955, Faculté de Médecine,
Université Paris Est, Créteil, France; 3Département de Réanimation Médicale et de Médecine Hyperbare Centre Hospitalier
Universitaire Angers, Pres L’Unam, France; and 4Laboratoire de Biologie Neurovasculaire et Mitochondriale Intégrée, CNRS
UMR 6214–INSERM U1083, Université Angers, Pres L’Unam, France

Abstract were published. In 2014, several publications raised an important

Sepsis and acute kidney injury (AKI) represent an important burden
in intensive care unit clinical practices. The Journal published
important contributions in sepsis for novel therapeutic approaches
suggesting that combined molecular targets (e.g., dual inhibition
of IL-1b and IL-18, and coadministration of endothelial progenitor
cells and stromal cell–derived factor-1a analog) could perform
better. The clinical effectiveness of 1,25-dihydroxyvitamin D was
reported in a double-blind, randomized, placebo-controlled trial.
Although its experimental properties appeared favorable in the pro-
and antiinflammatory cytokine balance, 1,25-dihydroxyvitamin D
failed to improve survival. Strategies for decreasing antimicrobial
resistances are of particular importance. Effective (aerosolized
antibiotics for ventilator-associated pneumonia) and ineffective
(procalcitonin algorithm for antibiotic deescalation) approaches
point shared by survivors from sepsis and/or AKI. The increased
number of survivors over time brought out long-term sequelae,
leading to a poor outcome after hospital discharge. Among them,
cardiovascular events and chronic kidney disease may explain the
significant increase in the risk of death, which can persist up to
10 years and significantly increases the use of health care. Postdischarge
survival represents a new target for future research in sepsis and
AKI to find how we can prevent and manage long-term sequelae.
A milestone of the year was the Ebola outbreak. The Journal
contributed to our better understanding of Ebola virus disease
with a paper underlying the crucial role of a large implementation
of pragmatic supportive care, including fluid infusion and
correction of metabolic abnormalities, to save more lives.
Keywords: sepsis; acute kidney injury; long-term outcomes; ICU

Sepsis
Molecular Targets in Sepsis: The Dual
Strategies
Despite hundreds of publications that have
led to a better mechanistic understanding of
sepsis, all clinical trials based on molecular
approaches have shown disappointing
results. Rather than discouraging future
efforts, this should drive the search for
novel approaches. The genetically driven
proinflammatory response is a central
mechanism in the innate response to sepsis
and involves many cytokines and their
respective receptors. In 2014, the Journal
published two papers focusing on IL-1
pathway modulation using two original
approaches. Van den Berghe and colleagues
studied the combined modulation of IL-1b
and IL-18 in a mouse model involving
cecal ligation and puncture (1). Genetically,
IL-1b– and IL-18–deficient mice and
combined IL-1b and IL-18 neutralization
by an IL-1 receptor antagonist and an
anti–IL-18 antibody, respectively, were
protective against lethal endotoxin
challenge. This role was explored further
by Meyer and colleagues in a clinical
study looking at the effect of the IL-1
receptor antagonist gene in volunteers
challenged with endotoxin (2). The authors
reported the association between this gene
and survival and organ failure–free days
in patients with septic shock. Both
studies suggest that a combined target
of IL-1b and IL-18 could be a potential
treatment strategy in selected patients
with septic shock.
The complex role of IL-1b and IL-18
in Pseudomonas aeruginosa–induced
pneumonia was documented by Faure
and colleagues, who reported two key
mechanisms: a subtle failure of our innate
defense system and the fantastic adaptive
capacity of P. aeruginosa (3). P. aeruginosa
carries a needle-like appendage, called
type-3 secretion system (T3SS), that is
responsible for translocating exotoxins
in host cells. T3SS promotes inflammation
and recruitment of neutrophils and
inhibition of P. aeruginosa internalization

( Received in original form February 13, 2015; accepted in final form April 8, 2015 )
Correspondence and requests for reprints should be addressed to Frédérique Schortgen, M.D., Ph.D., Service de Réanimation Médicale, CHU Henri Mondor,
51 avenue de Tassigny, 94000 Créteil, France. E-mail: frederique.schortgen@hmn.aphp.fr
Am J Respir Crit Care Med Vol 191, Iss 11, pp 1226–1231, Jun 1, 2015
Copyright © 2015 by the American Thoracic Society
DOI: 10.1164/rccm.201502-0307UP
Internet address: www.atsjournals.org

1226 American Journal of Respiratory and Critical Care Medicine Volume 191 Number 11 | June 1 2015
PULMONARY, SLEEP, AND CRITICAL CARE UPDATE
into macrophages. Through T3SS,
P. aeruginosa triggers the Nod-Like
Receptor family CARD domain
containing 4 (NLRC4). The NLRC4-
coupled inflammasome is a multimeric
protein complex of innate immunity that
is involved in IL-1b and IL-18 secretion.
Usually, the NLRC4-inflammasome
increases intracellular pathogen clearance,
but P. aeruginosa is able to decrease its
own clearance via NLRC4 inflammation
activation via T3SS. By using an
appropriate design of P. aeruginosa
functional and nonfunctional T3SS strains,
the authors demonstrated that the
NLRC4-coupled inflammasome, when
activated by functional T3SS, increases
lung injury by enhancing the innate
inflammatory response, especially the IL-1b
and IL-18 pathways. These results suggest
that a dual inhibition of IL-1b and IL-18
may provide a promising means of
treating multidrug-resistant infections.
The roles of endothelial progenitor
cells (EPCs) and stromal cell–derived
factor (SDF)-1a, which facilitates
EPC recruitment, are not completely
understood. Fan and colleagues assessed
the respective role of various doses of EPCs
or SDF-1a analog alone or in combination
in mice subjected to cecal ligation (4).
EPC therapy improved survival at a
threshold of 106 cells, decreased lung
vascular leakage, and attenuated liver and
kidney injury. When a SDF-1a analog was
coadministered with subthreshold EPC
infusion, the authors reported a synergistic
improvement in survival. Combined
therapeutic strategies may represent
a novel approach with an improved
benefit/risk ratio because lower doses
may be used, thereby minimizing
potential side effects.
Clinical Targets
Inflammation and immunomodulation: the
end of an old paradigm! Cathelicidin,
a “broad-spectrum” antimicrobial peptide,
is up-regulated by 1,25-dihydroxyvitamin
D (1–25 VitD) and has activity against
gram-positive and gram-negative bacteria
as well as fungi and viruses. Cathlicidin-
deficient animals have increased
susceptibility to bacterial infections,
whereas animals with cathelicidin
overexpression are protected. In addition,
1–25 VitD inhibits proinflammatory
cytokines while increasing antiinflammatory
Pulmonary, Sleep, and Critical Care Update
cytokine production, with beneficial effects
seen in in vitro and in animal studies.
A phase IIa, double-blind, randomized,
placebo-controlled trial by Leaf and
colleagues reported the effect of 1–25 VitD
in patients with severe sepsis or septic
shock (5). 1–25 VitD did not increase
plasma cathelicidin concentration, and
cytokine assays were not altered. These
disappointing results suggest the need for
an additional phase II trial to better define
the dose and timing of administration.
Similar findings were reported in a single-
center, double-blind, placebo-controlled
trial including critically ill patients with
vitamin D deficiency below 20 ng/ml.
Vitamin D administration did not alter
hospital length of stay, hospital mortality,
or 6-month mortality (6). However, when
generating hypotheses for future studies,
it should be considered that hospital
mortality was reduced in the a priori
stratified, most severe vitamin D deficiency
subgroup.
Corticosteroid use in patients with
septic shock is still debated. Using
Ingenuity Pathway Analysis, Wong
and colleagues reported a retrospective
study in pediatric patients with septic
shock and compared gene regulation in
patients who did and did not receive
corticosteroids (7). They identified 319 gene
probes that were regulated differently
between the two groups. These genes
were predominantly related to adaptive
immunity and were down-regulated in
patients treated with corticosteroids. These
findings may in part explain the double-
edge effect of corticosteroids, which
may improve the effects of exogenous
vasopressors but may also have potential
adverse effects such as hyperglycemia,
nosocomial infections, and intensive care
acquired myopathy.
Statins have antiinflammatory
properties and have been shown to
prevent adult respiratory distress syndrome
(ARDS) in experimental models. Large
observational studies as well as prospective
single center trials and metaanalyses have
suggested that patients with sepsis may
have better outcomes with statins. These
studies were not confirmed with large-scale
trials in patients with ventilator-associated
pneumonia (VAP) (8) or in patients
with ARDS due to septic origin (9). In
the latter, rosuvastatin was associated
with side effects such as impaired
hepatic and renal function.
The countless failed attempts to
modulate the host inflammatory response
in sepsis raise many unanswered
questions. Indeed, our pathophysiological
approach is based on the paradigm of
a proinflammatory “cytokine storm,”
which leads to organ dysfunction and
ultimately to death. Therefore, new
paradigms based on immune stimulation
have been proposed in sepsis because
the immune-suppressive phase is the
predominant immunologic response.
These new paradigms have to be validated
on clinically relevant endpoints (10, 11).
Old treatments and new recipes? Is it
possible to decrease antibiotic resistance by
giving more antibiotics? In a double-blind,
placebo-controlled, randomized study in
intubated critically ill patients, Palmer
and colleagues compared antibiotics
(vancomycin and/or aminoglycosides) in
combination with systemic antibiotics
with placebo aerosols in patients with
suspected VAP (12). Aerosolized antibiotics
eradicated 26 of 27 organisms, whereas
placebo aerosols eradicated only 2 of 23
organisms (P , 0.001). The authors did
not report new antibiotic resistances,
and aerosolized antibiotics significantly
reduced the Clinical Pulmonary Infection
Score. Of note, systemic antibiotics were
concomitantly administered, and it is still
unknown whether aerosolized therapy
alone delivers sufficient antibiotic
concentration to the alveoli.
The Surviving Sepsis Campaign: an
unfathomable source of inspiration for
RCTs! The year 2014 was an excellent
year for randomized controlled trials in
the domain of septic shock; most of them
were inspired by the Surviving Sepsis
Campaign (SSC) recommendations (13).
The international experts used the Grading
of Recommendations Assessment,
Development and Evaluation (GRADE)
system to guide assess quality. Less than
10% of the main recommendations were
graded 1A. The initial hemodynamic
resuscitation protocol of the SSC was
based mainly on a single-center trial
by Rivers and colleagues (14). The
study demonstrated that aggressive
hemodynamic, early protocol-called,
goal-directed therapy reduced mortality
compared with standard care. The Rivers
protocol was assessed in two large RCTs:
ProCESS (15) and ARISE (16). Both
trials reported no improvement in survival,
and, compared with the Rivers trial,
1227

both reported a lower mortality in the
control group.
Fluid challenge is the cornerstone
of hemodynamic management in patients
with septic shock. Crystalloids are
recommended as first-line treatment (13).
Albumin may be used as second-line
treatment in accordance with the SSC
recommendation when patients require a
“substantial” amount of crystalloids.
Caironi and colleagues tested the
hypothesis that maintenance of albumin
above 30 g/L until discharge from the
intensive care unit (ICU) or until Day 28
after randomization would be associated
with a better survival at Day 28 (17).
Despite significant improvement of mean
arterial pressure and lower fluid balance
in the albumin group, there was no
significant difference in mortality at Days
28 and 90. The authors reported a post hoc
analysis in the subgroup of patients with
septic shock at inclusion, showing
a reduced mortality in the albumin group.
These remain, however, hypothesis-
generating data. A recent metaanalysis
assessing albumin administration as fluid
challenge or as replacement did not
demonstrate a decrease in mortality
among patients with severe sepsis or
septic shock (18).
Among the initial hemodynamic
resuscitation targets, the SSC recommends
setting mean arterial pressure (MAP) at
>65 mm Hg. The SEPSISPAM trial
compared targets of MAP 65 to 70 mm Hg
versus 80 to 85 mm Hg in patients with
septic shock (19). Increasing MAP to 80
to 85 mm Hg as compared with the SSC
recommendation did not significantly
decrease mortality at Day 28. There were no
overall significant differences in adverse
effect profiles between the two groups, but
the incidence of newly diagnosed atrial
fibrillation was higher in the high-MAP
arm. Among patients with chronic
hypertension (a priori stratification), those
who were treated with the higher MAP
target developed less renal failure as
assessed by the doubling of plasma
creatinine and renal replacement therapy
requirements.
The aim of transfusion is to increase
oxygen delivery during septic shock, but
this increase is usually not associated with
an increase in oxygen consumption. A
liberal transfusion strategy was reported
to be associated with higher morbidity,
especially in nonleukoreduced transfusion.
1228 American Journal of Respiratory and Critical Care Medicine Volume 191 Number 11 | June 1 2015
PULMONARY, SLEEP, AND CRITICAL CARE UPDATE
In 1999, Hebert and colleagues compared
two transfusion thresholds (7 vs. 9 g/dl)
in critically ill patients and reported no
significant difference in Day 30 mortality,
but only 5% of patients had septic shock
(20). The threshold of 7 g/dl contrasts with
the higher thresholds used in the early goal-
driven therapy (9–10 g/dl) in patients with
low central venous oxygen saturation within
the first 6 hours (14). The Danish
Transfusion Requirements in Septic Shock
trial (TRISS) compared 7 versus 9 g/dl
transfusion thresholds in patients admitted
in the ICU with septic shock. Mortality at
Day 90, ischemic events, and use of life
support were similar in the two groups (21).
The restrictive group received significantly
fewer transfusions. Of note, the TRISS trial
did not provide data on the beneficial
effects of early transfusion (within the first
6 h) in the management of septic shock.
Early and adequate antibiotic
administration is associated with improved
survival in patients with severe sepsis.
Consequently, broad-spectrum antibiotics
are used liberally, and deescalation is
compromised when bacterial cultures are
not informative. Biological markers to
assist physicians with early cessation of
antibiotic therapy may be helpful in patients
who have a fast recovery of their sepsis-
induced organ failure. This may help to
reduce antibiotic use, antibiotic resistance,
and costs. SSC suggests the use of a low
procalcitonin cut-off to assist clinicians
and highlights that “clinical experience with
this strategy is limited and potential of
harm remains a concern.” Shehabi and
colleagues investigated a low procalcitonin
cut-off (0.1 ng/ml) algorithm in critically
ill patients with undifferentiated infection
or suspected sepsis (22). There was no
significant reduction in time until antibiotic
cessation, antibiotic-free days, and overall
antibiotic exposure in the experimental
group compared with the control group.
It is impossible to end this update on
sepsis treatment without mentioning the
2014 Ebola outbreak. A critical care
perspective refreshed our knowledge and
demystified Ebola virus disease (23). This
paper underlines care evidence and the
crucial role of initial resuscitation, which
is based on fluid infusion and correction
of metabolic abnormalities. Large
implementation of pragmatic supportive
care should save more lives than the
unproven Ebola virus–specific medical
therapies heralded by the media.
Short- and Long-Term Outcomes:
The Good and the Bad Side of
Sepsis Care
The number of sepsis survivors has been
increasing over time (24). Severe sepsis is,
however, a heterogeneous disease with
several variable factors, including the
source of infection. In the PROWESS
study, patients with urosepsis had the lowest
mortality and represented the only subgroup
in which activated protein C increased
mortality (25). This illustrates how the
benefit–risk ratio of interventions varies
according to the risk of dying. Comparing
outcomes in different causes of septic shock,
Leligdowicz and colleagues found a wide
range of crude mortality data for 20 different
sources of infections (26). They confirmed
the lowest mortality in urosepsis (21.1%)
and observed the highest risk (84.5%) in
disseminated Candida infections. After
adjustment for severity and appropriateness
of treatment, the different risks of mortality
persisted between sources of infection.
The accumulation of unsuccessful trials
testing interventions to reduce sepsis
mortality may be explained by the
heterogeneity of included patients. Future
research should aim to identify subgroups
of patients with sepsis who will benefit
the most from interventions.
Clinical expertise is deemed an
important factor influencing patient
outcomes. The inverse relationship between
hospital/ICU volume and better outcome
has not been consistently reported and can
depend on country, regional organization,
case mix, and statistical method for
adjustment. Two studies from the United
States, published in 2014, showed a
significant association between the high
volume of hospital admissions of patients
with severe sepsis and better survival
(25, 26). Walkey and colleagues (27)
reported an adjusted survival gain of 7%,
and Gaieski and colleagues (28) reported
a 36% increase in odds of survival.
Understanding this relationship may
provide valuable insight for clinical
practice and ICU organization.
Unfortunately, the design of these studies
does not allow identification of survival
mediators. Also, a minimal safe case
volume cannot be determined. The lowest
quartile of hospital volume in the study
of Walkey was particularly large
(i.e., 30–314 patients with sepsis admitted
per year) and overlaps the high volume
PULMONARY, SLEEP, AND CRITICAL CARE UPDATE
ranges of the Gaieski study. Interestingly,
the benefits of being managed in a high-
volume hospital were maximal in patients
with one organ failure only and were not
observed in the most severely ill patients
(28). In everyday practice, more attention
is usually given to the most severely ill
patients despite the fact that the outcome
will be grave regardless of the action taken.
The findings of Gaieski and colleagues
(28) suggest that efforts should be invested
in patients in a less critical state who
would benefit the most from our expertise.
Patients with severe sepsis are
particularly exposed to ICU adverse events.
Implementation of quality improvement
programs may help to reduce morbidity and
improve survival. VAP is usually targeted
by quality programs. VAP prevention
is hampered by many factors, such as case
mix, a large number of risk factors and
preventives measures, and complex and
subjective definitions. A new metric has
been recently proposed: the ventilator-
associated events (VAEs). The definition
of VAE is based on indirect criteria for
worsening gas exchange (i.e., level of PEEP
and FIO2), inflammation criteria, and the
start of a new antimicrobial agent. In
two ICUs in The Netherlands, Klein-
Klouwenberg and colleagues implemented
a novel surveillance paradigm for VAE to
identify VAE measures and to determine
whether they are reproducible, feasible,
and simple (29). VAEs were poorly
correlated with VAP, with many events
being explained by patients worsening
related to other reasons than respiratory
tract infections. VAE surveillance was
successfully implemented in an electronic
system that might help to reduce the
work load of surveillance. Minor changes
in the algorithm, however, significantly
modified the results. Thus, the
reproducibility of surveillance seems
questionable to allow hospital comparison.
Another important question not explored
by this study is whether VAE can be
prevented.
Because the number of sepsis survivors
has dramatically increased over the last
20 years, postdischarge survival has become
a leading issue assessed by a growing
number of research based on “big data”
analysis. Three studies were published in
the Journal. Among severe sepsis hospital
survivors older than 65 years, Yende and
colleagues reported that patients requiring
ICU admission had a 3-fold higher 1-year
Pulmonary, Sleep, and Critical Care Update
mortality compared with matched control
subjects and a 1.5-fold higher 1-year
mortality compared with matched ICU
patients not admitted for severe sepsis
(30). Because persistent inflammation and
a procoagulant state may promote ischemic
cardiovascular complications, the authors
explored the incidence of postdischarge
cardiovascular (CV) events. Thirty
percent of ICU patients with severe sepsis
experienced at least one CV event after
discharge. The risk of postdischarge CV
events was 2-fold higher than in matched
control subjects but was similar compared
with ICU patients with nonsevere sepsis.
Attempts to improve survival after ICU
discharge have been unsuccessful (31).
Rehabilitation represents one of the
proposed measures. Tested in randomized
control trials, physical therapy showed
several beneficial effects, including
improved physical activity, respiratory
muscle function, and length of stay, but had
no effect on mortality. In a large matched
cohort of 15,535 survivors of sepsis in
Taiwan, Chao and colleagues reported that
postdischarge physical therapy significantly
reduced 10-year mortality with a dose
effect (32). Such a benefit contradicts the
results of randomized controlled trials,
but firm conclusions cannot be drawn
from “big data” analysis. This study
identified populations that could benefit
the most from rehabilitation: patients
with an elevated Charlson score, prolonged
mechanical ventilation, and prolonged
length of stay. These factors may prove
useful for designing future studies.
The role of increased postdischarge
morbidity on health consumption has
been compared between patients with
severe sepsis and patients without sepsis
by Prescott and colleagues (33). They
confirmed an increased risk of death in
patients with severe sepsis in the year after
hospitalization. The number of days spent
in health care facilities was significantly
higher in the year after compared with
before hospitalization. Finally, only 20%
of sepsis survivors remained alive without
the need for rehospitalization at 1 year.
These observations raise important
questions for future research (Figure 1).
What is the role of comorbidities, and
how do we prevent chronic disease
destabilization? What is the impact of acute
care quality on delayed morbidity? What
is the place of postdischarge follow-up,
and what interventions could improve
Sepsis AKI
CV events CKD
Destabilization
of preexisting
comorbidities
Decreased longevity
Quality of Absence of post-
acute care discharge follow up
Figure 1. Proposed mediators for decreased
longevity in sepsis and/or patients with acute
kidney injury. AKI = acute kidney injury; CKD =
chronic kidney disease; CV = cardiovascular.
longevity? What are the conditions of dying
after hospitalization, and are we providing
appropriate end-of-life supportive care?
As discussed by Wunch, the increase in
postdischarge healthcare consumption
can be viewed as a success when the
improvement in posthospital care
creates “true ICU survivors” (34).
AKI: Could Early Prediction Help with
Sequela Prevention?
AKI clearly increases inpatient mortality.
Recent efforts have been made to improve
early detection of AKI and to identify
preventive measures limiting the pathologic
process. A small increase in serum
creatinine (Screat) of 26 mmol/L has been
added in recent definitions to increase
its sensitivity. Screat is, however, a poor
marker of glomerular filtration rate and
increases late after injury. Awaiting Screat
elevation delays the implementation of
therapeutic measures. An impressive
number of AKI biomarkers has been,
therefore, studied, with variable results
on their performance to predict AKI, the
need for renal replacement therapy, and
mortality. In a large population of ICU
patients, Bihorac and colleagues evaluated
the ability of two urinary biomarkers,
tissue inhibitor of metalloproteinases
(TIMP)-2 and insulin-like growth factor
binding protein 7 (IGFBP7), to predict
early occurrence of AKI within the 12 hours
of inclusion (35). The performance of the
urinary product of [TIMP-1] 3 [IGFBP7]
was compared with standard parameters
used for AKI detection. Urine output
was not included, although it is probably
more sensitive than Screat elevation to
1229
 PULMONARY, SLEEP, AND CRITICAL CARE UPDATE

predict early AKI (36). The prediction
of AKI was better when the urinary
[TIMP-1] 3 [IGFBP7] was added to the
usual parameters with an area under the
curve increasing from 0.70 to 0.86. Thus,
[TIMP-1] 3 [IGFBP7] represents one of
the best reported AKI biomarkers. The
prediction of biomarkers was improved
when including usual parameters compared
with biomarkers alone; this finding is
a powerful reminder that diagnosis should
perform better when based on a global
clinical judgment rather than on
biomarkers alone. The final diagnosis of
AKI was adjudicated by a panel of expert
nephrologists. It would have been
interesting to test the performance of
experts to predict AKI occurrence against
biomarkers. Although clearly useful for
patient selection in the research domain,
prediction of AKI could be misinterpreted
by clinicians. Patients classified as “no risk”
should not be managed as “no matter for
the kidney.”
As described above in sepsis, the
growth of AKI survivors brought out long-
term sequelae (37). The increased risk of
long-term mortality and of chronic kidney
disease was initially evaluated and
confirmed in patients with severe AKI
requiring renal replacement therapy (38).
In 2,000 ICU patients, Linder and
colleagues evaluated the impact of mild AKI
defined by a small increase of 26 mmol/L
of Screat on 10-year survival (39). The
mortality jumped in the first 28 days in
patients with AKI. Among 28-day and
1-year survivors, the 10-year mortality was
still significantly higher in patients with
mild AKI despite propensity matching.
There was a “dose effect” association with
a higher risk of death in the more severe
classes of AKI. This study does not explain
the long-lasting negative impact of AKI on
outcomes (Figure 1). Sepsis is a common
cause of AKI and may explain long-term
complications and mortality. The authors
did not, however, find any interaction
between sepsis and AKI on outcome. We
have now strong evidence showing that
AKI, whatever its severity, promotes the
development of chronic kidney disease,
increasing the burden of complications,
particularly cardiovascular events (40). The
alarming observation reported by Linder
and colleagues regarding the impact of mild
AKI on outcome raises the question of
the usefulness of a post-ICU discharge
follow-up. The large number of affected
patients (53%) represents an important
task for physicians (39). Further research
is therefore needed to better refine
targeted populations. n
Author disclosures are available with the text
of this article at www.atsjournals.org.

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