respiratory exchange - cleveland clinic · 2013. 12. 20. · 1987 to 2007 and determined that...

RespiratoryExchange

Research and news for

Physicians from the Cleveland

Clinic Respiratory Institute

Winter | 2011

Also in this Issue

Translational Research at Cleveland Clinic's Asthma Center

pg 7

Introducing our Expanded MICU and New Bronchoscopy Suites

pg 6

Pulmonary Sarcoidosis Mouse Model May Aid Discovery of DiseaseMechanisms

pg 10

A Unique Lung Transplant ProgramBy Marie Budev, DO, MPH; Gosta Petterson, MD, PhD; Kenneth McCurry, MD

continued on page 2

One out of every 10 lung transplants in the US was performed

at Cleveland Clinic in 2009. These included three heart/double-

lung and three double-lung/liver transplants. We attribute these

high numbers and good outcomes to more aggressive donor

utilization, teamwork and strong institutional support. We expect

to have performed more than 120 transplants in 2010, based

on our volume estimates through mid-December.

We welcome complex cases, and care for many patients who

have been turned down by other centers for being too old or

having multiple co-morbidities. We evaluate many hundreds of

end-stage lung disease patients every year, from the United

States and elsewhere. The new lung allocation scores (LAS)

have not affected our average wait times, in which almost

one-third of those listed get new lungs in 30 days, and 90

percent are transplanted within a year. Nationally, only 40

percent get a transplant in that time. Although we transplant

more high-acuity cases, our hospital and 30-day mortality

remain low. Our survival rates are generally at or above the

national average.

Cleveland Clinic performed 157 lung transplants in 2009, setting an international record for lungs transplanted

in a single year. The survival outcomes at one year for the patients transplanted in 2009 remains at or above

the national average and our long-term survival also is above the national average.

72580_CCFBCH_ACG.indd 1 1/17/11 12:18 PM

With five lung transplant surgeons and a team of transplant pulmonologists, supported

by specialists in Infectious Disease, Immunology and other specialties, our program

is well-prepared for what may be an annual 200 or more lung transplants in the near

future. Over the years, we have built a professional environment where physicians can

thrive and practice medicine to the best of their abilities. As a result, everyone works

as a team and the patient gets the very best care before, during and well beyond

surgery. We have the support of the full institution, from nurses to administrators.

Our transplant coordinators are experienced, competent and sensitive to our patients.

Kenneth McCurry, MD, was designated as the UNOS primary surgeon and surgical direc-

tor of Heart and Heart-Lung Transplant in 2010. Marie Budev, DO, MPH, was designated

as the UNOS primary physician and medical director in 2009. Gosta Pettersson, MD,

PhD, primary surgeon and surgical director until 2009, continues to study all aspects of

lung transplantation and to refine its techniques.

Cleveland Clinic is a leader in research and innovation in lung transplantation. Team

members lead and participate in multicenter trials, including studies of primary graft

dysfunction, acute rejection therapy, and induction therapy and ex vivo perfusion.

Dr. McCurry has a research appointment in the Department of Pathobiology, where he is

investigating means to increase utilization and developing therapies to improve post-trans-

plant outcomes. His research interests include reperfusion ischemia injury – a persistent

cause of morbidity and mortality in the early post-transplant period. One advantage of high

patient volumes is the opportunity to perform more randomized studies.

Cleveland Clinic recently received two R34 planning grants from the NIH. The first is ex-

amining antibody mediated rejection in lung transplant and its treatment and the second

is looking at lung transplant and chronic rejection.

A Unique Lung Transplant Program continued

Dear Colleagues:I am pleased to present to you the 2011

issue of Respiratory Exchange.

As you will see in the pages that follow,

we have had a busy year at the Cleveland

Clinic Respiratory Institute. Our experts

in Pulmonary, Allergy and Critical Care

Medicine; Thoracic and Cardiovascular

Surgery; Thoracic Imaging; and Pulmonary

Pathology cared for nearly 90,000 patients.

We also saw significant increase in our

staff this past year, with a total of 15 physi-

cians joining our Institute. This growth has

allowed us to expand our existing services

particularly in the areas of lung transplant,

bronchology and medical intensive care as

well as to increase our specialists available

in the community at regional sites.

In this year’s issue, you can read about

our latest clinical programs and research,

including one especially notable highlight,

our lung transplant program performing

157 lung transplants in 2009, a world-record

number for a single center.

Thank you for picking up this issue of

Respiratory Exchange. We hope you enjoy

these articles showcasing our recent work.

For past issues, please visit out website at

http://my.clevelandclinic.org/pulmonary.

Please feel free to contact us at our toll-free

number for physicians, 866.CCF.LUNG

(866.223.5864), if you have any questions or

would like to refer a patient. As always, we

welcome the opportunity to work with you.

Sincerely,

Herbert P. Wiedemann, MD, MBA

Chairman, Cleveland Clinic

Respiratory Institute

2 | Respiratory Exchange


Winter 2011 | 3

A greater use of lungs from donation after cardiac death (DCD) could help increase the

number of transplants. Today, most transplanted organs come from donation after brain

death, reflecting a long-standing bias in favor of brain death organs. A 2008 study at

Cleveland Clinic evaluated all DCD lung transplants performed in the United States from

1987 to 2007 and determined that survival after lung transplant using DCD donors was

excellent and, in fact, better than survival after brain-death donation.1

In 2007, Dr. Pettersson performed the world’s first bronchial artery revascularization

(BAR) in lung transplantation. In lung transplant, these arteries are routinely ignored, leav-

ing bronchi dependent on venous blood supply. As a result, serious and sometimes fatal

bronchial healing problems occur in 15 percent of lung transplant patients. Dr. Pettersson

revascularized the bronchi by attaching the patient’s left mammary artery to a major

bronchial artery in the donor lungs. Since then, 26 patients have been transplanted with

BAR at Cleveland Clinic, with 25 patients having excellent airway healing. Assessment of

long-term results (e.g., incidence of BOS) is underway.

A recent study appearing in the Journal of the American Medical Association shows a

wide variability in five-year survival among lung transplant centers in the U.S. It suggests

that the choice of where a patient has lung transplantation may be among the most impor-

tant determinants of success. Although in this study high volume centers (more than 50 a

year) do not always have the best outcomes, at Cleveland Clinic, this is not the case. The

Cleveland Clinic Lung Transplant Program is able to combine high volumes with high

acuity, to achieve outcomes that are at or surpass the national average.

Dr. Pettersson revascularized

the bronchi by attaching

the patient’s left mammary

artery to a major bronchial

artery in the donor lungs.

Since then, 26 patients have

been transplanted with BAR

at Cleveland Clinic, with

25 having excellent air-

way healing. Assessment

of long-term results (e.g.,

incidence of BOS) is

underway. References

1. Mason et al. Should lung transplantation be performed using donation after cardiac death? The United States experience. J Thoracic Cardiovasc Surg 2008; 136:1061-1066.



Antibody-mediated Rejection after Lung Transplant: Is it Clinically Significant?By Carol Farver, MD

The major focus of rejection has been

acute cellular rejection involving specific T

lymphocytes, but the improved detection of

circulating antibodies against the donor lung

present in the lung recipient has introduced

another potential form of graft injury, known

as antibody-mediated rejection (AMR). This

form of rejection is well-documented as a

cause of organ failure in other solid organs,

such as the heart and kidney, but its role in

lung transplantation is not clear. Currently,

a focused effort to study this problem by an

interdisciplinary team of physicians from the

Cleveland Clinic Transplant Center, including

pathologists, pulmonologists, immunologists

and surgeons is underway.

Antibody-mediated rejection is a form of

graft injury thought to be the result of anti-

bodies to donor HLA antigens in the recipient

after transplantation, which cause activa-

tion of complement in the alveoli of the new

donor lung and alveolar injury. This injury

can cause a number of respiratory symp-

toms that may include diffuse pulmonary

infiltrates, severe hypoxemia, blood-tinged

sputum and, in the most fulminant cases, re-

spiratory failure. This clinical picture is quite

nonspecific in this setting and can be difficult

to distinguish from complications of infection

or cellular rejection. It may occur within

minutes or days of transplantation, but also

has been implicated in bouts of unexplained

respiratory illness in these patients up to

two years after surgery.

Lung transplantation is now an accepted and increasingly common therapy for patients with pulmonary disorders

resistant to other therapies and who are progressing toward end-stage lung disease. Though the long-term outcomes

are improving, unfortunately, they remain disappointing compared to those of other solid organs, such as heart and

kidney. The reported median survival is approximately five years and rejection and infection remain the leading

causes of death.

Figure 1. A biopsy from a transplanted lung in a patient with antibody-mediated rejection (AMR). This pathology shows evidence of capillaritis with hemorrhage, hemosiderin-leaden macrophages and acute inflammatory cells within the interstitial capillaries. (Hematoxylin and eosin; 200x).


Winter 2011 | 5

The pathologic pattern of injury is simi-

larly nonspecific. The most commonly seen

pathology includes diffuse alveolar damage

(DAD)/acute respiratory distress syndrome

(ARDS) or a small vessel vasculitis (Figure

1), but other patterns of injury also may be

possible. As techniques to measure these

anti-donor antibodies in the peripheral blood

as well as in the transplanted lung have been

developed and improved, it has allowed for

more sensitive detection of them and for

correlation of their presence with both the

clinical symptoms and the lung pathology.

The pulmonary pathology section of the

Pathology and Laboratory Medicine Institute,

including myself and Valeria Arrossi, MD, are

working in conjunction with Marie Budev,

DO, MPH, Medical Director of the Cleveland

Clinic Lung Transplantation Program and

Medhat Askar, MD, PhD, Peter Lalli, PhD,

Diane Pidwell, PhD and Lynne Klingman of

the Allogen Laboratories to study this impor-

tant clinical problem more closely.

Figure 2. A positive immunofluorescence stain for C4d in a lung biopsy from a transplant patient with antibody-mediated rejection. The antibody binds to the capillary within the alveolar wall and produces a linear green immunofluorescent staining pattern, characteristic of C4d activation of the endothelium. (C4d IF; 100x)

We are presently conducting a study that

will measure these antibodies in the blood

before transplantation and at each clinic visit

after transplantation and evaluate positive

staining for antibodies to C3d and C4d as

a measure of complement activation in the

surveillance biopsy specimens taken from the

transplanted lung (Figure 2). We hope this

work will define more clearly the clinical and

pathologic picture of AMR as a first step to

improving outcomes in these patients.

Reach Dr. Carol Farver at 216.225.7695

or [email protected].

As techniques to measure

these anti-donor antibodies

in the peripheral blood as

well as in the transplanted

lung have been developed

and improved, it has al-

lowed for more sensitive

detection of them and for

correlation of their pres-

ence with both the clinical

symptoms and the lung

pathology.



Introducing our Expanded MICU and New Bronchoscopy SuitesIncreasing our capacity to better serve you

Cleveland Clinic recently expanded its medical intensive care unit

(MICU) and opened new bronchoscopy suites to meet an increasing

demand for these services.

MICU

Our MICU, led by Jorge A. Guzman, MD, now has 43 beds to better handle higher volumes

due to growth in our lung transplant and critical care transport programs and high-acuity

patients. Board-certified intensivists provide in-house coverage 24/7. We project more than

2,000 admissions per year due to this increased capacity. In view of our high transfer popu-

lation (35 percent of admissions), patient outcomes remain excellent, with mortality rates

below the risk-adjusted predicted values and improving infection rates.

Bronchoscopy Suites

In 2010, we opened four new bronchoscopy suites to accommodate increasing diagnostic

and therapeutic bronchoscopy volumes. We have some of the world’s most extensive experi-

ence with electromagnetic navigation, lung transplant-related airway disease, self-expanding

metallic stents, management of airway complications due to histoplasmosis, benign airway

diseases and metallic stent removal. In 2009, we performed 2,572 bronchoscopies, a 38

percent increase in five years. Importantly, our complication rates remained low.

No Patient Too Sick… No Patient Too Far

Cleveland Clinic’s Critical Care Transport is

designed to help critical care patients any

where in the world get the care they need.

We transport critically ill and injured patients

via ground mobile ICU, rotor wing aircraft

(helicopter), and fixed wing aircraft (jet).

• Our transport teams are staffed with Acute

Care Nurse practitioners (ACNPs), formally

trained as critical care interventionalists

• Treatment can begin during transport, thus

providing the highest possible quality of care

• We can transport patients requiring special

critical care needs including intra-aortic

balloon pumps, ventricular assist devices

or extra corporeal membrane oxygenation

To transfer a patient, call 800.533.5066 The new bronchoscopy suites were possible in part thanks to a generous contribution by Patricia Brundige in memory of her husband, Thomas.


Winter 2011 | 7

Research AdvancesCleveland Clinic’s Asthma Center leverages translational research to support and enhance patient care and outcomesBy Sumita Khatri, MD, MS

Physicians and specialists from a variety of medical and surgical disciplines as well

as subspecialties work collaboratively at Cleveland Clinic’s Asthma Center to deliver

state-of-the-art clinical services and novel agents or approaches to diagnose and

treat primary adult and pediatric asthma patients.

Moreover, under the leadership of co-directors

Sumita Khatri, MD, MS, David Lang, MD, and

Serpil Erzurum, MD, the Asthma Center remains

at the forefront of developing innovative treatments

through clinical trials and leveraging translational

research that supports and enhances patient care.

For example, we are involved in a unique research

partnership with the U.S. Environmental Protection

Agency to evaluate whether hospital presentations

for asthma in Northeast Ohio are temporally as-

sociated with poor air quality, and whether certain

sources of air pollution may partially explain pat-

terns of hospital presentations. Our preliminary work

has demonstrated that proximity to major highways

and roadways is a risk factor in asthma morbidity.

Another research project is investigating hyaluronan

(HA) as a central mediator of infl ammation and

remodeling in the asthmatic airway. Our research

will determine the utility of HA as a biomarker for

asthma and disease activity. We also are investi-

gating low molecular weight HA as a therapeutic

for asthmatic infl ammation. Additionally, clinical

investigators are examining the pathways between

HA and lymphocytes that occur within the lung dur-

ing asthmatic infl ammation, which may lead to the

development of new, novel therapeutics.

Cleveland Clinic researchers also are investigat-

ing how angiogenic remodeling is involved in the

genesis of asthma. Circulating CD34+CD133+

pro-angiogenic stem cells are essential in new

blood vessel formation. During their post-natal life,

these cells reside in the bone marrow. Although

rarely found in the peripheral blood circulation,

these stem cells can be rapidly mobilized by

angiogenic factors. These stem cells have opened

new perspectives of angiogenesis and how it may

play a role in the origins of asthma. Our clini-

cal investigators have shown circulating bone

marrow-derived CD34+CD133+ progenitor cells

in asthma are higher than in healthy controls, and

are key players in the initiation of vascular remod-

eling in the airways. More recently, we reported

that these progenitors regulate eosinophil traffi ck-

ing to asthmatic lungs via increased expression of

eotaxin-1, a main chemoattractant for eosinophils.

These progenitor cells release their pre-synthesized

eotaxin content after contact with vascular cells

of allergen-exposed lungs. Circulating progenitors

also have the potential to differentiate into several

lineages relevant to asthma including mast cells

and eosinophils. These fi ndings provide emerg-

ing evidence that circulating pro-angiogenic stem

cells are pro-infl ammatory. Our ongoing research

is investigating whether pro-angiogenic stem

cell-derived eotaxin can serve as a biomarker for

disease outcome, and if inhibition of these stem

cells can benefi t clinical outcomes in asthmatics.

Finally, Cleveland Clinic is collaborating with the

National Institutes of Health in the Severe Asthma

Research Program (SARP), an observational study

to better characterize asthma’s pathology. Through

such NIH-sponsored research programs and

investigator-initiated studies, Asthma Center investi-

gators are making advances in the understanding of

the pathophysiology of asthma, therapeutic targets

for asthma, and epidemiology of asthma. Moreover,

profi ling of asthma enables physicians to better

determine which patients will benefi t from various

therapeutic modalities, such as biologic therapies or

interventions, such as bronchial thermoplasty.

Recommended Reading

Asosingh K, Erzurum SC. Angioplasticity in asthma. Biochem Soc Trans. 2009 Aug;37(Pt 4):805-10.

Asosingh K, Swaidani S, Aronica M, Erzurum SC: Th1- and Th2-dependent endothelial progenitor cell recruitment and angiogenic switch in asthma, J Immunol 2007, 178:6482-6494.

Asosingh K, Hanson JD, Cheng G, Aronica MA, Erzurum SC: Allergen-induced, eotaxin-rich, proangiogenic bone marrow progenitors: a blood-borne cellular envoy for lung eosinophilia, J Allergy Clin Immunol 2010, 125:918-925

Dunnill MS. The pathology of asthma, with special reference to changes in the bronchial mucosa. J Clin Pathol. 1960 Jan;13:27-33.

Khatri SB, Holguin FC, Ryan PB, Mannino DM, Erzurum SC, and Teague WG. Association of ambient ozone exposure with airway infl ammation and allergy in adults with asthma. J of Asthma 2009; 46: 777-785.

Khatri SB, Newman C, Rose J, Ross K, Pillai M, Holstein A, Tailor S, Hammond S, Norris G. Associations of Air Quality with Asthma During the Cleveland Multiple Air Pollutant Study (CMAPS). Am J Respir Crit Care Med. 2010; 181:A6827.

Norris G, M. Landis M, Gilmour I. EPA Research Highlights: Tracking Air Polution Sources for Exposure,Health, Ecology, and Regulation. EM-Journal of Air & Waste Management Association, 2009.



Bronchial Thermoplasty: A New Asthma Therapy Available at Cleveland Clinic. By Thomas Gildea, MD and Sumita B. Khatri, MD, MS

Bronchial thermoplasty (BT) is a new therapeutic modality recently FDA-approved for the treatment of severe refractory

asthma not well controlled on high-dose inhaled corticosteroids and long-acting bronchodilator therapy. BT involves the

application of radiofrequency energy in a controlled manner to provide thermal treatment to airways. This new procedure,

which occurs in three separate sessions, is now offered as part of the comprehensive management of patients with asthma

in the Respiratory Institute. Clinical trials demonstrate the feasibility, relative safety and improved clinical outcomes in

patients with severe asthma who undergo BT when medical therapies do not control their symptoms. Similar to the criteria

in the multi-center AIR2 clinical trial, patients who are 18 to 65 years old, current non-smokers for the past year, and have

refractory symptomatic asthma on appropriate controller therapy are considered for this treatment at Cleveland Clinic.

Asthma is a chronic inflammatory condition of the airways char-

acterized by episodic symptoms of breathlessness, cough, and

wheezing. The chronic airway inflammation can lead to persistent

airflow obstruction that can be difficult to manage and control, even

with the best available medical therapies. Bronchoconstriction in

asthma is characterized by increased airway smooth muscle (ASM),

airway closure and hyperresponsiveness temporarily reversed with

acute bronchodilators, but medical therapy targeting ASM is not

available. This potential gap in the management of asthmatics is

what is targeted by this new therapeutic modality, BT.

Background on Bronchial Thermoplasty:

The use of this technology to treat airway smooth muscle began with

animal studies which showed feasibility of using radiofrequency ener-

gy to decrease ASM.1 Subsequent clinical studies and trials in patients

that were non-asthmatics or had mild to moderate persistent asthma,

and finally moderate to severe refractory asthma were performed and

helped identify appropriate candidates, anticipated adverse events,

and expected outcomes.2-5

Observational studies in mild to moderate persistent asthmatics

demonstrated a steady improvement in airway hyperresponsiveness

and symptom-free days up to two years after BT. In the Research in

Severe Asthma (RISA) trial, patients with severe asthma undergoing

BT were studied for safety, changes in asthma symptoms and ability to

reduce daily inhaled or oral corticosteroids4. After treatment, there were

reductions in rescue inhaler use and improved asthma quality of life

scores. The Asthma Intervention Research (AIR) trial was a prospective

randomized non-blinded study performed to determine whether asthma

control could be improved after BT. Morning peak flow, rescue medica-

tion use, Asthma Quality of Life Questionnaire (AQLQ) and Asthma

Control Questionnaire (ACQ) scores were all significantly improved.3

With BT treatment, there was an encouraging reduction in the number

of mild exacerbations with 10 fewer mild exacerbations per subject per

year. Cleveland Clinic participated in the latest randomized clinical trial,

the AIR2 trial. This study included a control ‘sham’ group that received

bronchoscopy; however, radiofrequency energy was not delivered across

the BT catheter.5 Results showed a significant improvement in asthma

quality of life in the BT group, a significant decrease in severe exacer-

bations, and an 84 percent reduction in Emergency Department (ED)

visits in those receiving BT.

Clinical trials demonstrate that adverse events can occur with

bronchial thermoplasty, making appropriate patient selection key

to the success of this procedure. The most frequent side effects are

symptoms of airway irritation such as cough, dyspnea, wheeze and

bronchospasm.6 Therefore, close post-procedure monitoring for early

and aggressive management of short-term exacerbations (up to six

weeks after the last session) is warranted. Patients should be aware

that less frequent but severe adverse events can include infections,

pleurisy and bleeding.

What patients can expect:

Once a patient is referred for evaluation for bronchial thermoplasty, our

office will contact the patient, gather outside records, and schedule a

visit with specialists who perform the procedure. Any further necessary

testing will be performed to properly assess candidacy for BT.

A full course of treatment requires three separate bronchoscopic proce-

dures. Each lower lobe is treated in its own procedure and then both

upper lobes are treated in the same procedure. The right middle lobe

is not treated. Each is separated by approximately two to three weeks.

Patients are assessed prior to and on the day of the procedure to ensure

relative disease stability before proceeding with the treatment.5


Winter 2010 | 9

Bronchoscopy is performed under conscious sedation, (fentanyl/

midazolam/ topical lidocaine) via a transnasal approach with a flex-

ible bronchoscope. Glycopyrrolate is used to decrease secretions.

Radiofrequency (RF) or thermal energy is directed in the airways by

deploying a wire basket in a catheter via the (2 mm) working channel

with the intent of treating accessible airways 3 to 10 mm in diameter.

Each actuation of the system delivers RF energy to heat the tissue.

The technique requires meticulous catheter placement of each 5 mm

treatment zone with direct approximation, but no overlap. A treatment

map is generated to assure complete, but not duplicate, treatment in

all reachable segments. Patients are observed for airway reactivity,

asthma exacerbations, or other complications during an extended re-

covery and monitoring period during which bronchodilators are given

and spirometry performed. Patients are discharged when they have

clinically recovered and spirometry is within 20 percent of baseline.

To summarize, recent clinical trials demonstrate the feasibility, relative

safety, and improved clinical outcomes in patients with severe asthma

who undergo BT when medical therapies do not control their symp-

toms. Long-term studies are ongoing to evaluate the duration of effect

and safety of BT.

Dr. Thomas Gildea is the Head of the Section of Bronchoscopy in

the Respiratory Institute. He can be contacted at 216.444.6490 or

[email protected]. Dr. Sumita B. Khatri is Co-Director of the Asthma

Center and Medical Director, Bronchial Thermoplasty Program.

She can be contacted at 216.445.1701 or [email protected].

Bronchial Thermoplasty Being Performed at Cleveland Clinic

Differences in airway caliber during bronchoscopy noted between visualized right upper airway (smaller, untreated) and the left lower airway (larger, previ-ously treated) in asthmatic patient.

Catheter deployed making contact and delivering energy (note blanching).

Requirements for Bronchial Thermoplasty at Cleveland Clinic:

• Age 18 – 65 years

• Ongoing severe persistent asthma symptoms despite

treatment with inhaled corticosteroid and LABA therapy:

Corticosteroid dose (beclomethasone equiv.) (μg/day) ≥

1,000, and

LABA dose (salmeterol equiv.) (μg/day) ≥ 100

• Oral corticosteroid dose (mg/day) ≤ 30

• Pre-Bronchodilator FEV1 (% Predicted) ≥ 50%

• Non-smoker for past year with < 10-pack year history

• Absence of other conditions: interstitial lung disease,

Churg-Strauss syndrome, pulmonary hypertension, allergic

bronchopulmonary aspergillosis, arrhythmias, immunosup-

pressant therapy, or need for pacemaker/defibrillator.

For more information or to refer a patient for evaluation, please

contact the thermoplasty coordinator Joan Scharf (scharfj@

ccf.org), Dr. Sumita Khatri ([email protected]) or call the referral

line at 216.445.6266.

References

1. Danek CJ, Lombard CM, Dungworth DL, et al. Reduction in airway hyperresponsiveness to methacholine by the application of RF energy in dogs. J Appl Physiol. Nov 2004;97(5):1946-1953.

2. Miller JD, Cox G, Vincic L, Lombard CM, Loomas BE, Danek CJ. A prospective feasibility study of bronchial thermoplasty in the human airway. Chest. Jun 2005;127(6):1999-2006.

3. Cox G, Thomson NC, Rubin AS, et al. Asthma control during the year after bronchial thermoplasty. N Engl J Med. Mar 29 2007;356(13):1327-1337.

4. Pavord ID, Cox G, Thomson NC, et al. Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma. Am J Respir Crit Care Med. Dec 15 2007;176(12):1185-1191.

5. Castro M, Rubin AS, Laviolette M, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med. Jan 15 2010;181(2):116-124.

6. Cox G, Miller JD, McWilliams A, Fitzgerald JM, Lam S. Bronchial thermoplasty for asthma. Am J Respir Crit Care Med. May 1 2006;173(9):965-969.



Pulmonary Sarcoidosis Mouse Model May Aid Discovery of Disease Mechanisms By Carmen M. Swaisgood, PhD, and Daniel A. Culver, DO

A major limiting factor to discovering the mechanisms involved in

the pathogenesis of sarcoidosis is the lack of an animal model that

approximates the human disease. The models typically used in the past

15 years have been helpful for studying the acute events in Th1- or Th2-

polarized responses to complex protein mixes, such as purified protein

derivative. Progress toward developing an acceptable sarcoidosis animal

model had been hindered by the lack of sarcoid-specific antigens. While

the antigen(s) causing sarcoidosis are not known, increasing molecular

and immunologic evidence point to mycobacterial virulence factors as

strong potential candidates. We recently reported the development of

an antigen-specific sarcoidosis murine model using a microbial peptide

associated with human sarcoidosis granulomas. (Figure 1)

Using a peptide corresponding to a fragment of mycobacterial superoxide dismutase A

(sodA) isolated from sarcoidosis patients, we developed a pulmonary model of sarcoid-

osis granulomatous inflammation. This work was done in collaboration with investigators

from Vanderbilt University, who had previously isolated the sodA peptide and had shown

specific immune responses to it in sarcoidosis patients but not control subjects. Features

of this model strongly resemble the human disease, including:

• Hilar lymphadenopathy and parenchymal infiltrates were present in the sodA-treated

mice, with no gross abnormalities of the heart, liver or spleen and no beads or granulo-

mas found in these tissues.

• Extensive granuloma formation developed throughout the lungs of sodA-treated mice

(Figure 2A). Most noncaseating granulomas were concentric to the bead, had several

multinucleated giant cells and were localized to the bronchoarterial bundle (Figure 2B).

These histological features correlate well with those observed in human sarcoid lungs.

• Macrophages were interspersed throughout the granuloma, albeit most abundantly in

the innermost layers closest to the beads (Figure 3A). In addition, CD4+ T cells were

abundantly present in the middle layers of mouse granulomas (Figure 3B).

• There was a significant increase in lymphocytes in the BAL of sodA-treated compared

to control mice, with a CD4/CD8 skew.

• CD4+ cells from bronchoalveolar lavage responded to the sodA, similar to the immune

responses seen in humans.

Figure 2. Lung Granuloma Formation in Mice Four Days After Challenge. Lungs were paraffin embedded, cut and stained with Hematoxylin and Eosin. (A) Lung of a mouse sensitized and challenged with sodA. (B) A granuloma showing multinucleated giant cell (black arrow) around the bead (b).

(A)

(B)


Winter 2010 | 11 Winter 2011 | 11

• Blocking of the Type II major histocompatability complex abolished the immune

recognition of sodA by CD4+ T cells. This correlates with the human disease in which

mycobacterial antigens presented by these MHC Class II alleles are recognized by

sarcoidosis CD4+ T cells.

• As observed in human sarcoid BAL fluid, sodA caused the increase of Th1 cytokines

IL-2 and IFN-γ compared to untreated mice. In contrast, the levels of Th2 cytokines

IL-4 and IL-5 in the untreated and the sodA-treated mice were the same.

This pulmonary sarcoidosis mouse model shows the immunopathological features seen

in active sarcoidosis. These include: a) development of noncaseating granulomas from

peptides unique to sarcoidosis; b) cell type and Th1 cytokine patterns similar to those

observed in sarcoidosis subjects at presentation; c) dependence on MHC Class II alleles

in generating immune responses. This model will facilitate studies aimed at identifying

the relevant mechanisms leading to sarcoidosis resolution or progression to fibrosis.

Contact Dr. Carmen Swaisgood at 216.444.4968 or [email protected] and Dr. Daniel

Culver at 216.444.6508 or [email protected].

Reference

Swaisgood CM, Richter K, Moeller S, Klemenc J, Ruple L, Culver DA, Drake WP. Development of a sarcoidosis murine lung granuloma model using mycobacterial antigen sodA. Am J Respir Cell Mol Biol 2010.

Figure 3. Immunohistochemical Analysis of Leukocytes Present in the Lung Granulomas of sodA-treated Mice. (A) Macrophages (B) CD-4+ T cells

Figure 1. Timeline of Murine Model of Lung Sarcoidosis. Mice were sensitized with an emulsion of Incomplete Freund's Adjuvant (IFA) and sodA peptide on day 1 and challenged via tail vein injection on day 14 with sodA-coupled beads, which embolized to the lungs. Lungs and BAL were collected four days after challenge on day 18.

Day 1 – Sensitization

Day 14 – Challenge

Day 18 – Collect

(A)

(B)



Clinicians for centuries have noted distinct

changes in the breath odor of patients with

certain diseases such as diabetes and renal

failure. However a catalytic point in breath

research was Linus Pauling’s identification

of over 250 breath compounds during the

1970s. Since this time, pivotal advance-

ments in the field of breath testing have

helped revolutionize our understanding of

the components of exhaled breath and their

etiology in disease. With major improvements

in detection technologies (infrared, electro-

chemical, chemiluminescence, of many) and

the application of sensitive mass spectrom-

eters, we are now able to qualitatively and

quantitatively measure the thousands of

identified compounds in exhaled breath.

Providing promise for future technologies,

a growing number of FDA approved devices

have emerged in the past decade for use in

monitoring asthma, diagnosing transplant

organ rejection and H. pylori infection, detect-

ing blood alcohol concentration (BAC), and

for monitoring breath gases during anesthe-

sia, mechanical ventilation, and respiration

among others.

Using highly sensitive equipment such as

selected ion flow tube mass spectrometry

(SIFT-MS) our team at the Cleveland Clinic

has the capability of measuring volatile

organic compounds (VOCs) in the parts per

trillion (ppt) range in human breath. With our

database of hundreds of analyzed samples

and access to multiple diseases our group is

moving towards identifying relevant VOCs in

disease and understanding the origins of VOC

from specific metabolic pathways.

In recent years, one arena we have contrib-

uted extensively to is the understanding of

the breath biomarker, nitric oxide (NO), in

asthma. In the early 1990s NO levels were

found to be elevated in the exhaled breath of

patients with asthma compared to controls

and later linked to eosinophilic airway inflam-

mation. However, initial NO detection devices

were large, cumbersome, and nearly impos-

sible to use outside of the research laboratory.

In 2003 the first NO asthma monitoring

desktop device received FDA clearance

representing a hallmark in new breath test-

ing technology. Advantages of exhaled NO

monitoring in asthma include its non-invasive

nature, ease of repeat measurements, and

use in adult and child populations with severe

airflow obstruction where other techniques

would be difficult or impossible to perform.

Originating from the concept that exhaled breath could serve as a window into the physiological state of the body,

breath analysis has emerged as new frontier in medical testing. Breath testing provides a potential clinical benefit as

a cost effective, non-invasive diagnostic tool for disease of the lung and beyond. With growing evidence of clinical

utility, standardization of methods, and new sensor and detection technologies the stage is set for breath testing

to gain considerable attention and wider application in upcoming years.

Single thin film nitric oxide sensor

Fabricated multiple array of thin film nitric oxide sensors

The Ohio Third Frontier Program at Cleveland Clinic: Advancements in Breath Testing and Sensor DesignBy Raed A. Dweik, MD


Winter 2011 | 13

To fully advance the breath analysis fi eld,

there had to be a close collaboration between

technical experts who typically have a device

looking for clinical application, the medi-

cal experts who have the clinical problem

looking for a test/biomarker that can be

helpful in diagnosis or monitoring, and

industry/commercial experts who can build

and commercialize the fi nal product. This

multidisciplinary collaboration is exactly

what we have accomplished in our ongoing

project: “Breath Analysis: Targeted Sensor

Development and Commercialization for

Health Care Diagnostics” that was funded

with a $3.8 million Third Frontier Award

from the Ohio Department of Development

(ODOD). Our team brings together a range

of world-leading capabilities in academia,

industry, and government with extensive

experience in sensor development and clinical

applications including recognized centers of

excellence such as the Electronics Design

Center at Case Western Reserve University

(CWRU), the Center for Industrial Sensors

and Measurement (CISM) at Ohio State

University (OSU), NASA Glenn Research

Center, Makel Engineering, Inc. (MEI),

and the Exhaled Breath Laboratory at the

Cleveland Clinic. Our team is currently devel-

oping several sensors for potential medical

applications including a sensor designed for

a home NO monitoring device for asthma.

The Ohio Third Frontier Program support we

received has resulted in promising prospects

for the future. At OSU a major accomplish-

ment has been successful improvements to

the NO sensor based on the electrochemi-

cal cell design. Based on the evolving OSU

design, NASA Glenn Research Center and

CWRU are currently developing advanced

methods for miniaturization of the NO

sensor technology. This has involved fabrica-

tion of thin fi lm sensors within the NASA

Microsystems Fabrication Clean Room and

testing of the sensor in the Chemical Sensor

Testing Laboratory. Further, the ability to

fabricate multiple, operational single sensors

on the same substrate has been demon-

strated which will allow connecting multiple

miniaturized sensors on a single compact

packaged platform to improve sensitiv-

ity and reduce power consumption. Makel

Engineering has focused on transitioning

the sensors developed by OSU, CWRU, and

NASA into portable systems for early clinical

evaluation at the Cleveland Clinic and later

for home monitoring.

Dr. Dweik, Director of the Pulmonary Vascular

Program, can be reached at 216.445.5763

or [email protected].

Recommended Reading

(Dweik RA, contributing author). ATS/ERS Recommendations for Standardized Procedures for the Online and Offl ine Measurement of Exhaled Lower Respiratory Nitric Oxide and Nasal Nitric Oxide, 2005. Am J Respir Crit Care Med 171(8):912-930.

Dweik, R. 2005. Nitric Oxide in Exhaled Breath: a Window on Lung Physiology and Pulmonary Disease. In D. S. A. Amann, editor. Breath Analysis for Clinical Diagnosis and Therapeutic Monitoring. World Scientifi c, Singapore.

Dweik, R. A., and A. Amann. 2008. Exhaled breath analysis: the new frontier in medical testing. Journal of Breath Researach 2(3):030301.

Dweik, R. A., R. L. Sorkness, S. Wenzel, J. Hammel, D. Curran-Everett, S. A. Comhair, E. Bleecker, W. Busse, W. J. Calhoun, M. Castro, K. F. Chung, E. Israel, N. Jarjour, W. Moore, S. Peters, G. Teague, B. Gaston, and S. C. Erzurum. Use of Exhaled Nitric Oxide Measurement to Identify a Reactive, At-risk Phenotype Among Patients With Asthma. Am J Respir Crit Care Med. 2010 May 15;181(10):1033-41.

Grob, N. M., and R. A. Dweik. 2008. Exhaled nitric oxide in asthma: progress since the introduction of standardized methodology. Journal of Breath Research(3):037002.

Grob, N. M., and R. A. Dweik. 2008. Exhaled Nitric Oxide in Asthma. Chest 133(4):837-839.

Grob, N. M., and R. A. Dweik. 2008. Exhaled nitric oxide in asthma. From diagnosis, to monitoring, to screening: are we there yet? Chest 133(4):837-9.

Pulmonary Hypertension Symposium 2010 Recap

The 7th annual Pulmonary Hypertension Symposium was held

on November 19, 2010 at Cleveland Clinic. The meeting was a

huge success with more than 130 participants who came from 19

states to hear state-of-the-art presentations by 26 distinguished

Cleveland Clinic and visiting faculty.

Summit attendees included physicians and other healthcare

professionals, researchers and scientists, industry representa-

tives, patients and care givers and patient advocacy groups.

Dr. Raed A. Dweik, Chair of the Symposium and Director of the

Pulmonary Vascular Program, presented the inaugural “Award

of Merit” to the key note speaker Dr. Nicholas S. Hill, Professor

of Medicine and Chief of Pulmonary, Allergy and Critical Care

Medicine at Tufts University School of Medicine. This annual

award is presented in recognition of extraordinary contribution

to the basic understanding and/or clinical management

of pulmonary hypertension.

The Ohio Third Frontier Program at Cleveland Clinic: Advancements in Breath Testing and Sensor DesignBy Raed A. Dweik, MD



Developing Breath Biomarkers to Aid Lung Cancer Diagnosis By Peter Mazzone, MD, MPH

Biomarkers are objectively measured indicators of the state of an

individual’s health. They range from commonly measured vital signs to

complex molecular signatures. There has been a tremendous amount

of interest in the development of novel biomarkers for cancer. A cancer

biomarker may help to identify someone at risk of developing cancer,

help to diagnose cancer at an early stage, determine the prognosis from

the cancer, predict or monitor the response to therapy, or advance our

understanding of the pathobiology of the cancer.

Lung cancer biomarkers have improved our management of lung cancer patients. Recent

examples of commonly used lung cancer biomarkers are PET scanning and EGFR muta-

tion analysis. There is promise that the development of novel lung cancer biomarkers

will lead to further improvement in our management of this disease in the near future.

Advances in chemoprevention will be most useful if biomarkers are able to identify those

at greatest risk of developing lung cancer. Advances in surgical and ablative therapies will

be most useful if biomarkers help us to identify lung cancer at the earliest possible stage.

Advances in systemic, targeted and individualized therapies may be developed based on

the discovery of new biomarkers capable of predicting the nature of one’s lung cancer and

the response to specific treatment choices.

A new biomarker can improve on currently used tests by being more accurate, less

invasive, less expensive, and/or novel in its intent. To have a clinical impact, the result of

the test must affect a decision to the benefit of the patient. In addition to being accurate,

an ideal test would be easy to administer, have low risk from its performance and be inex-

pensive. Our lung cancer program has been involved in the study of an unusual source of

biomarkers – the breath.

In prior editions of the Respiratory

Exchange, I have outlined our work in

discovering breath biomarkers for lung

cancer diagnosis. In our most recent work,

(unpublished) we recruited approximately

92 patients with untreated lung cancer and

137 control subjects. The control subjects

were either at risk for developing lung

cancer or presented with indeterminate lung

nodules. Study subjects breathed into a

crude, portable breath collection instrument

that drew tidal mixed expiratory breath over

a colorimetric sensor array. The colorimet-

ric sensors were composed of chemically

Colorimetric sensor array.

Sample of a color fingerprint demonstrating changes in color due to exposure to exhaled breath generated from a colorimetric sensor array.

Recommended Reading

Machado RF, Laskowski D, Deffenderfer O, et al. Detection of lung cancer by sensor array analyses of exhaled breath. Am J Respir Crit Care Med 2005;171:1286-1291.

McCulloch M, Jezierski T, Broffman M, Hubbard A, Turner K, Janecki T. Diagnostic accuracy of canine scent detection in early- and late-stage lung and breast cancers. Int Can Therap 2006;5:30-39.

Mazzone PJ, Hammel J, Dweik RA, Na J, Czich C, Laskowski D, Mekhail T. Lung cancer diagnosis by the analysis of exhaled breath with a colorimetric sensor array. Thorax, 2007;62:565-568. doi: 10.1136/thx.2006.072892.

Mazzone PJ. Analysis of volatile organic compounds in the exhaled breath for lung cancer diagnosis. J Thorac Oncol 2008;3:774-780.

Mazzone PJ. Progress in the development of a diagnostic test for lung cancer through the analysis of breath volatiles. J Breath Res 2008;3:10.1088/1752-7155/2/3/037014.


Winter 2011 | 15

reactive dyes printed on a disposable cartridge. The dyes change their color based on the

chemical mixture to which they are exposed. The change in colors is analyzed for patterns

that can discriminate the breath of lung cancer patients. Our initial analysis suggested an

accuracy of around 75 percent for distinguishing lung cancer from controls. The accuracy

improved when we considered subtypes of lung cancer. For example, we were able to

distinguish adenocarcinoma from controls with an accuracy of 80 to 85 percent, and ad-

enocarcinoma from squamous cell carcinoma with an accuracy approaching 90 percent.

The colorimetric sensor array technology used in our most recent work has made exciting

advances since the completion of this project. The latest version of the sensor is com-

posed of pigments printed on a nanoporous medium rather than dyes on a flat surface.

This has led to increased stability of the sensor while maximizing the surface area for

reaction. These changes, in concert with the use of advanced imaging systems, have

improved the sensitivity of the sensor system into at least the low parts per billion level

for all relevant chemical classes (>100-fold improvement over the former system). This

sensitivity is equivalent to that of the canine olfaction system. We have worked with the

sensor developers to design a breath collection interface and delivery system capable of

consistently and comfortably collecting and delivering the alveolar portion of the breath to

the advanced sensor. We will be leading a multi-institutional trial of this system, begin-

ning in Spring 2011. We also will begin to use this system to look at other disease states.

In concert with the colorimetric sensor system, we are studying a second breath analy-

sis technology. Our single photon ionization mass spectrometer is capable of detecting

exhaled volatiles at parts per trillion concentration in real-time. Though this device could

become smaller and easier to use over time, its current utility will be to help identify the

nature of the discriminatory breath components. This information will allow us to refine

the sensor elements of point of care systems, such as the above colorimetric sensor array,

optimizing their accuracy.

In addition to breath analysis, imaging advances are certain to impact the management

of lung cancer. We are currently collaborating with our chest radiology partners to evalu-

ate one of these advances, computer-aided detection of lung nodules applied to chest

X-rays, in a large scale lung cancer screening study supported by the Ohio Department

of Development. Subjects at risk for developing lung cancer are randomized to have the

advanced chest X-ray or a sham chest X-ray. We have recruited approximately 1,300

subjects to date.

The lung cancer screening trial cohort is an ideal group to assist with our breath test

work. In addition, we are hoping to leverage the resources supporting the screening study

to grow our blood biorepository of individuals at risk for developing lung cancer and those

with proven lung cancer. Many lines of blood test development for lung cancer are being

studied. A well-annotated blood biorepository will allow us to participate in blood test de-

velopment and validation studies capable of leading to clinical advances for our patients.

It is an exciting time for lung cancer researchers. Advances in chemoprevention, early

detection, prognostication and prediction of treatment response will all require the de-

velopment of novel lung cancer biomarkers. We are hopeful that we will see progress in

these areas in the very near future.

Dr. Peter Mazzone, Director of the Lung Cancer Program, can be reached at

216.445.4812 or [email protected].

The improved sensor

contains more chemi-

cally reactive elements,

a higher surface area

for interaction with the

breath, and improved

flow across the indica-

tors. The result is a

greatly improved sensitiv-

ity to low concentration

volatiles.


16 | Respiratory Institute | Staff Directory 2011

Department of Respiratory, Allergy and Critical Care Medicine

HerbertP.Wiedemann,MD,MBAChairman, Respiratory Institute

216.444.8335

Specialty Interests: critical care (including adult respiratory distress syndrome and sepsis), general pulmonary medicine, exercise testing (dyspnea evaluation)

LoutfiAboussouan,MD

216.839.3820

Specialty Interests: general pulmonary medicine, neuromuscular diseases, sleep medicine, long-term ventilator care

JafarAbunasser,MD

216.444.1997

Specialty Interests: critical care

MuzaffarAhmad,MD

216.444.6506

Specialty Interests: pulmonary function lab, asthma, lung cancer

OlufemiAkindipe,MD

216.444.0569

Specialty Interests: Lung Transplantation

FransiscoAlmeida,MD,MS

216.444.6503

Specialty Interests: Advanced Diagnostic and Interventional Bronchoscopy

RendellAshton,MDAssociate Director, MICU Director, Pulmonary and Critical Care Fellowship Program

216.446.5321

Specialty Interests: critical care, lung cancer, physician education

MarieBudev,DO,MPH

Medical Director, Lung Transplantation

216.444.3194

Specialty Interests: lung transplantation, pulmonary hypertension, gender specific pulmonary issues

RobertCastele,MD

440.878.2500

Specialty Interest: general pulmonary medicine

JeffreyT.Chapman,MD

Director, Interstitial Lung Disease Program

216.444.4222

Specialty Interests: interstitial lung disease, pulmonary hypertension, lung transplantation

ChiragChoudhary,MD

(216) 444-6090


JosephCicenia,MD

216.444.8606

Specialty Interests: advanced diagnostic bronchoscopy, general pulmonary medicine

DanielCulver,DODirector, Sarcoidosis Program

216.444.6508

Specialty Interests: sarcoidosis, interstitial lung disease, hypersensitivity pneumonitis

EhabDaoud,MD

Director, Critical Care Medicine Fellowship Program

216.444.6317


RaedA.Dweik,MD

Director, Pulmonary Vascular Disease Program; Joint Appointment with Pathobiology

216.445.5763

Specialty Interests: asthma, pulmonary hypertension, chronic beryllium disease, critical care, bronchoscopy, nitric oxide in lung physiology and disease, exhaled markers in lung disease

SerpilC.Erzurum,MDChairman, Department of Pathobiology, Lerner Research Institute; Director, Cleveland Clinic General Clinical Research Center; Co-Director Asthma Center

216.445.5764

Specialty Interests: asthma, pulmonary vascular disease, respiratory physiology

SamarFarha,MD

216.444.3229

Specialty Interests: critical care, pulmonary hypertension

AndrewGarrow,MD

216.445.9797

Specialty Interests: critical care medicine, sleep medicine

Respiratory Institute Staff Directory


Winter 2011 | 17

ThomasR.Gildea,MD,MSHead, Section of Bronchoscopy

216.444.6490

Specialty Interests: pulmonary hypertension, interventional bronchology, lung transplantation

JorgeGuzman,MD

Head, Section of Critical Care Medicine; Director, MICU

216.445.5765

Specialty Interests: critical care, sepsis, shock

TarikHanane,MD

216.445.5765

Specialty interest: critical care

UmurHatipoglu,MD

Quality Improvement Officer

216.636.5344

Specialty interests: asthma, acute respiratory distress syndrome, general (diagnostic) pulmonary medicine and critical care medicine

GustavoHeresi,MD

216.636.5327

Specialty interests: acute respiratory distress syndrome, pulmonary hypertension, sepsis

DavidHolden,MD

216.986.4000

Specialty Interest: general pulmonary medicine

ManicaIsiguzo,MD

216.839.3820

Specialty Interests: general pulmonary medicine

ConstanceA.Jennings,MD

216.445.4184

Specialty Interests: pulmonary hypertension, pulmonary thrombo-embolism, interstitial lung disease, advanced lung disease

SumitaKhatri,MD,MS

Co-Director, Asthma Center Joint Appointment with Pathobiology

216.445.1691

Specialty Interests: asthma

CharlesLane,MD

216.444.6503

Specialty Interests: lung transplantation, critical care

CatherineLazar,MD

216.445.5444


MichaelMachuzak,MD

Medical Director, Center for Major Airway Diseases

216.444.2718

Specialty Interests: rigid and flex-ible bronchoscopy, endobronchial ultrasound, laser, electrocautery, stent placement, bronchoscopic lung volume reduction, transtracheal oxygen cath-eter placement; lung cancer, pleural diseases, COPD

PeterMazzone,MD,MPH

Director, Lung Cancer Program

216.445.4812

Specialty Interests: lung cancer, critical care, physician education

GlennMeden,MD

Chief, Division of Pulmonary and Critical Care Medicine at Hillcrest Hospital, Director, ICU at Hillcrest Hospital

440.312.7140

Specialty Interests: general pulmonary, critical care

AtulC.Mehta,MDChief Medical Officer, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates

216.444.2911

Specialty Interests: lung transplantation, lung volume reduction surgery, endobron-chial and bronchoscopic procedures and interventions, transtracheal oxygen therapy

OmarA.Minai,MD

216.444-6500

Specialty Interests: pulmonary hypertension, interstitial lung diseases, lung cancer, COPD, sleep apnea

KathrinNicolacakis,MD

216.444.6500


ThomasOlbrych,MD

440.312.7140

Specialty Interests: general pulmonary medicine, cystic fibrosis, lung transplantation

MitchellOlman,MDJoint Appointment with Pathobiology

216.445.6025

Specialty interest: interstitial lung disease

BeverlyV.O’Neill,MD

Vice President, Medical Operations Euclid Hospital

216.692.7848

Specialty Interests: general pulmonary medicine, long-term ventilator patients

JosephG.Parambil,MD

216.444.7567

Specialty Interests: interstitial lung disease, pulmonary hypertension, general pulmonary medicine


18 | Respiratory Institute | Staff Directory 2011

BohdanPichurko,MDDirector, Pulmonary Function Lab

216.445.6789


JenniferRamsey,MD,MS

216.445.8407

Specialty Interests: critical care and general pulmonary medicine

DeborahRathz,MD,PhD

Joint Appointment with Emergency Medicine

216.445.8318


AnitaReddy,MD

216.444.4506

Specialty Interests: critical care, acute lung injury, interstitial lung disease, lung transplant

MadhuSasidhar,MD

Head, Section of Respiratory Therapy

216.445.1838

Specialty Interests: critical care, lung cancer, general pulmonary medicine

JamesK.Stoller,MD,MS

Executive Director, Leadership Development; Chairman, Education Institute

216.444.1960

Specialty Interests: clinical epidemiology, alpha1-antitrypsin deficiency, respiratory therapy

CarmenM.Swaisgood,PhD

Joint Appointment with Pathobiology

216.445.6153

Specialty Interests: sarcoidosis, interstitial lung disease, asthma

AdrianoTonelli,MD

216.444.0812

Specialty Interests: pulmonary hypertension

Section of Allergy and Clinical Immunology

DavidM.Lang,MDHead, Section of Allergy and Clinical Immunology; Director, Fellowship Program

216.445.5810

Specialty Interests: asthma, allergic disorders, sinusitis, urticaria, anaphylaxis, latex allergy, aspirin sensitivity

SusanAbouhassan,MD

216.444.9536

Specialty Interests: general allergy and clinical immunology

MarkA.Aronica,MD


216.444.6933

Specialty Interests: asthma, allergic disorders

SandraHong,MD

440.204.7400

Specialty Interests: allergy, asthma

FredH.Hsieh,MD


216.444.3504

Specialty Interests: asthma, allergic disorders, mast cell function

RachelKoelsch,MD

216.444.6933

Specialty Interests: pediatric and adult allergic rhinitis, asthma, food allergies, bee and wasp sting allergy, eczema, medication allergies, hives

LilyC.Pien,MD

216.444.6933

Specialty Interests: allergic rhinitis, asthma, drug allergies, latex allergy, medical education

CristineRadojicic,MD

216.444.6933

Specialty Interests: pediatric and adult allergic rhinitis, asthma

PARTneRS In oTheR DePARTMenTSDiagnostic Radiology

Section of Thoracic Imaging

MoulayMeziane,MDHead, Section of Thoracic Imaging

216.444.0282

Specialty Interests: thoracic radiology, CT, transthoracic chest biopsies, oc-cupational lung diseases, lung cancer

AhmedEl-Sherief,MD

216.445.7050

Specialty Interests: thoracic imaging

RuffinJ.Graham,MD

216.444.8756

Specialty Interests: pulmonary thromboembolism, lung cancer and thromboembolic disease

OmarLababede,MD

216.444.9014

Specialty Interest: thoracic imaging


Winter 2011 | 19

CharlesLau,MD

216.444.1014


Tan-LucienH.Mohammed,MD

216.444.3867

Specialty Interests: cardiopulmonary imaging/transplantation imaging, interstitial lung disease, upper airway disease

RahulRenapurkar,MD

216.445.7050


BarbaraRisius,MD

216.444.6422

Specialty Interest: thoracic radiology

RuchiYadav.MD

216.445.7050


Pulmonary Pathology

CarolF.Farver,MD

Director, Pulmonary Pathology

216.445.7695

Specialty Interest: pulmonary pathology

AndreaArrossi,MD

216.444.9120

Specialty Interests: pathology of interstitial lung disease, and pleural and pulmonary tumors

CharlesV.Biscotti,MD

216.444.0046

Specialty Interests: cytopathology, gynecologic pathology

Thoracic and Cardiovascular Surgery

GöstaPettersson,MD,PhDVice Chairman, Thoracic and Cardiovascular Surgery

216.444.2035

Specialty Interests: lung and heart-lung transplantation

DouglasJohnston,MD

216.444.5613

Specialty Interests: lung and heart transplantation

GonzaloGonzalez-Stawinski,MD

216.444.6708

Specialty Interests: heart transplantation, lung transplantation, transplant immunology, reoperative adult cardiac surgery

KennethMcCurry,MD

Surgical Director, Lung Transplantation Joint Appointment with Pathobiology

216.445.9303

Specialty interests: lung and heart transplantation, ventricular assist devices, heart failure surgery, and lung and heart ischemia- reperfusion injury

NicholasG.Smedira,MD

Surgical Director, Kaufman Center for Heart Failure

216.445.7052

Specialty Interests: lung and heart-lung transplantation; pulmonary thromboendarterectomy

Section of General Thoracic Surgery

ThomasW.Rice,MDHead, Section of General Thoracic Surgery

216.444.1921

Specialty Interests: esophageal, pulmonary, mediastinal, chest wall and diaphragm surgery; minimally invasive (laparoscopic and thoracoscopic) and pediatric general thoracic surgery; lung volume reduction surgery

DavidMason,MD

216.444.4053

Specialty Interests: general thoracic surgery, lung transplantation, minimally invasive thoracoscopic and laparaoscopic surgery, lung cancer, esophageal cancer, malignant mesothelioma

SudishMurthy,MD,PhD

Surgical Director, Center for Major Airway Diseases

216.444.5640

Specialty Interests: esophageal, pulmonary, mediastinal, chest wall and diaphragm surgery; minimally invasive lung volume reduction surgery; lung transplant surgery

Respiratory Exchange

Herbert P. Wiedemann, MD, Medical Editor

Megan Frankel, Marketing Manager

Ann Milanowski, Managing Editor

Michael Viars, Art Director/Designer

Respiratory Exchange is written for physi-cians and should be relied upon for medical education purposes only. It does not provide a complete overview of the topics covered and should not replace the independent judgment of a physician about the appropriateness or risks of a procedure for a given patient.

© 2011 The Cleveland Clinic Foundation

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