Respiratory Exchange 2008 - Cleveland Clinic

RespiratoryExchange

Research and News for

Physicians from the Cleveland

Clinic Respiratory Institute

Fall | 2008

Also in this Issue

High Altitude Survival

pg 4

Clinical Utility of Exhaled Nitric Oxide

pg 6

Bronchoscopic Treatments for Severe Emphysema

pg 12

Raising the BAR in Lung Transplant By Gösta B. Pettersson MD, PhD, Director Lung Transplant and Heart Lung Transplant Program; Atul C. Mehta, MBBS; and the Cleveland Clinic Lung Transplant Team

continued on page 2

With 72 lung transplants performed in 2007, the second highest volume in the United States, Cleveland Clinic continues to remain one of the premier lung transplant centers in the country. The transplant program continues to be a leader in developing and offering innovative approaches in the field of transplantation that may impact short- and long-term outcomes.

Currently, lung transplantation continues to demonstrate mortality

of close to 50 percent at five years. Significant early complications

following single- and double-lung transplantation include airway

healing issues (necrosis, dehiscence and subsequent stenosis),

which may lead to lung infections and rejections, and contribute

to development of bronchiolitis obliterance syndrome/oblit-

erative bronchiolitis (BOS/OB). All these complication could

possibly directly or indirectly relate to ischemia, particularly

of the airways and the airway anastomsis.

2 | Respiratory Exchange

Dear Colleagues:Patients with complex respiratory

disorders benefit from the expertise of a

multidisciplinary team of specialists. At

Cleveland Clinic, experts in the Respiratory

Institute (Pulmonary, Allergy and Critical

Care Medicine) collaborate with spe-

cialists in Thoracic and Cardiovascular

Surgery, Thoracic Imaging and Pulmonary

Pathology to care for these patients.

In this issue of Respiratory Exchange,

you will find articles that illustrate the

continued growth of our clinical pro-

grams, research funding and application

of innovative technologies, particularly in

the areas of breath analysis, pulmonary

hypertension, asthma, bronchoscopy and

lung transplantation.

For additional information about our

ongoing clinical and research activities

in respiratory disorders, please visit cleve-

landclinic.org/pulmonary (current and

previous issues of Respiratory Exchange

are available here) and clevelandclinic.

org/thoracic.

We hope you’re able to spend a few

minutes reviewing Respiratory Exchange,

and that you find it valuable and informa-

tive. 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

Currently, the standard surgical approach in lung transplantation

involves restoration of only pulmonary artery blood flow to the lungs,

but the bronchial artery blood supply is ignored. Bronchial artery

revascularization (BAR) is a surgical technique intended to restore

bronchial arterial circulation to transplanted lungs. Cleveland Clinic’s

Transplant Surgical Team currently is conducting a prospective pilot

study offering BAR at the time of transplantation with the reasoning

that by restoring bronchial blood supply both short- and long-term

outcomes in lung transplant patients may be improved.

Historically, consideration of BAR has been weighed against its techni-

cal difficulty, its complications and potential consequences of a failed

procedure, combined with the fact that the described complications

were not that frequent and BAR might offer minimal or no benefit and

therefore unnecessary. Gösta B. Pettersson, MD, PhD, Director, Lung

and Heart Lung Transplant program, Cleveland Clinic, has the world’s

largest experience with BAR, performing this procedure in more than

100 patients while in Copenhagen.

Recently the Copenhagen lung transplant group published long-term

follow up data:

1. The overall survival for this Copenhagen patient series was better

than for any other large single center lung transplant series

2. The survival was better for the first five-year period, including all

the BAR patients than for the second.

BAR surgical technique. Normal appearing tracheal anastomosis one week after transplant surgery.

Raising the BAR in Lung Transplant continued

Standard surgical approach. Some necrosis and ischemia is evident at the anastomotic site one week after transplant surgery.

Respiratory Exchange

Herbert P. Wiedemann, MD, Medical Editor

Megan Frankel, Marketing Manager

Ann Bungo, Managing Editor

Anne Drago, Graphic 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.

© 2008 The Cleveland Clinic Foundation

Removal of the esophagus from the block, taking care not to damage the retroesophageal intercostobraonchial artery.

Fall 2008 | 3

Recommended Reading

Burton CM, Milman N, Carlsen J, Arendrup H, et al: The Copenhagen National Lung Transplant Group: Survival after Single Lung, Double Lung, and Heart-Lung Transplantation. J Heart Lung Transplant 2005;24:1834-43.

Pettersson G, Nørgaard MA, Arendrup H, et al. Direct bronchial artery revascularization and en bloc double lung transplantation - Surgical techniques and early outcome. J Heart Lung Transplant 1997;16:320-333.

Herrera JM, McNeil KD, Higgins RSD, et al. Airway complications after lung transplantation. Treatment and long-term outcome. Ann Thorac Surg. 2001;71:989-994.

Giudicelli R, Thomas P, Massard G, et al. Tracheobron-chial healing after lung and heart-lung transplantation. Eur J Cardiothorac Surg. 1993;7:453-456.

Colquhoun IW, Gascoigne AD, Au J, et al. Airway com-plications after pulmonary transplantation. Ann Thorac Surg. 1994;57:141-145.

Wilson IC, Hasan A, Healey M. Healing of the bronchus in pulmonary transplantation. Eur J Cardiothorac Surg. 1996;10:521-527.

Alvarez A, Algar J, Santos F, et al. Airway complications after lung transplantation. A review of 151 anastomoses. Eur J Cardiothorac Surg. 2001;19:381-387.

Kamler M, Nowak K, Bock M, Herold U, Motsch J, Hagl S, Gebhard MM, Jakob H et al. Bronchial Artery Revascularization Restores Peribronchial Tissue Oxygenation After Lung Transplantation. J Heart Lung Transplant 2004;23:763-6.

Hyytinen et al. Bronchial Artery Revascularization Improves Tracheal Anastamotic Healing After Lung Trans-plantation. Scand Cardiovasc J 34; 213-218, 2000.

Bando et al. Obliterative bronchiolitis after lung and heart-lung transplantation. An analysis of risk factors and management. J Thorac Cardiovasc Surg 1995; 110(1):4-13.

Nørgaard et al. Revascularization of the Bronchial Arteries in Lung Transplantation: An Overview. Ann Thorac Surg 1996; 62: 1215-21.

Nørgaard et al. Does bronchial artery revascularization influence results concerning bronchiolitis obliterans syndrome and/or obliterative bronchiolitis after lung trans-plantation? Eur J Cardiothorac Surg 1998; 14(3): 311-8.

Daly RC et al. Routine immediate direct bronchial artery revascularization for single-lung transplantation. Ann Thorac Surg 1994; 57(6): 1446-52.

3. Survival was better after en bloc double lungs (all performed with

BAR) than after sequential double lungs. The five- year survival after

en bloc double-lung transplantation with BAR was an impressive

75 percent and this was better than after sequential double-lung

transplantation, despite earlier date of surgery, a higher percentage

of COPD and alpha-1-deficiency patients, and older age (mean 47

years vs. 34 years). Although there were patients who had single-

lung transplantation or combined heart and lung transplantation with

BAR, the number in these groups were small. The Copenhagen clini-

cal experience, with 106 BAR procedures, is unique and larger than

the published BAR experience of the rest of the world combined.

Currently, we have enrolled more than 50 patients in the BAR pilot

study with 10 procedures performed (five en bloc double-lung trans-

plants and five single-lung transplants) since December 2007. Eight

of the nine patients had primary normal airway healing and selective

angiography demonstrating revascularization success, the tenth patient

not yet examined. One patient had evidence of airway ischemia and ne-

crosis and failed revascularization on angiography, but the anastomosis

still eventually healed without stenosis within 10 weeks of surgery.

Thus far, the early experience with BAR at Cleveland Clinic is promising

and comparable to the Copenhagen experience with a high success rate

associated with normal healing of the airway. Our long term hope is,

of course, to duplicate the long-term outcomes of the Copenhagen

experience in terms of BOS and better survival. At this time, this is

the only study of its kind being offered in the world and has the poten-

tial to change the standard approach to lung transplantation.


High Altitude Survival How the biology of Tibetans may help find new treatments for hypoxia-related diseasesBy Cynthia Beall, PhD, and Serpil Erzurum, MD

For 20,000 years, people have been thriving in their rugged and unforgiv-ing mountainous terrain, the Tibetan Plateau, nearly three miles above sea level where oxygen levels are low. Despite their oxygen-starved environment, Tibetans are healthy and do not develop altitude-related sickness. Researchers at Cleveland Clinic and Case Western Reserve University have uncovered the unique biology that protects Tibetans from high-altitude sickness, which may lead to new clinical treatments for hypoxia-related diseases.

The low barometric pressure at high altitude

causes lower arterial oxygen content among

Tibetan highlanders, who somehow maintain

normal levels of oxygen use as indicated by

basal and maximal oxygen consumption levels

that are consistent with sea level predictions.

In our study, we investigated how Tibetans

offset physiological hypoxia and achieve

normal oxygen delivery. We discovered that

Tibetans have higher blood flow in their

systemic circulation, which is achieved by

higher levels of production of nitric oxide (NO),

the main endothelial factor regulating blood

flow and vascular resistance.

The natural experimental study design com-

pared Tibetans at 4200m and U.S. residents

at 206m. Forearm blood flow, an indicator

of systemic blood flow, was measured nonin-

vasively using plethysmography at rest, after

breathing supplemental oxygen, and after

exercise. The Tibetans had more than double

the forearm blood flow of low-altitude resi-

dents, resulting in even greater than sea level

oxygen delivery to tissues. Strikingly, Tibetans

had more than 10-fold higher circulating

concentrations of NO.

The findings, which are reported in the

article, “Higher Blood Flow and Circulating

NO Products Offset High Altitude Hypoxia among Tibetans,” published in the November

6, 2007, Proceedings of the National Academy of Sciences, describe this newly discov-

Hemodynamics and oxygen delivery among Tibetan and sea level populations. (A and B) Tibetan forearm blood flow (A) and oxygen delivery (B) were greater than sea level controls. (C) The greater forearm blood flow of Tibetans compared with the sea level population accounts for the greater oxygen delivery (R2 = 0.96 and P < 0.001). (D) Higher hemoglobin concentrations of Tibetans as compared with sea level population contributes modestly to greater oxygen delivery (R2 = 0.13 and P < 0.001).

Searching for Answers in IPFBy Jeffrey T. Chapman, MD

Given the complexity of the immu-nopathologic process in idiopathic pulmonary fibrosis (IPF), a multi-pronged attack with several medications and novel therapeutic approaches may be required. Currently being tested is an empirical clinical strategy to treat IPF with a combination of agents having low toxicity and cost that might retard progression of this illness.

We have recently joined the National Institutes

of Health-funded IPF Clinical Research Network

(“IPF-Net”), a group of 11 sites throughout the

U.S. formed to evaluate multi-drug therapeutic

trials for stabilizing the disease. As a new member

of the IFP-Net, we will soon begin enrollment in

these trials for patients with newly diagnosed IPF.

One of these upcoming trials is the Sildenafil Trial

of Exercise Performance in Idiopathic Pulmonary

Fibrosis (STEP-IPF trial), for late-stage disease.

This trial has been designed for patients with moderate to severe lung disease. In the

24-week study, eligible patients will receive either sildenafil or placebo for the first 12

weeks, followed by sildenafil for the next 12 weeks. The study expects to enroll about

200 patients beginning later this year.

We also will be enrolling patients for the Evaluating the Effectiveness of Prednisone,

Azathioprine, and N-Acetylcysteine in People With Idiopathic Pulmonary Fibrosis

(PANTHER study). This study will evaluate the effectiveness of the antioxidant

N-acetylcysteine (NAC), alone and in combination with an established IPF medica-

tion regimen, at preventing the loss of lung function in people with early-stage IPF.

These trials will be a valuable option for our patients with IPF in our growing

interstitial lung disease program.

Dr. Jeffrey Chapman is a Cleveland Clinic pulmonologist and the local PI

for the IPF Clinical Research Network. He can be reached at 216.444.4222

or [email protected].

Cleveland Clinic has recently been accepted into the NHLBI-sponsored Idiopathic Pulmonary Fibrosis Research Network. Dr. Chapman is the site Principal Investigator.

The IPF Network conducts clinical trials, and related pathophysiology studies, related to IPF. The IPF Network is similar to other NHLBI networks that we are participating in, including networks for ARDS, severe asthma, and COPD (long- term oxygen therapy).

ered, distinctive and different adaptation

to high-altitude hypoxia that is character-

ized by blood flow and oxygen delivery

rates substantially higher than any reported

previously. Natural experiments such as this

one that extend the known range of healthy

human biological variation provide important

and fundamental knowledge about general

patterns and mechanisms of oxygen delivery

in human biology.

The next step in this research is to find out

how Tibetans produce so much NO. The

metabolic pathways and genetic features

that allow Tibetans to produce high levels

of NO will be investigated next.

Knowing how NO offsets hypoxia may lead

to new treatment methods for patients who

suffer from hypoxia-related diseases such

as heart disease, pulmonary hypertension,

cystic fibrosis, chronic obstructive pulmonary

disease and sleep apnea.

Dr. Serpil Erzurum, Chairman of Pathobiology

and a member of the Respiratory Institute,

collaborated with colleague Cynthia M. Beall,

PhD, a professor of physical anthropology

at Case Western Reserve University on this

research. Dr. Erzurum can be reached at

216.445.5764 or [email protected].

Fall 2008 | 5


Clinical Utility of Exhaled Nitric Oxide (FENO) By Raed A. Dweik, MD, FCCP

Nitric oxide (NO) is endogenously synthesized by nitric oxide synthases (NOSs) that are widely expressed in various tissues including the lungs. Once produced, NO is freely diffusible and enters target cells activating soluble guanylate cyclase to produce guanosine 3’, 5’-cyclic monophosphate (cGMP) that mediates the majority of NO effects. The functions and effects of NO in the lung/airways reflect its key roles as a vasodilator, bronchodila-tor, neurotransmitter and inflammatory mediator. The unique lung anatomy allows NO produced in the airways to be detected in exhaled breath. This was accomplished in the early 1990s with the advent of chemiluminescence ana-lyzers that could detect low levels of NO in the parts per billion (ppb) range.

Interestingly, patients with asthma have high levels of exhaled NO in their exhaled breath that returns to normal levels after treatment with corticosteroids, making exhaled NO a po-tentially useful marker of airway inflammation. Although these findings clearly suggest a role for NO in asthma pathogenesis, the exact role of NO in asthma and airway reactivity remains elusive despite intense research in this area. Whether NO is beneficial through its broncho-dilator and antioxidant effects or harmful by inducing inflammation remains unclear. It also is possible that it may play both roles depend-ing on the level and the airway milieu in a particular patient or at a particular stage of the disease. In either case, measuring exhaled NO has shown clinical utility in monitoring the inflammatory component of asthma.

The use of exhaled NO in monitoring asthma is promising for several reasons. It is non-invasive, it can be performed repeatedly, and it can be used in children and patients with severe airflow obstruction where other techniques are difficult or not possible to per-form. Exhaled NO may also be more sensitive than currently available tests in detecting airway inflammation, which may allow more optimum therapy.

Several issues, however, needed to be ad-dressed before exhaled NO could become a useful clinical tool in routine asthma monitoring and management. First, a better understanding

of the role of NO in asthma pathogenesis was needed. Second, the methods and equipment for measuring NO needed to be standardized. Third, large population studies were needed to determine the normal range of exhaled NO lev-els and the effect of confounding factors. Last, but not least, interpretative strategies needed to be devised and put in place for the different potential uses and applications. While the answers have not always been straightforward and simple, most of these issues have either already been addressed or are currently under investigation, allowing exhaled NO measure-ment to make the transition from the research to the clinical arena.

The American Thoracic Society (ATS) has pub-lished standards for performing measurements of exhaled NO. The guidelines recommend the use of the term FENO (the fractional exhaled NO concentration) to describe levels of NO in exhaled breath. FENO is expressed in parts per billion, which is equivalent to nanoliters per liter (nl/L). Several commercial analyzers are available to measure NO levels in exhaled breath based on the ATS guidelines. One such device was approved by the FDA in 2003.

The standardization of FENO measurement was followed by several large clinical and population studies demonstrating that FENO levels can be useful in the diagnosis of asth-ma and in monitoring disease activity/airway inflammation and response to therapy. These

studies have also identified various possible

confounders that affect FENO including age,

gender, weight, height, diurnal variation,

and food intake, among others. Observations

that have been consistent in the literature,

however, are that atopic individuals tend to

have higher FENO while smokers tend to

have lower FENO.

A more difficult problem to address in the NO

field has been the establishment of normal

healthy population values for FENO. While

several studies have tried to address this issue

of normative values, they were done in differ-

ent populations, addressed different potential

confounders, and reported their results in dif-

ferent ways. Furthermore, “reference values”

derived from a “normal” population may not

be applicable in patients with asthma. This

raises the question whether normal values are

at all useful when it comes to the use of FENO

in asthma. Thus, defining different cut points

for different clinical settings may be more clini-

cally useful than normative values.

Recommended ReadingGrob, 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.

Dweik, R. A. 2007. The lung in the balance: arginine, methylated arginines, and nitric oxide. Am J Physiol Lung Cell Mol Physiol 292(1):L15-7.

Gill, M., G. R. Graff, A. J. Adler, and R. A. Dweik. 2006. Validation study of fractional exhaled nitric oxide measure-ments using a handheld monitoring device. J Asthma 43(10):731-4.

Akpinar-Elci, M., K. J. Stemple, O. C. Elci, R. A. Dweik, K. Kreiss, and P. L. Enright. 2006. Exhaled nitric oxide mea-surement in workers in a microwave popcorn production plant. Int J Occup Environ Health 12(2):106-10.

Dweik, R. A. 2005. Nitric oxide, hypoxia, and superoxide: the good, the bad, and the ugly! Thorax 60(4):265-7.

Khatri, S. B., J. Hammel, M. S. Kavuru, S. C. Erzurum, and R. A. Dweik. 2003. Temporal association of nitric oxide levels and airflow in asthma after whole lung allergen challenge. J Appl Physiol 95(1):436-40; discussion 435.

Dweik, R. A. 2002. Nitric oxide production in the lung and its regulation by oxygen. In N. Marczin and M. H. Yacoub, editors. Disease Markers in Exhaled Breath: basic mecha-nisms and clinical applications (NATO Science Series). IOS press, Amsterdam, Netherlands. 11-17.

Ozkan, M., and R. A. Dweik. 2001. Nitric Oxide and Airway Reactivity. Clinical Pulmonary Medicine 8(4):199-206.

Khatri, S. B., M. Ozkan, K. McCarthy, D. Laskowski, J. Hammel, R. A. Dweik, and S. C. Erzurum. 2001. Alterations in exhaled gas profile during allergen-induced asthmatic response. Am J Respir Crit Care Med 164(10 Pt 1):1844-8.

Dweik, R. A., S. A. Comhair, B. Gaston, F. B. Thunnissen, C. Farver, M. J. Thomassen, M. Kavuru, J. Hammel, H. M. Abu-Soud, and S. C. Erzurum. 2001. NO chemical events in the human airway during the immediate and late antigen-induced asthmatic response. Proc Natl Acad Sci U S A 98(5):2622-7.

Dweik, R. A. 2001. The promise and reality of nitric oxide in the diagnosis and treatment of lung disease. Cleve Clin J Med 68(6):486, 488, 490, 493.

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

Combined with the fact that there is con-siderable overlap in FENO between healthy individuals and asthmatics, it is very clear from reviewing the literature that the FENO value by itself is not sufficient. FENO value should be taken within the clinical context: Was the measurement obtained in someone who has symptoms or in an asymptomatic individual? Was it performed as a screening or to aid in the diagnosis? Is the individual known to have asthma? And if so is he/she on therapy? Do they have previous levels and how does this level compare? Once the clini-cal setting is taken into consideration, certain cut points become very useful: FENO levels above 45-50 ppb predict steroid responsive-ness while levels below 35 ppb suggest optimal asthma control in an asthmatic on therapy. FENO levels above 20-25 ppb suggest the presence of asthma in a steroid-naive individual with symptoms while lower levels are not likely to be associated with airway inflammation.

Thus, advances in technology and standard-ization made FENO measurement simple and allowed us to easily perform it in different settings from diagnosis, to monitoring, to screening, and possibly others. In order for this simple yet powerful tool to achieve its potential, however, we need to understand what FENO levels mean in different clinical settings. While some tests are difficult to per-form and easy to interpret, others like FENO are easy to perform but may need consider-able skill to interpret.

New guidelines on FENO interpretation are forthcoming from the American Thoracic Society, expected out early 2009.

Dr. Raed Dweik serves as Chairman of the ATS committee charged with writing the guidelines for the interpretation of FENO in clinical practice and is Director of the Pulmonary Vascular Program within Cleveland Clinic’s Respiratory Institute. Contact him at 216.445.5763 or [email protected].

Jean Wall Bennett Chair for Emphysema Research Established

James K. Stoller, MD, MS, Head, Section of Respiratory Therapy, Department of Pulmonary and Critial Care Medicine, is the first to hold the Jean Wall Bennett Chair for Emphysema Research.

This endowed chair is a gift of Mr. Joseph

Bennett in memory of his late wife, Jean

Wall Bennett, who suffered from the

disease and was treated by Dr. Stoller.

The new chair will advance emphysema

research at Cleveland Clinic. Dr. Stoller’s

interests include emphysema in general

and also Alpha-1-Antitrypsin Deficiency,

a genetic form of the disease. Active

research in both areas is underway.

One current study with Alpha-1-

Antitrypsin Deficiency is examining

the role of CT as a way to measure the

lung disease progression in emphysema

as an alternative to breathing tests.

Dr. Stoller is also Cleveland Clinic’s site

PI for the largest randomized clinical

trial of the effectiveness and safety of

long-term home oxygen therapy for

COPD (chronic obstructive pulmonary

disease). The results will help Medicare

decide whether to extend coverage for

home oxygen treatment to patients with

moderate disease. Currently, Medicare

limits coverage of home oxygen therapy

to beneficiaries with severe COPD (very

low blood oxygen levels while resting).

Fall 2008 | 7

Women’s Menstrual Cycles Could Offer Clues to Lung Disease TherapiesBy Kewal Asosingh, PhD, and Samar Farha, MD

The changes that a woman's body undergoes during her monthly menstrual cycle could offer clues into potential therapies for people who have advanced lung diseases and need ways to improve how they absorb oxygen.

During a portion of the menstrual cycle, a

woman’s ovaries and the lining of her uterus

become enriched with blood vessels in prepa-

ration for possible reproduction. But if there is

no fertilized egg, the uterine lining is discarded

as the menstrual flow. The uterus returns to

its normal state until the process starts again

the following month.

Scientists have studied different factors that

control blood vessel formation and regression

in the uterus. Among these are hormones such

as estrogen; proteins that control blood vessel

growth such as vascular endothelial growth

factor; and adult stem cells, derived from bone

marrow that circulates in the blood, called

endothelial progenitor cells (or EPC).

The question was do these factors also en-

courage blood vessel formation in the lungs?

As part of a team of pathologists and pul-

monologists, we found that microscopic blood

vessels in the lung increase and decrease

in the same rhythm as a woman’s uterine lining changes. These blood vessels are critical to

pulmonary gas transfer – the exchange of oxygen for carbon dioxide that occurs in the lungs

with each breath we take. The study monitored and tested 10 healthy, non-smoking women

in their early 30s during their menstrual cycles (four healthy, non-smoking males were used

as a control group). We also looked at blood vessels in mice receiving estrogen or placebo.

Among our findings:

• Mice that received estrogen had a greater number of microvessels and more and smaller

alveoli. Together the smaller alveoli and the rich networks of new blood vessels increase the

surface area available for transferring gases.

• Circulating EPCs clearly are related to changes in gas exchange in lung tissues.

• The lung-diffusing capacity in women increased by 10 percent when the blood vessel

formation was at its peak during the menstrual cycle, demonstrating improved gas transfer.

Lung tissues from ovariectomized female mice exposed to estrogen (B, D, E) or placebo (A, C) for 2 wk. A and B: lungs of estrogen-exposed mice have greater numbers of vessels as identified by endothelial cells that are positive (brown staining) for von Willebrand factor but smaller alveoli than control ovariectomized female mice. Arrowheads identify microvessels. Magnification x 400. C and D: alveolar capillary unit from the lungs of ovariectomized mice exposed to estrogen compared with placebo. Immunopositivity for von Willebrand factor identifies endothelial cells. Magnification x 1,000. E: capillaries containing erythrocytes are identified as they traverse through alveolar walls. Magnification x 1,500. a, Alveolar spaces; open arrowheads, capillary lining; black arrowheads, red blood cells.

Farha, S. et al. J Appl Physiol 103: 1789-1795 2007. Used with permission.


Recent Awards

Team Receives $3.8 Million 3rd Frontier Grant from State of Ohio

A multi-institutional team led by Raed Dweik, MD, was

awarded in June one of six Ohio Biomedical and Research

Commercialization Partnership 3rd Frontier Grants.

The $3.8 million grant awarded to Cleveland Clinic, in

collaboration with NASA Glenn Research Center, The

Ohio State University, Case Western Reserve University,

and Makel Engineering, Inc., was to develop a nitric oxide

sensor that will enable asthma patients to monitor their

asthma at home. The proposal aims to re-develop a sensor

used in the aerospace industry, and the project’s emphasis

will be on testing and commercializing sensors already

produced in Ohio.

Serpil Erzurum, MD, is a collaborating investigator, and

other Cleveland Clinic staff include Daniel Laskowski,

RPFT, Metin Aytekin, PhD, and Jennie Newman.

2008 Howard Hughes Medical Institute Physician-Scientist Early Career Award

Fred Hsieh, MD, of the Section of Allergy/Immunology, is

the recipient of a 2008 Howard Hughes Medical Institute

Physician-Scientist Early Career Award.

This award provides a total of $375,000 ($75,000 per year) to

support Dr. Hsieh's research over five years (August 1, 2008 –

July 31, 2013).

Dr. Hsieh’s work focuses on the immune system’s mast

cells, which play a central role in asthma. They release

histamine and other factors that lead to inflammation and

constriction in the lungs. Dr. Hsieh thinks that people with

asthma might produce more stem cells that can develop

into inflammatory cells like mast cells than healthy people.

He hopes to find out by examining how, when, and why

stem cells develop into mast cells by studying mouse

models and people with asthma.

Dr. Hsieh already has found that some blood-forming stem

cells can produce mast cells in asthmatic lungs. Now he

wants to find out if endothelial stem cells – found in the lin-

ing of the lungs – also can produce mast cells and whether

they overproduce those cells in people with asthma.

It’s clear that the same factors that cause blood vessel development

in the uterus and ovaries during a menstrual cycle are critical factors

to how well lungs transfer gases. This understanding of what governs

gas transfer in the lung could lead to therapies that encourage blood

vessel formation in the lungs of patients with advanced lung diseases.

Any way we can improve or augment oxygen intake by these patients

will be a step forward in their care.

The research also might lead to new understanding of episodic airflow

obstruction, such as asthma, which may worsen in some women

around the time of their menstrual cycle.

Understanding what underlies the cause of these diseases can help us

to treat the symptoms better. We are currently recruiting participants

for an ongoing study to understand pulmonary arterial hypertension.

Women are particularly predisposed to diseases of the arteries and

veins within the lungs. These diseases might involve the same causes

that we revealed in our research. This gives us hope that we can iden-

tify new therapies for women with these types of diseases.

Other collaborators on the project were Serpil Erzurum, MD, Daniel

Laskowski, Lauren Licina and Raed Dweik, MD, all of Pathobiology;

Herbert Wiedemann, MD, Chairman, Cleveland Clinic Respiratory

Institute; and Haruki Sekigushi and Douglas Losordo, MD, both of the

Northwestern Memorial Hospital Division of Cardiology in Chicago. The

report appeared in the Journal of Applied Physiology (http://jap.physiol-

ogy.org/; 2007 103: 1789-1795). It was supported by the National

Institutes of Health’s National Heart, Lung, and Blood Institute.

Dr. Kewal Asosingh is a member of the Pathobiology Department

in Lerner Research Institute. Contact him at 216.445.7191

or [email protected]. Dr. Samar Farha is a pulmonologist in the

Cleveland Clinic Respiratory Institute and was the lead researcher

on the project. Contact her at 216.444.3229 or [email protected].

The research also might lead to new

understanding of episodic airflow

obstruction, such as asthma, which

may worsen in some women around

the time of their menstrual cycle.

Fall 2008 | 9


Idiopathic pulmonary arterial hypertension

(IPAH) is a fatal disease of unknown etiol-

ogy characterized by a progressive increase

in pulmonary artery pressure and vascular

growth. Symptoms include dyspnea, fatigue,

syncope, edema and dizziness. Chronic liver

disease, some rheumatologic disorders, or

congenital heart malformations also can

result in an associated pulmonary hyperten-

sion. There is evidence from animal models

of pulmonary hypertension, mice genetically

deficient in endothelial NO synthase, and

complementation studies with gene transfer

of NO Synthases for the concept that NO is

a critical determinant of pulmonary vascular

tone. We and others have shown that levels

of NO are lower in lungs of patients with

IPAH as compared to healthy controls.

Separate from its vasodilatory effects, NO

binds to several targets within the mito-

chondrial respiratory chain. For example,NO

competes with oxygen for binding to complex

IV in the mitochondrial respiratory chain

of oxygenated cells. Recently, NO was also

found to trigger mitochondrial biogenesis

in cells. Previous studies have identified

abnormal mitochondrial function, basically

site-specific defects in electron transport

chain, in avian idiopathic pulmonary hyper-

tension that lead to lower respiratory chain

coupling and inefficient use of oxygen, which

in turn contribute to the development of

pulmonary hypertension syndrome in chick-

ens. Similarly, Fawn Hooded rats (FHR), a

spontaneously pulmonary hypertensive strain,

have abnormal mitochondria with reduced

expression of electron transport chain com-

ponents. In a recent study, we questioned

whether abnormal energy metabolism might

Changes in bioenergetics of IPAH endothelial cells uncoveredBy Weiling Xu, MD, Donald Neumann, MD*, Frank DiFilippo, PhD*, and Serpil C. Erzurum, MD

Cleveland Clinic researchers have identified a metabolic abnormality in the lungs of patients with idiopathic pulmonary arterial hypertension (IPAH), which could lead to new therapies and improved care of this rare but deadly disease. IPAH primarily strikes young adults and is about twice as common in women than in men.

be present in the human IPAH. We hypoth-

esized that in the low NO state of IPAH that

pulmonary artery endothelial cells may have

an altered cellular metabolic energy path-

way. To test this, we measured the oxygen

consumption, ATP content, glycolytic rate

and mitochondrial morphology, activity and

expression of mitochondrial complexes of

pulmonary artery endothelial cells isolated

from IPAH lungs in comparison to pulmonary

artery endothelial cells from healthy controls.

Our research findings, “Alterations of cellular

bioenergetics in pulmonary artery endothelial

cells,” were published in the Jan. 16, 2007,

issue of the Proceedings of the National

Academy of Sciences.

A significant decrease of oxygen consumption

was found in IPAH cells as compared with

healthy controls. Glucose metabolism was

subserving the primary role for energy-require-

ments of IPAH cells as shown by the measure

of nearly 3-fold greater glycolytic rate of IPAH

cells as compared to healthy control cells.

Positron emission tomography (PET) scan

with 18F- fluoro-deoxy-D-glucose (FDG) was

used to evaluate the glucose metabolism in

the lungs of IPAH patients in comparison

to healthy controls. FDG PET scan revealed

higher glucose metabolic activities in lungs of

IPAH patients than in controls, confirming that

the glycolytic rate was also higher in vivo, and

that relative uptake of FDG in patient’s lungs

may have promise as a marker of IPAH dis-

ease activity, or in the diagnosis of the disease.

Overall, this study supports that there is a

fundamental alteration in cellular bioenerget-

ics in IPAH, linking the human disease to

avian and murine forms of PAH, species in

which inefficient cellular use of oxygen has

been shown to predispose to development

of pulmonary hypertension. The next step in

the research is to understand the molecular

mechanisms that lead to these alterations, so

that we can develop new drug therapies to

improve mitochondrial function.

Contact Dr. Serpil C. Erzurum at

216.445.5764 or [email protected].

PET/CT image of IPAH patient, with PET image on the right and CT image on the left. FDG standardized uptake in IPAH lung is higher than in healthy lung (not shown).

* Nuclear Medicine, Cleveland Clinic

The year 2007 brought continued growth for the Cleveland Clinic Lung and Heart/Lung Transplant Program, one of the most active in the country.

The Transplant Program completed its 626th

transplant since the program’s inception

in 1990, and in 2007, performed 72 lung

transplants, including three heart/lung

transplants and the first lung-liver transplant

in Ohio, reinforcing Cleveland Clinic’s posi-

tion among the leading lung transplantation

programs, both in Ohio and nationally. More

than 415 end-stage lung disease patients

were evaluated from all across the country

and the world by the transplant team.

The Transplant Program continues a

reputation for accepting and transplanting

challenging, complex patients. Cleveland

Clinic’s Lung Transplant Team is involved

in a series of multicenter trials aimed at

therapy of primary graft dysfunction, acute

rejection and induction therapy. In addi-

tion, our surgeons have pioneered certain

transplant surgical techniques, including

bronchial artery revascularization, which

may improve outcomes further by reducing

ischemic injury (see lead article in this issue

of Respiratory Exchange).

The average waiting time for a graft in our

program remains stable despite the new Lung

Allocation Score (LAS). Currently, our aver-

age waiting time is 75 days. The Transplant

Program has achieved very strong survival

rates that are at or above the national average.

Median and long-term outcomes continue

to improve, with a one-year survival rate of

86 percent and two-year survival rate of 74

percent. A continued emphasis on quality

assurance and quality improvement remains

central to the program, reflected by the de-

crease in post-transplant length of stay to

an average of 13 days.

PercentPercent

0

20

40

60

80

100

12 Months 24 Months

Lung Transplant Survival Rate

In 2007, the U.S. Department of Health and

Human Services identified Cleveland Clinic as

one of six “high performing” centers for lung

transplantation, based on volume, growth

and clinical outcomes. (HHS Final Report.

“Transplant Center Growth and Management

Collaborative: Best Practices Evaluation,”

Sept. 2007.)

To refer a patient for consideration for

lung transplant or heart/lung transplant,

please call our transplant coordinator at

216.444.8282, option 3.

Lung Transplant Center of Excellence

Fall 2008 | 11

75

50

37

50

65 6572

64

25

0

Number of transplants in 2002–2007

20032002 2004 2005 2006 2007

L I S T E D PAT I E N T S C A N WA I T AT H O M E

Any wait-listed transplant candidates

within a 1,000-mile radius of Cleveland

Clinic can wait at home until a donor is

located. Once a donor is found, patients

are transported within hours via private

plane to Cleveland.

For continuity of care, we follow our patients

for the life of their transplant along with

local physicians. Our transplant physicians

are committed to helping the transplanted

patients receive as much care as possible

close to their homes. The goal is to return

each transplant patient to his or her pri-

mary care physician or referring physician

within three to six months after transplant.


Bronchoscopic Techniques May Provide New Treatments for Severe Emphysema PatientsBy Thomas Gildea, MD, Michael Machuzak, MD, and Atul Mehta, MD

Emphysema is a serious health issue that afflicts about 3 million people in the U.S., causing nearly 14,000 deaths every year. Current medical treat-ment for emphysema includes medication and/or supplemental oxygen, pulmonary rehabilitation and, in rare cases, lung volume reduction surgery (LVRS) or lung transplantation.

Although LVRS is an effective procedure, it is associated with a morbidity rate of 40 percent

and a mortality rate of 10 percent to 15 percent two years post-surgery (even in an appropriate

patient group). For this reason, researchers have developed novel, investigational endobronchi-

al valve devices that allow air to exit from the lung parenchyma, but not to re-enter, potentially

leading to less volume that occurs following LVRS. Researchers hope the endobronchial valves

may achieve the benefits of LVRS, but without its surgical risks and complications.

I B V ( I N T r A - B r O N C H I A L V A L V E )

Over the last few years, Cleveland Clinic pulmonologists have been participating in several

multicenter trials to assess the efficacy and safety of bronchoscopic treatments for patients

with severe emphysema.

One such device is manufactured by Spiration Inc., Redmond, Wash. The IBV® valve is an

umbrella-shaped nitinol framed prosthesis with a synthetic polymer cover. The flexible nitinol

frame enables the valve to maintain contact with the airway wall and prevent air from passing

into the diseased portions of the lungs while allowing for mucus and air to escape. This creates

a one-way valve effect and redirects inspired air from the diseased upper lobes to the healthier

lower lobes.

While the patient is under anesthesia, the valve is inserted through the working channel of a

flexible bronchoscope. The calibrated balloon determines the size of the valve for a preselected

airway segment. Under direct vision, the valve deployment device is passed through the work-

ing channel of the bronchoscope and installed. The valves are intended to be permanent but

they can be removed via a minimally invasive procedure.

In the first human pilot study (Wood et al Journal of Thoracic and Cardiovascular Surgery

2007, Jan:133(1):65-73), 30 patients received IBV valves at five centers, including Cleveland

Clinic. Although the clinical trial was not designed to establish the efficacy of the valves, data

was collected to provide guidance for future studies. A majority of patients experienced signifi-

cant improvements in health-related quality of life as measured by the St George’s Respiratory

Questionnaire with an improvement of 9.8 (+/-9.6), 6.9 (+/- 12.9) and 6.8 (+/- 14.3) at

one, three and six months, respectively. Nevertheless, the physiological tests did not show

statistically significant improvements.

The pilot study continued to include 98 patients and is being published soon. The most com-

mon procedure complication was bronchospasm in eight cases. These all resolved but one

was serious and two severe. Pneumothorax was the most common device complication and

occured in eight cases. Two cases did not require intervention but one episode was a tension

IBV Valve by Spiration, Inc.

Zephyr EBV Valve by Emphasys Medical

Animal image of fibrin plug for biologic lung volume reduction by Aeris Therapeutics Inc.

Bronchial bypass by Broncus Technologies

Fall 2008 | 13

pneumothorax with death. Pneumothorax likely results from greater

lung volume changes than are necessary for significant improvement,

so the treatment pattern was revised.

The improved health-related quality of life outcomes might have been

due to a placebo effect among patients participating in a pilot study,

and so Spiration is sponsoring a larger research trial that is expected

to recruit more than 300 patients at 29 centers, including Cleveland

Clinic. This IBV valve study, currently under way, is a randomized,

blinded trial, which is expected to eliminate the placebo effect and

help investigators determine the physiological efficacy and safety of

the IBV valve. Patients will be selected based on strict inclusion and

exclusion criteria to reduce the risks for complications.

E B V ( E N D O B r O N C H I A L V A L V E )

The Zephyr® EBV valve from Emphasys Medical, Redwood City, Calif.,

has completed a multicenter clinical trial and is before the FDA for

review. Investigators at Cleveland Clinic have case by case permission

to use this valve in compassionate use protocols for persistent bron-

chopleural fistula, treatment for severe emphysema and giant bullae.

E x H A L E A I r W A y S T E N T S f O r E M P H y S E M A

Another trial currently enrolling at Cleveland Clinic is the EASE (Exhale

Airway Stents for Emphysema) trial sponsored by Broncus Technologies,

Mountain View, Calif. This is a randomized, double-blind study to

evaluate the safety and effectiveness of the Exhale® drug-eluting

stent in patients with homogeneous emphysema and severe hyperinfla-

tion. This technique involves creating artificial airways, or “airway

bypasses”, across the wall of poorly functioning existing airways.

Airway bypass is done in the operating room under general anesthe-

sia. A bronchoscopy is performed where a Doppler probe is used to

identify safe areas to place stents. A needle with a balloon is first used

to perforate the airway and dilate the opening. A balloon loaded with

the drug-eluting stent is then deployed across the airway wall. Trapped

air is now able to pass out of the areas of emphysema without getting

blocked by the diseased airways characteristic of COPD/emphysema.

Pilot trials of this device have been conducted internationally with

these airway bypass stents (Cardoso et al Journal of Thoracic and

Cardiovascular Surgery 2007 Oct;134(4):974-81). Thirty-five patients

received the airway bypass procedure with a median of eight stents

implanted per patient. At one-month follow-up, differences in lung

function tests of hyperinflation, modified Medical Research Council

scale, six-minute walk, and St George's Respiratory Questionnaire were

observed. At the six-month follow-up, statistically significant improve-

ments were demonstrated in residual volume and dyspnea. One death

occurred due to bleeding during the procedure.

B I O L O g I C L u N g V O L u M E r E D u C T I O N

Yet another procedure in trials has been developed, biologic lung vol-

ume reduction, sponsored by Aeris Therapeutics Inc., Woburn, Mass.

A process of instilling biologic chemical reagents into targeted areas

of the lung results in scar tissue collapsing areas of diseased lung,

improving lung mechanics.

Biologic lung volume reduction (BLVR) is performed by selecting

targeted subsegments. A double lumen catheter is advanced out deep

into the lung. A mixture of chemicals and a form of fibrin glue is rapidly

instilled and allowed to gel in place. The process is repeated in

several segments based on the protocol.

Phase I of the study (Reilly J et al Chest. 2007 Apr;131(4):1108-13)

enrolled six patients with advanced heterogeneous emphysema. Three

patients received unilateral treatment at two pulmonary subsegments

and three patients received unilateral treatment at four pulmonary

subsegments. BLVR was not associated with any serious complications.

Improvements were observed in mean vital capacity (+7.2 +/- 9.5%;

range, -2% to +19%), mean residual volume (RV) (-7.8 +/- 8.5%;

range, +1% to -22%), mean RV/total lung capacity ratio (-6.6

+/- 4.7%; range, -1% to -15%), mean 6-min walk distance (+14.5

+/- 18.5%; range, 0 to +51%), and in mean dyspnea score.

Cleveland Clinic participated in two Phase II multicenter trials, one for

patients with homogenous disease and the other for patients with het-

erogeneous disease. Results of these trials have not yet been published.

Cleveland Clinic is preparing for the BLVR Phase III clinical trial.

Specific inclusion/exclusion criteria have not yet been set.

Cleveland Clinic doctors involved in these trials are Atul C. Mehta,

MD, Thomas R. Gildea, MD, and Michael Machuzak, MD.

Patient recruitment for these studies is under way. For more

information, please call Yvonne Meli, RN, BC, at 216.445.4215

or [email protected].

Researchers hope the endobronchial valves

may achieve the benefits of LVRS, but with-

out its surgical risks and complications.


A S T H M A S u M M I T 2 0 0 7

The Asthma Summit focused on research and clinical care advances

by global leaders in asthma. The meeting highlighted perspectives on

future research that will influence the practice of asthma care, and

described the most up to date diagnostic tools, asthma educational

programs and new insights into clinical care. More than 175 attendees

from around the world were provided detailed information on recent

innovations in asthma and potential interface with new technology.

M A j O r A I r W A y D I S E A S E S u M M I T 2 0 0 7

The Major Airway Disease Summit in April 2007 focused on the

interfaces among innovative technology, research, and clinical care.

The summit provided a unique perspective on cutting-edge technolo-

gies that will influence the future management of patients with major

airway disease.

L u N g S u M M I T 2 0 0 7 : I N N O V A T I O N S I N r E S P I r A T O r y T H E r A P y M A N A g E M E N T A N D C L I N I C A L P r A C T I C E

This summit in May 2007 addressed the issues of supply of RTs,

demand for their services and manpower in respiratory care today.

Key issues in managing a respiratory therapy group, current issues

regarding new modes and optimal strategies of mechanical ventilation,

and optimal aerosol delivery were addressed.

FIRST C

LASS

SOR

TEDU

.S. Postage PA

IDB

erea, OH

Permit N

o. 296

The Cleveland C

linic FoundationC

enter for Continuing Education TR

17

9500 Euclid Avenue

Cleveland, O

H 4

4195

Asthma Summit 2007Innovations in Pulmonary, Allergy and Critical Care Medicine

April 12, 2007InterContinental Hotel and

Bank of America Conference CenterCleveland, Ohio

www.clevelandclinicmeded.com/asthma07

Registration Form

Asthma Summit 2007Innovations in Pulmonary, Allergy and Critical Care Medicine

April 12, 2007

FEES:

$225.00 Physician

$146.25 CompreCare Affiliate Member ID#_____________________________

$135.00 CCF Alumni

$135.00 Cleveland Clinic Health System Physician’s Organization Member

$125.00 Resident*/Fellow*/Nurse/Respiratory Therapist

*Letter from program director must be received in our office prior to the summit to register.

Payment must be received prior to admittance to the Summit. Purchase orders are not accepted.

Go to: www.clevelandclinicmeded.com/asthma07 Once you register online, please do not mail or fax in a registration form.

CCF main campus, family health centers, and CCHS community hospital employees (physicians and non-physicians) should register online at the above web address.

Complete the information below if registering by mail or fax: PLEASE PRINT

Last Name First Name Ml Degree

Address

City State Zip

Phone Fax

Specialty E-Mail

I require a vegetarian lunch

I will attend the Reception

Total amount enclosed or to be charged $_______________________________

MAIL Make check payable to: The Cleveland Clinic Educational Foundation or charge the following account: Visa MasterCard American Express Discover

Card Number Exp: Date

Signature (not valid without signature) 3 Digit V-Code,on back of card

FAX NUMBER 216-445-9406

MAILING ADDRESS The Cleveland Clinic Educational Foundation P.O. Box 931653 • Cleveland, OH 44193-1082

Summit 011500 • Office Use Only

Fee __________ Date ___________

M.O.P. ________ CXL/Fee ________

Asthma Sum

mit 2007

Innovations in Pulmonary, Allergy and Critical Care M

edicine

ww

w.clevelandclinicm

eded.com/asthm

a07

April 1

2, 2

007

InterContinental H

otel and Bank of A

merica C

onference Center

Cleveland, O

hio

A

B

C

BREAK OUT SESSION REGISTRATION

2:30 - 3:00 pm A

B

C

3:00 - 3:30 pm

Asthma Center Major Airway Disease SummitInnovations in Pulmonary and Critical Care Medicine

April 13, 2007InterContinental Hotel and

Bank of America Conference CenterCleveland, Ohio

www.clevelandclinicmeded.com/airway07

Registration Form

Major Airway Disease SummitInnovations in Pulmonary and Critical Care Medicine

April 13, 2007

FEES:

$225.00 Physician

$146.25 CompreCare Affiliate Member ID#_____________________________

$135.00 CCF Alumni

$135.00 Cleveland Clinic Health System Physician’s Organization Member

$125.00 Resident*/Fellow*/Nurse/Respiratory Therapist *Letter from program director must be received in our office prior to the summit to register.

Registration Fee includes attendance, syllabus, Continental Breakfast, breaks and lunch.

Payment must be received prior to admittance to the Summit. Purchase orders are not accepted.

Go to: www.clevelandclinicmeded.com/airway07 Once you register online, please do not mail or fax in a registration form.




Address

City State Zip

Phone Fax

Specialty E-Mail

I require a vegetarian lunch


MAIL Make check payable to: The Cleveland Clinic Educational Foundation or charge the following account: Visa MasterCard American Express Discover


Signature (not valid without signature) 3 Digit V-Code,on back of card

FAX NUMBER 216-445-9406

MAILING ADDRESS The Cleveland Clinic Educational Foundation P.O. Box 931653 • Cleveland, OH 44193-1082

Summit 011465 • Office Use Only

Fee __________ Date ___________

M.O.P. ________ CXL/Fee ________

PR

E-SO

RTE

DFI

RST

CLA

SSU

.S. Po

stag

ePA

IDB

erea

, O

HPe

rmit

No.

296

The

Cle

vela

nd C

linic

Fou

ndat

ion

Cen

ter

for

Con

tinui

ng E

duca

tion

TR17

9500 E

uclid

Ave

nue

Cle

vela

nd, O

H 4

4195

Maj

or A

irway

Dis

ease

Sum

mit

Inno

vatio

ns in

Pul

mon

ary

and

Criti

cal C

are

Med

icin

e

ww

w.c

leve

land

clin

icm

eded

.com

/airw

ay07

Apr

il 13, 2007

Inte

rCon

tinen

tal H

otel

and

B

ank

of A

mer

ica

Con

fere

nce

Cen

ter

Cle

vela

nd, O

hio

Breath Analysis Summit 2007: Clinical Applications of Breath Testing

Register Today!

www.clevelandclinicmeded.com/breath07

November 1 - 3, 2007 | Cleveland, Ohio

This Summit will be this year’s scientific meeting of the International Association for Breath Research (IABR). The meeting will be held in collaboration with the National Aeronautics and Space Administration (NASA), the Environmental Protection Agency (EPA), the Monell Chemical Senses Center, and the Electrochemical Society (ECS). Proceedings will be published in the newly established Journal of Breath Research (JBR).

This Summit will bring industry executives, entrepreneurs, and investors together with scientists, environmentalists, and clinicians to discuss key trends, future directions, and upcoming technologies in breath analysis and medicine.

The major focus this year will be on medical applications in addition to environmental and bioterrorism issues. Topics to be covered will include:

• nitric oxide • exhaled breath condensate • electronic nose and sensor arrays • mass spectrometry and benchtop instrumentation • cutting edge sensor technologies

Medical applications will include:• asthma, COPD, pulmonary hypertension, and other respiratory diseases• gastrointestinal diseases • occupational diseases • critical care • cancer

InterContinental Hotel and Bank of America Conference Center

Scientific Meeting of the International Association for Breath Research (IABR)

Department of Pulmonary, Allergy, and Critical Care Medicine

Summit Directors:Raed A. Dweik, Cleveland ClinicGary W. Hunter, NASA Local Organizing Committee:Raed A. Dweik, Cleveland ClinicSerpil C. Erzurum, Cleveland ClinicAlan Gelperin, Monell Chemical Senses Center Gary W. Hunter, NASA Dan Laskowski, Cleveland Clinic Joachim Pleil, EPA

International Organizing Committee:Anton Amann, AustriaRaed Dweik, USAJörg Ingo Baumbach, Germany Terence Risby, USAJochen Schubert, GermanyDavid Smith, United KingdomPatrik Spanel, Czech Republic Hideo Ueda, Japan

General Information Location: InterContinental Hotel & Bank of America Conference Center9801 Carnegie AvenueCleveland, OH 44106Phone: 216-707-4100 or 877-707-8999 Fax: 216-707-4101

Hotel Accommodations: Guests need to make their reservations directly with Hotel Reservations no later than 5:00 PM (Eastern Time) on October 1, 2007, by calling (216) 707-4000 or toll free (877) 707-8999. Please identify yourself as being with the Cleveland Clinic Breath Analysis Summit 2007 (online code Y26) for a special rate of $119 single/double plus tax. The hotel and conference center is located on the campus of The Cleveland Clinic.

www.clevelandclinicmeded.com/breath07

CALL FOR ABSTRACTSSubmission deadline: on or before September 1, 2007

For complete abstract submission details and Summit information, please visit:

Pulmonary Hypertension Summit 2007 Translating Discoveries Into Patient Care

November 16 – 17, 2007 | Cleveland, OhioInterContinental Hotel and Bank of America Conference Center

Department of Pulmonary, Allergy, and Critical Care Medicine

ww

w.cl

evel

andc

linic

med

ed.c

om/P

Hsu

mm

it07

Reg

iste

r on

line

at

The

Cle

vela

nd C

linic

Fou

ndat

ion

Cen

ter

for

Con

tinui

ng E

duca

tion

TR17

9500 E

uclid

Ave

nue

Cle

vela

nd, O

hio

44195

Pulm

onar

y Hy

pert

ensi

on

Sum

mit

2007

Nov

embe

r 16

– 1

7, 2

007

| C

leve

land

, Ohi

oIn

terC

onti

nen

tal

Hot

el a

nd

Ban

k of

Am

eric

a C

onfe

rence

Cen

ter

Location:InterContinental Hotel and Bank of America Conference Center 9801 Carnegie AvenueCleveland, OH 44106Phone: 216-707-4100 or 877-707-8999 Fax: 216-707-4101

Hotel Accommodations:A block of rooms has been reserved at The InterContinental Hotel until October 11, 2007. To make your reservations, contact the Hotel Reservations Department at 216-707-4100 or 1-877-707-8999. Please identify yourself as being with the Cleveland Clinic Pulmonary Hypertension 2007 Summit, (online code x36) for a special rate of $189 single/double plus tax. The hotel and conference center is located on the campus of The Cleveland Clinic.

Ground Transportation: Taxi service is available from Cleveland Hopkins International Airport to the InterContinental Hotel and Bank of America Conference Center. As an alternative, take the rapid transit train from the airport to the Terminal Tower in downtown Cleveland and from there take a taxi to the InterContinental Hotel and Bank of America Conference Center. Information: For further information about this summit, contact UNITECH Communications® at:Local: 216-297-7330 Toll Free: 800-238-6750Web Address: www.clevelandclinicmeded.com/PHsummit07For questions about registering online, call 216/297-7300.If you have any special needs that require additional assistance, please call us. Requests must be received at least 2 weeks prior to the summit.For emergency phone calls during the summit, please call 216-707-4100 and ask for the Cleveland Clinic Registration Desk.

Registration and Cancellation: Pre-registrations are accepted by fax or online until 4:00 pm EST November 15, 2007. To register after this date you must do so on-site. In case of cancellation, a full refund will be made if canceled by November 7, 2007. After November 7, 2007, a $50 cancellation fee will be deducted from your refund. Written notification of your cancellation is required in order to process your refund. NO REFUNDS WILL BE ISSUED AFTER DECEMBER 15, 2007.

Parking: Free parking is available in the 100th Street Visitor’s Parking Garage. Bring your parking ticket to the summit registration desk for validation (self-park only). Valet parking is available at the hotel for an additional charge.

Accreditation: The Cleveland Clinic Foundation Center for Continuing Education is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Cleveland Clinic Foundation Center for Continuing Education designates this educational activity for a maximum of 15.75 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.This activity may be submitted for American Osteopathic Association Continuing Medical Education credit in Category 2.Cleveland Clinic (OH-045) is an approved provider of continuing education by the Ohio Nurses Association, an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation (OBN-001-91). Provider status valid through 10-1-09.

Faculty Disclosure:The Cleveland Clinic Foundation Center for Continuing Education has implemented a policy to comply with the current Accreditation Council for Continuing Medical Education Standards for Commercial Support requiring resolution of all faculty conflicts of interest. Faculty declaring a relevant commercial interest will be identified in the activity syllabus.

Registration Form

Pulmonary Hypertension Summit 2007 November 16 – 17, 2007

FEES:

q $150.00 Physician

q $100.00 Nurse/Physician Assistant

q $100.00 Resident/Fellow* *(Letter from program director must be received in our office prior to the course.)

Patients are invited to attend at no charge. Seating is limited. Please call 216-445-5763 to register before November 16, 2007

REGISTER ONLINE: www.clevelandclinicmeded.com/PHsummit07Once you register online, please do not mail or fax in a registration form.


Fee includes: Syllabus, continental breakfast, two lunches, refreshment breaks, and reception.

Payment must be received prior to admittance to the summit. Purchase orders are not accepted.



Address

City State Zip

Phone Fax

Specialty E-Mail

q I require vegetarian lunches. q I will attend the reception.


MAIL Make check payable to: The Cleveland Clinic Educational Foundation or charge the following account: q Visa q MasterCard q American Express q Discover


Signature (not valid without signature) 3 Digit V-Code, on back of card

FAX NUMBER 216-445-9406

MAILING ADDRESS The Cleveland Clinic Educational Foundation P.O. Box 931653 • Cleveland, Ohio 44193-1082

Course 011463 • Office Use Only

Fee __________ Date ___________

M.O.P. ________ CXL/Fee ________

The Cleveland Clinic Educational Foundation Center for Continuing Education acknowledges educational grants for partial support of the summit from:

PLATINUM GOLD SILVER

BRONZE

CONTRIBUTOR Curascript

PR

E-SO

RTE

DFI

RST

CLA

SSU

.S. Po

stag

e Pa

idB

erea

, O

HPe

rmit

No.

296

B r E A T H A N A L y S I S S u M M I T 2 0 0 7 : C L I N I C A L A P P L I C A T I O N S O f B r E A T H T E S T I N g

In November 2007, the Respiratory Institute hosted the first

“International Breath Analysis Summit”, which was also the third

Scientific Meeting of the International Association for Breath Research

(IABR). Directed by Raed A. Dweik, MD, the summit was held in

collaboration with NASA, the U.S. EPA, the Monell Chemical Senses

Center and the Electrochemical Society. Participants in the two

and a half day summit came from 22 countries and 18 states and

discussed key trends, future directions and upcoming technologies in

breath analysis and medicine.

P u L M O N A r y H y P E r T E N S I O N S u M M I T 2 0 0 7

The Pulmonary Hypertension Summit 2007, on November 16 and

17, attracted more than 220 participants from 20 states and five

countries to hear presentations by about 40 distinguished Cleveland

Clinic and visiting faculty. The next Pulmonary Hypertension

Symposium will be Nov. 8, 2008, and the next Pulmonary

Hypertension Summit will be in Fall 2009.

Educational Summit RecapRespiratory Institute Dedicated to Helping Professionals Continue to Develop

Cleveland Clinic Respiratory Institute is committed to offering forums for renowned researchers in pulmonary diseases to present their latest findings and providing professionals with insights they can integrate into their clinical practice. The Respiratory Institute was proud to sponsor five innovation summits in 2007.

Fall 2008 | 15

Outcomes Data AvailableThe latest outcomes data from Cleveland

Clinic departments involved in the

treatment of respiratory diseases are

available. Our outcomes booklet offers

summary reviews of medical and surgical

trends and approaches. Charts, graphs

and data illustrate the scope and volume of procedures performed in our

departments each year. To view outcomes booklets for respiratory diseases

as well as many other Cleveland Clinic medical and surgical disciplines,

visit clevelandclinic.org/quality.

Online Access to Your Patient’s Treatment ProgressWhether you are referring from near or

far, our new eCleveland Clinic service,

DrConnect, can streamline communica-

tion from Cleveland Clinic physicians

to your office. This new online tool offers

you secure access to your patient’s treatment progress at Cleveland Clinic.

With one-click convenience, you can track your patient’s care using the

secure DrConnect Web site. To establish a DrConnect account, visit

eclevelandclinic.org or e-mail [email protected].

Cleveland Clinic Ranked One of America’s Top Hospitals Cleveland Clinic is ranked among the top hospitals in the country, accord-

ing to the latest U.S.News & World Report’s annual survey of “America’s

Best Hospitals.” In the Respiratory Disorders category, Cleveland Clinic

is ranked #5. For details, visit clevelandclinic.org.

CME CalendarPhysicians are welcome to attend the following upcoming symposia:

Obesity Summit 2008 | Sept. 10-12

InterContinental Hotel and Bank of America

Conference Center, Cleveland Clinic

Cleveland, Ohio

The 5th Annual Pulmonary Arterial

Hypertension Symposium 2008 | Nov. 8



Cleveland, Ohio

Biologic Therapies in Special Populations –

Infections, Malignancies, Cardiovascular

Disease, and Other Comorbidities

May 7-9, 2009

Featuring: Mini-symposium on 'Managing

Complex Cases in Biologic Therapies'



Cleveland, Ohio

17th World Congress for Bronchology,

and the 17th World Congress for

Bronchoesophagology | June 16-19, 2012

Cleveland, Ohio

For more information about the

above events, call the Cleveland Clinic

Department of Continuing Education

at 216.444.5696 or 800.762.8173,

or visit clevelandclinicmeded.com.

1

Outcomes | 2007

Respiratory Institute

16 | Respiratory Institute | Staff Directory 2008

Department of Pulmonary, Allergy and Critical Care Medicine

Herbert P. Wiedemann, MD, MBA Chairman, Respiratory Institute

216.444.8335

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

Loutfi Aboussouan, MD

216.839.3820

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

Muzaffar Ahmad, MD

216.444.6506

Specialty Interests: pulmonary function lab, diagnostic techniques including fiberoptic bronchoscopy, asthma, lung cancer

Rendell Ashton, MD

216.446.5321

Specialty Interests: critical care, lung cancer, physician education

Marie Budev, DO, MPH Associate Medical Director, Lung Transplantation

216.444.3194

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

Robert Castele, MD

440.878.2500

Specialty Interest: general pulmonary medicine

Jeffrey T. Chapman, MD Director, Interstitial Lung Disease Program

216.444.4222

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

Daniel Culver, DO

Director, Sarcoidosis Program

216.444.6508

Specialty Interests: sarcoidosis, interstitial lung disease, hypersensitivity pneumonitis

Raed A. 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

Serpil C. Erzurum, MD Chairman, 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, lung cancer

Samar Farha, MD

216.444.3229

Specialty Interests: critical care, pulmonary hypertension

Andrew Garrow, MD

216.445.9797

Specialty Interests: critical care medi-cine, sleep medicine

Thomas R. Gildea, MD Co-Director, Center for Major Airway Diseases

216.444.6490

Specialty Interests: pulmonary hyperten-sion, interventional bronchology, lung transplantation

Jorge Guzman, MD

Head, Section of Critical Care Medicine

216.445.5765

Specialty Interests: critical care, sepsis, shock

David Holden, MD

216.986.4000

Specialty Interest: general pulmonary medicine

Constance A. Jennings, MD

216.445.4184

Specialty Interests: pulmonary hyperten-sion, pulmonary thromboembolism, interstitial lung disease, advanced lung disease

Michael Machuzak, MD

216.444.2718

Specialty Interests: rigid and flexible bronchoscopy, endobronchial ultrasound, laser, electrocautery, stent placement, bronchoscopic lung volume reduction, transtracheal oxygen catheter placement; lung cancer, pleural diseases, COPD

Peter Mazzone, MD, MPH Director, Lung Cancer Program; Director, Pulmonary and Critical Care Fellowship Program

216.445.4812

Specialty Interests: lung cancer, critical care, physician education

Fall 2008 | 17

Atul C. Mehta, MD Vice Chairman, Department of Pulmonary, Allergy and Critical Care Medicine; Medical Director, Lung Transplantation; Head, Section of Bronchology

216.444.2911

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

Omar A. Minai, MD

216.445.2610

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

Thomas Olbrych, MD

216.445.8733

Specialty Interests: general pulmonary medicine, cystic fibrosis

Beverly V. O’Neill, MD

216.692.7848

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

Joseph G. Parambil, MD

216.444.7567

Specialty Interests: interstitial lung dis-ease, pulmonary hypertension, general pulmonary medicine

Anita Reddy, MD

216.444.4506

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

Hina Sahi, MD

216.839.3820

Specialty Interests: general pulmonary medicine

Madhu Sasidhar, MD

216.445.1838

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

James K. Stoller, MD, MS

Head, Section of Respiratory Therapy; Executive Director, Leadership Development

216.444.1960

Specialty Interests: clinical epidemiol-ogy, alpha1-antitrypsin deficiency, respiratory therapy

Section of Allergy and Clinical Immunology

David M. Lang, MD Head, Section of Allergy and Clinical Immunology

216.445.5810

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

Mark A. Aronica, MD Joint Appointment with Pathobiology

216.444.6933

Specialty Interests: asthma, allergic disorders

Sandra Hong, MD

440.204.7400

Specialty Interests: allergy, asthma

Fred H. Hsieh, MD Joint Appointment with Pathobiology

216.444.3504

Specialty Interests: asthma, allergic disorders, mast cell function

Rachel Koelsch, MD

216.444.6933

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

Lily C. Pien, MD

216.444.6933

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

Cristine Radojicic, MD

216.444.6933

Specialty Interests: pediatric and adult allergic rhinitis, asthma

Department of Diagnostic Radiology

Section of Thoracic Imaging

Moulay Meziane, MD Head, Section of Thoracic Imaging

216.444.0282

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

Ruffin J. Graham, MD

216.444.8756

Specialty Interests: pulmonary thromboembolism, lung cancer and thromboembolic disease

18 | Respiratory Institute | Staff Directory 2008

Jeffrey P. Kanne, MD

216.444.3158

Specialty Interests: hematopoietic stem cell transplantation, interstitial lung dis-ease, lung transplantation, occupational lung diseases, congenital disorders of the heart and lungs

Omar Lababede, MD

216.444.9014

Specialty Interest: thoracic imaging

Tan-Lucien H. Mohammed, MD

216.444.3867

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

Barbara Risius, MD

216.444.6422

Specialty Interest: thoracic radiology

Department of Pulmonary Pathology

Carol F. Farver, MD Director, Pulmonary Pathology

216.445.7695

Specialty Interest: pulmonary pathology

Andrea Arrossi, MD

216.444.9120

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

Charles V. Biscotti, MD

216.444.0046

Specialty Interests: cytopathology, gynecologic pathology

Department of Thoracic and Cardiovascular Surgery

Gösta Pettersson, MD, PhD Vice Chairman, Thoracic and Cardiovascular Surgery; Surgical Director, Lung Transplantation

216.444.2035

Specialty Interests: lung and heart-lung transplantation

Gonzalo Gonzalez-Stawinski, MD

216.444.6708

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

Nicholas G. 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

Thomas W. Rice, MD Head, 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

David Mason, MD

216.444.4053

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

Sudish Murthy, 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

Fall 2008 | 19

C O N T A C T I N f O r M A T I O N

General Patient Referral

24/7 hospital transfers or physician consults

800.553.5056

Pulmonary Appointments/Referrals

216.444.6503 or 800.223.2273,

ext. 46503

Allergy Appointments/Referrals

216.444.3386 or 800.223.2273,

ext. 43386

On the Web at

clevelandclinic.org/pulmonary

I N S T I T u T E L O C A T I O N S

Main Campus

9500 Euclid Avenue / A90

Cleveland, OH 44195

Beachwood Family Health

and Surgery Center

26900 Cedar Road

Beachwood, OH 44122

Pulmonary and Allergy: 216.839.3800

Brunswick Family Health Center

3724 Center Road, Suite 100

Brunswick, OH 44212

Pulmonary: 330.225.8886

Euclid Hospital

Medical Office Building

99 Northline Circle, Suite 235

Euclid, OH 44119

Pulmonary: 216.692.7848

Hillcrest Hospital Atrium

6780 Mayfield Road

Mayfield Heights, OH 44124

Pulmonary: 440.312.7140

Cleveland ClinicIndependence

Cleveland ClinicStrongsville

Cleveland ClinicBrunswick

Cleveland ClinicWestlake

Cleveland Clinic

Lake Erie

Cleveland ClinicBeachwood

Cleveland ClinicWilloughby Hills

LORAIN COUNTY

CUYAHOGA COUNTY

SUMMIT COUNTY

MEDINACOUNTY

LAKE COUNTY

PORTAGECOUNTY

GEAUGACOUNTY

EuclidHospital

Hillcrest Hospital

Cleveland Clinic Facilities

Independence Family Health Center

5001 Rockside Road

Crown Center II

Independence, OH 44131


Strongsville Family Health

and Surgery Center

16761 SouthPark Center

Strongsville, OH 44136


Westlake Family Health Center

30033 Clemens Road

Westlake, OH 44145

Allergy: 440.899.5555

Willoughby Hills Family Health Center

2570 SOM Center Road

Willoughby Hills, OH 44094

Allergy: 440.943.2500

The Cleveland Clinic FoundationRespiratory Institute / AC311 9500 Euclid Avenue Cleveland, OH 44195

07-PUL-003

Introducing the Future of Healthcare

Innovative new buildings improve patient access, experience.

This fall, Cleveland Clinic is introducing

the future of healthcare with the open-

ing of the Sydell and Arnold Miller Family

Pavilion and the Glickman Tower.

These buildings, which represent the larg-

est construction and philanthropy project

in Cleveland Clinic history, embody the

pioneering spirit and commitment to quality

that define Cleveland Clinic. These struc-

tures are a tangible expression of institutes,

our new model of care that organizes

patient services by organ and disease.

At 1 million square feet, the Miller Family

Pavilion is the country’s largest single-use

facility for heart and vascular care. The

12-story Glickman Tower, new home to the

Glickman Urological & Kidney Institute, is

the tallest building on Cleveland Clinic’s

main campus.

Both will help us improve patient experience

by increasing our capacity and by consoli-

dating services, so patients can stay in one

location for their care.

With 278 private patient rooms, more

than 90 ICU beds and a combined total of

nearly 200 exam rooms and more than 90

procedure rooms, patients will have faster

access to Cleveland Clinic cardiac and

urological services.

For details, including a virtual tour, please

visit meetthebuildings.com.

R E S P I R AT O R y E x C H A N G E r E S E A r C H A N D N E W S f O r P H y S I C I A N S f r O M

T H E C L E V E L A N D C L I N I C r E S P I r A T O r y I N S T I T u T E

Documents

Respiratory Exchange 2008 - Cleveland Clinic