2012 – Acute Lung Injury - Department of Medicine - University of ...

The Division of Pulmonary,
Allergy, and Critical Care
Medicine at UPMC
In This Issue
2 2012 Pittsburgh International Lung Conference
3 The Acute Lung Injury Center of Excellence
4 Severe ARDS Secondary to H1N1 Infection
5 Educational Opportunities
6 Acute Lung Injury MSC
7 Transfusion-Associated Complications in the ICU
Summer 2012
Meet the Acute Lung Injury
Center of Excellence Team
Rama K. Mallampalli, MD
Director, Acute Lung Injury Center
of Excellence
Professor of Medicine
Email:
mallampallirk@upmc.edu
Michael Donahoe, MD
Director, Medical Intensive Care
Unit (MICU)
Associate Professor of Medicine
Email:
donahoem@upmc.edu
John W. Kreit, MD
Fellowship Director, Pulmonary
and Critical Care Medicine
Professor of Medicine
Email:
kreitjw@upmc.edu
Janet S. Lee, MD
Associate Professor of Medicine
Email:
leejs3@upmc.edu
Beibei Chen, PhD
Research Assistant Professor
Email:
chenb@upmc.edu
To learn more about how UPMC is transforming
pulmonary, allergy, and critical care medicine, go to
UPMCPhysicianResources.com/Pulmonology
Bryan J. McVerry, MD
Director, Translational Research
in Acute Lung Injury
Associate Director, MICU
Assistant Professor of Medicine
Email:
mcverrybj@upmc.edu
Prabir Ray, PhD
Professor of Medicine and
Immunology
Email:
rayp@pitt.edu
Mauricio Rojas, MD
Assistant Professor of Medicine
Email:
rojasm@upmc.edu
Matthew E. Woodske, MD
Associate Director, Fellowship
Training Program
Assistant Professor of Medicine
Email:
woodskeme@upmc.edu
Yutong Zhao, MD, PhD
Associate Professor of Medicine
Email:
zhaoy3@upmc.edu
The Division of Pulmonary,
Allergy, and Critical Care
Medicine at UPMC
Pittsburgh, Pennsylvania
Comprehensive Lung Center
3601 Fifth Ave., Fourth Floor
Pittsburgh, PA 15213
T: 412-648-6161
F: 412-648-6869
Mark Gladwin, MD
Professor of Medicine
Chief, Division of PACCM
Editors
Matthew Woodske, MD
Assistant Professor
Division of PACCM
woodskeme@upmc.edu
Breann Fiorillo
fiorillobm@upmc.edu
Theresa Dobransky
dobranskyta@upmc.edu
Address correspondence to:
Theresa Dobransky, Editor
3459 Fifth Ave.
Division of PACCM, 628NW
Pittsburgh, PA 15213
For additional information
concerning Respiratory Reader or
requests for additional newsletter
copies, contact Theresa Dobransky
at dobranskyta@upmc.edu or call
412-624-8856.
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TRANS405937 JAB/CS 08/12
© 2012 UPMC
reader
respiratory
Affiliated with the University of Pittsburgh School of
Medicine, UPMC is ranked among the nation’s best
hospitals by U.S. News & World Report.
In This Issue:
The Acute Lung Injury Center of
Excellence, New Research of ARDS,
and More
Historically, UPMC has been home to many of the world’s
most recognized experts in lung disease. Our level of expertise
enables us to provide clinical services and specialized treatments
to patients who have complex disorders, including treatment
of acute lung injury (ALI) or its more severe form, acute
respiratory distress syndrome (ARDS). These life-threatening
disorders commonly occur after pneumonia, severe systemic
infection (sepsis), shock, or use of multiple blood products.
Despite many decades of study, the mortality for ARDS
remains high and the mechanisms that cause the disorder
are not well understood. At the Division of Pulmonary, Allergy,
and Critical Care Medicine at UPMC (PACCM), patients
afflicted with ARDS receive an intensive, multimodality, and
interdisciplinary approach to treatment. The Acute Lung Injury
Center of Excellence within PACCM integrates with the care of
critically ill patients to discover mechanisms that underlie this
illness and to develop newer strategies for ARDS therapy.
The Acute Lung Injury Center of Excellence, led by Rama
Mallampalli, MD, synergizes basic and translational discoveries
that can lead to novel treatments for patients with severe
acute lung injury. We focus on identification of new
biomarkers of ARDS and cutting-edge clinical and preclinical
initiatives of novel modalities (stem cell and immunomodulatory
drugs) that may reverse lung injury associated with viral and
bacterial pneumonia.
We encourage you to take a few minutes to read this publication,
as you will find valuable information on new initiatives and a
case study that discusses ARDS.
Continued on Page 2

2 Respiratory Reader
Division of Pulmonary, Allergy, and Critical Care Medicine at UPMC 3
In This Issue: (continued)
As always, for your convenience, we have
included a referral chart of our specialists with
contact information.
UPMCPhysicianResources.com offers even
more information on our latest treatments and
techniques for diagnosing and treating those
affected by ARDS. This site houses continuing
medical education programs, case studies,
newsletters, videos, and more.
We welcome any suggestions or comments on
how we might support you in the care of your
patients, and we are happy to arrange a consult
or provide more information. Please enjoy this
issue of Respiratory Reader.
2012 Pittsburgh International
Lung Conference
Acute Lung Injury: New Mechanisms,
Future PITTSBURGH Therapies, and INTERNATIONAL
the Translation
to Clinical LUNG Care CONFERENCE
PERSONALIZED MEDICINE OF LUNG DISEASE
Oct. 5 - Oct. 6, 2012
October 28 – 29, 2011 | Pittsburgh, Pennsylvania
University Center, Oakland Campus
The 11th Annual Pittsburgh International Lung Conference
will be held Oct. 5 - Oct. 6, 2012, and will focus on Acute Lung
Injury: New Mechanisms, Future Therapies and the Translation
to Clinical Care.
More than 40 worldwide leaders will speak over the course of
the two-day conference. Day one will focus on clinical features
of ARDS, including phenotypes, limitations of the consensus
definition, the relationship of phenotype to disease outcome, as
well as protocols for clinical management and relevant outcomes
for pre-clinical and clinical studies. Presentations and panel
With great enthusiasm and respect,
Mark T. Gladwin, MD
Professor of Medicine
Chief, Division of Pulmonary,
Allergy, and Critical Care Medicine
Director, Vascular Medicine Institute
Rama K. Mallampalli, MD
Professor of Medicine
Director, Acute Lung Injury Center of
Excellence
discussions will focus on evidence-based practices for the care
of patients who are critically ill with ARDS and also sepsis
and pneumonia.
Day two spotlights research into novel mediators of acute lung
injury, cell death and cytoprotection, as well as mechanisms of
stem cell therapy, and the role of lung innate immunity. Scientific
discussions will include symposia, panel discussions, and a
scientific poster session highlighting junior investigators in
the field.
The educational sessions will enhance the knowledge of attendees
on definitions, diagnosis, and clinical management of acute
lung injury; pre-clinical and clinical investigations; and new
discoveries about the basic science behind acute lung injury.
A maximum of 14 CME credits will be available for attendees.
For more information, please visit the conference website at
PittsburghLungConference.com.
The Acute Lung Injury Center of Excellence
By Bryan McVerry, MD
Director, Translational Research in Acute Lung Injury
Associate Director, Medical Intensive Care Unit
Associate Fellowship Director for Translational Science
Acute lung injury (ALI), and its most severe form, acute respiratory
distress syndrome (ARDS), represent life-threatening complications of
inflammatory disorders, including sepsis, trauma, pancreatitis, and
pneumonia. ALI causes a significant disease burden, affecting 150,000 to
200,000 people in the United States each year and leading to death in as
many as 35% of patients. Because only one large clinical investigation has
demonstrated improved mortality benefit, current and future research is
critically important to advance treatment options for this devastating
syndrome. The Acute Lung Injury Center of Excellence at UPMC aims to
provide state-of-the-art treatment to optimize chances of survival for
these complex patients, to discover new and promising therapies to
improve survival, to offer comprehensive follow-up, to promote long-term
functional recovery for survivors, and to understand the recovery process.
State-of-the-Art Care for Every Patient
At UPMC, we offer the most current therapies for patients with ARDS.
Optimal provision of supportive care includes low tidal volume mechanical
ventilation, conservative fluid management, attention to control of
hyperglycemia, and conservative use of blood product transfusions. A
subset of patients with ARDS will experience severe and refractory
impairment in their ability to oxygenate the blood, placing them at
significantly increased risk of death from the disorder. Several interventions
have been recommended as “rescue” therapies for patients with severe
disease. These so-called rescue therapies include muscle relaxation, inhaled
nitric oxide (iNO), high-frequency oscillatory ventilation (HFOV), prone
positioning, and extracorporeal membrane oxygenation (ECMO). Ideally,
these interventions are provided in specialized centers for the treatment of
ARDS. Because predicting those who will fare poorly is not possible at the
onset of disease, early referral to a tertiary center with expertise delivering
these modalities is essential to optimize the chances of survival. At UPMC,
we have extensive experience with provision of each of these life-sustaining
measures to the appropriate patients.
In recent years, much attention has been dedicated to long-term
functional outcomes of survivors of critical illness and specifically ARDS.
Physical and psychological debility may persist for years following
hospitalization with ARDS. In accordance with recent literature support,
we have developed and initiated a protocol for reduced sedation and early
mobilization of critically ill patients. This has been shown in multiple
studies to improve functionality of patients at discharge and to facilitate
their return to normal activity. In addition to our inpatient services, the
UPMC Comprehensive Lung Center is staffed with experts who provide
comprehensive, long-term outpatient follow-up to recognize and alleviate
complications from an ICU stay.
Clinical Research and Novel Therapeutics
ALI likely represents a constellation of different inflammatory disease
states, thus complicating the design of studies and limiting our ability to
interpret and apply data from clinical investigations. At UPMC, we have
developed the Acute Lung Injury Registry and Biospecimen Repository in
order to better understand the natural history and varying phenotypic
presentation of ALI and ARDS. This will help in the development of
targeted therapeutics in the future and ultimately enable clinicians to
personalize the approach to treatment of patients with ALI. Patients who
participate in this registry will help future patients by providing data for
planning and piloting potential therapeutic studies.
In the Acute Lung Injury Center of Excellence, we are involved in
large-scale clinical trials for the treatment of ARDS. We previously
recruited subjects for the ARDS Network Fluid and Catheter Treatment
Trial (FACTT), and we are currently enrolling patients in the multi-center
randomized, double-blinded, placebo-controlled Ganciclovir/
Valganciclovir for Prevention of Cytomegalovirus Reactivation in Acute
Injury of the Lung (GRAIL) study. In addition to clinical trials, we are
developing partnerships with industry and designing pilot therapeutic and
observational studies to take bench-top science to the bedside.
Cutting-Edge Translational Research
At the Acute Lung Injury Center of Excellence, we have an experienced
team of scientists exploring the mechanisms of disease at the bench in
search of novel therapeutic targets and strategies for future translation to
the bedside. Our investigators are well-funded by the National Institutes of
Health and represent leaders in the fields of lipid biology, alveolar barrier
regulation, pulmonary vascular physiology, and inflammation. This
provides a unique and collaborative approach to mechanistic exploration
at the bench and translation to the bedside.
With advances in critical care medicine and refinements in supportive care
modalities, survival from acute lung injury has been improving, but it
remains a significant public health problem and cause of death. However,
targeted treatments for this complex disorder remain elusive. This is in part
due to incomplete understanding of disease phenotypes and
pathophysiology. At UPMC, we are uniquely positioned to provide
state-of-the-art clinical care and access to clinical and preclinical trials, and
to mold future therapeutics through progressive translational research.
Affiliated with the University of Pittsburgh School of Medicine, UPMC is ranked among the nation’s best hospitals by U.S. News & World Report. www.dept-med.pitt.edu/PACCM Consults and referrals: Please call the UPMC Comprehensive Lung Center at 412-648-6161.

4 Respiratory Reader
Division of Pulmonary, Allergy, and Critical Care Medicine at UPMC 5
Case Presentation:
Severe ARDS Secondary to H1N1 Infection
By Matthew Synan, MD
Fellow
Pulmonary, Allergy, and Critical Care Medicine
A 45-year-old obese female with an unsubstantiated diagnosis of chronic
obstructive pulmonary disease (COPD) initially presented to the
emergency department (ED) for worsening dyspnea in December 2009.
She had been seen in the ED one week prior for similar respiratory
symptoms (cough and dyspnea) and had completed a course of
antibiotics, inhaled bronchodilators, and oral corticosteroids with marginal
improvement. She then developed a high fever and worsening dyspnea
and thus returned to the ED. Chest x-ray on the second presentation
revealed new bilateral multifocal infiltrates consistent with pneumonia.
She was admitted and antibiotics were initiated with ceftriaxone and
azithromycin. Over the following two days, she appeared to improve,
however she developed a high-grade fever on day three accompanied by
worsening dyspnea. After consultation with infectious disease specialists,
antibiotics were changed to vancomycin and piperacillin/tazobactam.
Unfortunately she deteriorated further, requiring intubation for hypoxemic
respiratory failure. She was then transferred to UPMC Presbyterian.
Upon arrival to the hospital, she was found to have significant hypoxemia
and bilateral infiltrates on chest x-ray (Figure A), consistent with acute
respiratory distress syndrome (ARDS). There was no evidence of heart
failure on exam or by echocardiogram. She was placed on low tidal volume
ventilation with high levels of PEEP to maintain oxygenation. Soon after
transfer, her outside hospital cultures returned positive for influenza,
subtype H1N1. She was continued on antibiotics and started on peramivir
(an investigational intravenous neuraminidase inhibitor with anti-H1N1
activity) immediately. Within 24 hours, her oxygenation worsened while
on maximum ventilatory settings, and thus she was commenced on prone
positioning, heavy sedation, and paralytics. She continued to have
desaturations despite this, thus the decision was made to place the patient
on venovenous extracorporeal membrane oxygenation (VV-ECMO). She
remained on VV-ECMO for nine days while her ARDS improved. She was
able to be extubated three days after ECMO decannulation and 17 days
after initial intubation.
Table 1
By Matthew Woodske, MD
Assistant Professor of Medicine
After a short rehabilitation stay for very mild deconditioning and mild
critical illness polymyopathy, the patient was discharged home. She has
been followed in the UPMC Comprehensive Lung Center for more than a
year. Her pulmonary function testing and CXR (Figure B) have now
returned to normal (Table 1).
ARDS is a common clinical entity which is associated with a high
mortality. ARDS and ALI are clinical syndromes defined by non-specific
clinical features including: (1) severe hypoxemia (PaO2/FiO2 ratio

6 Respiratory Reader
Division of Pulmonary, Allergy, and Critical Care Medicine at UPMC 7
Acute Lung Injury MSC
Transfusion-Associated Complications in the ICU
By Mauricio Rojas, MD
Assistant Professor of Medicine
By Janet Lee, MD
Associate Professor of Medicine
ARDS is a condition in which the lungs sustain severe widespread injury,
interfering with their ability to take up oxygen. The pathologic hallmark of
ARDS is tissue injury to one or both sides of the alveolar-capillary
interface, including the endothelial cells and the airway epithelium. For
example, sepsis may cause injury to the vascular endothelium, while
gastric aspiration or pneumonia may cause injury to the epithelial alveolar
lining. However, both injuries lead to a final common pathway in early
ARDS: markedly increased alveolar-capillary permeability leading to an
influx of protein rich fluid into the alveoli and hypoxemia.
When lung injury does occur, the effectiveness of the repair response is
dependent on many factors. Emerging evidence suggests that endogenous
stem cells may play a role in the repair process in ARDS. In addition, recent
studies suggest that intravenously infused exogenous mesenchymal stem
cells can potentially mitigate lung injury and induce repair. Conversely,
abnormalities in stem cell repair processes may explain susceptibility to
ARDS. For example, aged patients are increasingly susceptible to the
development of ARDS, and advancing age has been associated with
abnormal recruitment of stem cells to the lung in particular.
Bone-marrow derived stem cells can be divided in two groups:
hematopoietic stem cells (HSC) and mesenchymal stem cells (B-MSC).
B-MSCs were first described in the early 1970s as clonal, plastic adherent
cells capable of differentiating into several cell types. Recently it has been
demonstrated that B-MSC can transform into cells representing all three
embryological layers: endoderm, mesoderm, and ectoderm. These cells
also support hematopoiesis providing extracellular matrix, cytokines, and
growth factors to the HSC. The ability of B-MSC to create a tolerogenic
niche by direct interaction with immune cells and by secretion of
regulatory molecules makes them attractive therapeutic candidates in the
regulation of the inflammatory response to infection and injury.
Publications from our group have demonstrated compelling benefits from
the administration of B-MSC in animal models of lung injury. In a mouse
model of ALI, initiated by the administration of bacterial endotoxin,
infusion of mouse-derived B-MSC prevents the systemic inflammatory
response, attenuates lung injury, and protects against pulmonary edema, a
hallmark of ALI. Histological examination of lung sections demonstrated
that B-MSC infusion completely attenuated neutrophil infiltration and
B-MSC infusion also decreased the plasma levels of pro-inflammatory
cytokines after endotoxin, further supporting a protective role in ALI.
Since stem cells suppress inflammation in the mouse model by regulating
the immune response, we expanded our observations to study humanderived
B-MSC. Traditional methods of stem cell extraction and
proliferation have used a bone marrow aspirate from a live donor as the
main source of cells from which MSCs are purified. Because of the low
number of cells that are recovered from the biological sample, extensive
manipulation of recovered cells must be performed in order to obtain a
large enough sample for use. These limitations are an important obstacle
to translate B-MSCs into clinical applications as they may result in
chromosomal abnormalities and cellular dysfunction.
To overcome these limitations, Albert Donnenberg, from the University of
Pittsburgh, created a unique protocol to isolate and expand human MSCs.
Demonstrating the therapeutic effect of these cells, we inoculated our
mouse ALI/ARDS model with human B-MSCs and demonstarted
decreased pulmonary edema and inflammation, similar to prior observations
with mouse derived-stem cells.
These and other experimental data support using B-MSC-based therapy
to mitigate or reverse the deadly consequences of ALI and ARDS. This
type of novel therapeutic strategy may have far-reaching implications
for the future treatment of ARDS and other inflammatory conditions,
including acute myocardial infartion, graft versus host disease, and
Crohn’s disease. Phase I and II clinical trials have provided important
evidence that B-MSCs are well tolerated and elicit no increased incidence
of acute side effects when compared to placebo. We hope to advance the
therapeutic niche of B-MSC to include ARDS in the near future.
Often in discussing transfusion-associated complications in the intensive
care setting, we focus upon transfusion-related acute lung injury (TRALI).
But, what is TRALI TRALI is defined as acute lung injury of new onset
with symptoms during or within six hours of transfusion of blood
products[1]. The acute lung injury cannot be attributed to other wellestablished
risk factors for acute lung injury (ALI), such as pneumonia,
aspiration, pancreatitis, or sepsis. Although this definition appears
straight-forward, its application can be challenging in some real-life
situations, particularly in the ICU. For example, in cases where a major risk
factor for ALI is concurrent but transfusion precipitates onset of
symptoms within the pre-defined time frame, the event is referred to as
“possible” TRALI[1,2]. In addition, transfusion-associated cardiac overload
(TACO) can present similarly, but the definition is applied to cases where
left atrial hypertension is the primary explanation for acute pulmonary
edema in the setting of transfusion[3].
From 2005 to 2010, TRALI accounted for the highest number of
transfusion-related fatalities reported to the U.S. Food and Drug
Administration[4]. In addition, TACO has received increasing recognition,
possibly accounting for increased reporting of TACO-related fatalities
between 2005 and 2010. TRALI is uncommon, but is more frequently
observed with plasma containing blood components, such as fresh, frozen
plasma (FFP) or whole blood-derived platelet products, although packed
red blood cell (PRBC) transfusion can certainly promote TRALI.
The mechanism of injury is not completely understood, but most experts
would agree that TRALI requires two hits: (1) a susceptible recipient with
1. Kleinman S, Caulfield T, Chan P, Davenport R, McFarland J, McPhedran S,
Meade M, Morrison D, Pinsent T, Robillard P, Slinger P: Toward an understanding
of transfusion-related acute lung injury: Statement of a consensus panel.
Transfusion 2004;44:1774-1789.
2. Shaz BH, Stowell SR, Hillyer CD: Transfusion-related acute lung injury:
From bedside to bench and back. Blood 2011;117:1463-1471.
3. Toy P, Gajic O, Bacchetti P, Looney MR, Gropper MA, Hubmayr R, Lowell CA,
Norris PJ, Murphy EL, Weiskopf RB, Wilson G, Koenigsberg M, Lee D, Schuller R,
Wu P, Grimes B, Gandhi MJ, Winters JL, Mair D, Hirschler N, Sanchez Rosen R,
Matthay MA: Transfusion-related acute lung injury: Incidence and risk factors.
Blood 2012;119:1757-1767.
primed neutrophils and (2) transfusion of biologic response modifiers that
activates the recipient’s primed neutrophils[5]. In the majority of cases,
the biologic response modifier that is identified is human leukocyte
antigen (HLA) Class II antibody or human neutrophil antigen (HNA)
antibody. Consistent with this observation, recent data suggest that
donor-based TRALI mitigation strategies widely adopted in the U.S. since
2009, such as supply of plasma from primarily male or never-pregnant
female donors, appear to be reducing the risk of TRALI[5].
While transfusion risk factors have been widely studied, recipient risk
factors are now being increasingly recognized, and these include positive
fluid balance prior to transfusion, shock prior to transfusion, current
cigarette smoking, chronic alcohol abuse, liver surgery, high-peak
pressures if mechanically ventilated, and higher plasma IL-8
concentrations[5].
If there is concern that a patient is having a transfusion reaction, such as
TRALI or TACO, the transfusion must be stopped immediately and
supportive measures, such as oxygen therapy, be given in an intensive
care setting. Reporting the event to the local blood center is necessary so
that a full assessment can be performed, if possible, to determine the
cause. In challenging cases where TRALI is suspected, acute lung injury is
severe or likely to be protracted, and early referral to UPMC Presbyterian is
recommended for further evaluation and management. In one referral in
which transfusion was suspected to be a contributing factor, acute
exacerbation of subclinical pulmonary fibrosis was diagnosed[6].
4. U.S. Food and Drug Administration: Fatalities reported to fda following
blood collection and transfusion: Annual summary for fiscal year 2010.
http://wwwfdagov/biologicsbloodvaccines. Accessed Feb 21, 2012.
5. Kleinman SH, Triulzi DJ, Murphy EL, Carey PM, Gottschall JL, Roback JD,
Carrick D, Mathew S, Wright DJ, Cable R, Ness P, Gajic O, Hubmayr RD,
Looney MR, Kakaiya RM: The leukocyte antibody prevalence study-ii (laps-ii):
A retrospective cohort study of transfusion-related acute lung injury in recipients
of high-plasma-volume human leukocyte antigen antibody-positive or -negative
components. Transfusion 2011;51:2078-2091.
6. Woodske M, Donahoe MP, Yazer M, Lee JS: Acute exacerbation of subclinical
pulmonary fibrosis after red blood cell transfusion: A case report. Transfusion.
2011 Aug 9. doi: 10.1111/j.1537-2995.2011.03296.x.
Affiliated with the University of Pittsburgh School of Medicine, UPMC is ranked among the nation’s best hospitals by U.S. News & World Report. www.dept-med.pitt.edu/PACCM Consults and referrals: Please call the UPMC Comprehensive Lung Center at 412-648-6161.