Ganesh Raghu, MD, FCCP, FACP

Ganesh Raghu, MD, FCCP, FACP

Professor of Medicine and Laboratory Medicine (Adjunct)University of Washington, Seattle, WA, USA

Chief, Chest ClinicDirector, Interstitial Lung Disease, Sarcoid and

Pulmonary Fibrosis ProgramMedical Director, Lung Transplant ProgramUniversity of Washington Medical Center

Seattle, WA, USA

Interstitial lung disease

Medical Treatment -current trends

Interstitial Lung Disease(Immunocompetent Host)

Interstitial Lung Disease

UniqueEntities*

Collagen-VascularDiseases

Iatrogenic/Drug-induced

Conditions

Granulo-matous

Diseases**

Occupational/Environmental

Exposures

InheritedConditions***

Idiopathic InterstitialPneumonia (IIP)

* Langerhans’ cell granulomatosis, lymphangioleimyomatosis, alveolar proteinosis, idiopathic pulmonary capillaritis

** Sarcoidosis, hypersensitivity pneumonitis*** Tuberous sclerosis, Hermansky-Pudlak Syndrome, neruofibromatosis, metabolic storage

disorders, familial IPF

Interstitial Lung Disease(Immunocompetent Host)

Idiopathic InterstitialPneumonia (IIP)

Idiopathic PulmonaryFibrosis (UIP)

Non-IPFIIP

RBILD(DIP)

COP(BOOP)

NSIP AIP Eosinophilicpneumonia

LIP

Interstitial Lung DiseaseClinical Response to Currently Available Therapeutic Agents

● Sarcoidosis● Acute hypersensitivity pneumonitis● Drug induced (acute)● Environmental● Acute pulmonary capillaritis● Idiopathic BOOP● Respiratory bronchiolitis associated ILD● Chronic eosinophilic pneumonia● Primary alveolar proteinosis● Acute radiation pneumonitis● Lymphocytic interstitial pneumonia

Generally Favorable


● IPF● Chronic secondary, and advanced pulmonary fibrosis● Pulmonary fibrosis co-existing/associated with pulm.

HTN● Chronic idiopathic BOOP (subset of idiopathic BOOP)● BOOP associated with collagen vascular diseases● Chronic pulmonary hemorrhage syndromes● Pulmonary venoocclusive disease

Generally Unfavorable


● Obliterative bronchiolitis with or without associated ILD

● Acute interstitial pneumonia of unknown etiology● Langerhan cell granulomatosis● Lymphangioleiomyomatosis● Tuberous sclerosis● Pulmonary fibrosis associated with other inherited

disorders● Familial idiopathic pulmonary fibrosis

Generally Unfavorable

Idiopathic Interstitial Pneumonia (IIP)

NSIP LIP COP RBILD DIP AIPEosinophilicpneumonia

Steroid response (vast majority)

NSIP-f NSIP-c

IPF (UIP)

IIP

Non-IPF

Death (~ 3 years)

RelentlesslyProgressive

Subgroup

Subgroup (small)

Slow progression (+ adjunct immunosuppressive)

Death (several years ?)

Idiopathic Pulmonary Fibrosis:Clinical Course/Subgroups*

IPF

Progressionslowed by Rx

Cor pulmonale(2 Pulm hypertension)

Death

Slowlyprogressive

Respiratoryinsufficiency

Cor pulmonale(2 Pulm hypertension)

Death

Modified from Raghu: Chest 1987; 92:148-54

Death

Acutedeterioration

(? exacerbation)

Stable

Slowlyprogressive

Deathsecondary toother cause

Progressive

RapidlyProgressive

Continuedprogression

RxComplication

? trigger

Respiratoryinsufficiency

●Usual course:– Often insidious– Relentlessly progressive– No spontaneous remissions

●Treatment:– No data to support specific therapy, duration,

dosage, timing– Combined corticosteroids and azathioprine or

cyclophosphamide in all patients who do not have contraindications

– Initiate ‘early’ in the clinical course

Treatment

Idiopathic Pulmonary Fibrosis-ATS Statement

Guidelines for Diagnosis and Treatment

AJRCCM Feb 2000

●6 Months minimum, in the absence of complications or adverse effects

Treatment: Duration

Idiopathic Pulmonary Fibrosis- ATS Statement

Guidelines for Diagnosis and Treatment

At 6 months and 12 months

Improved Stable Worse

Continue therapyContinue low dose prednisoneSwitch to alternative therapy or different cytotoxic Rx or stop Rx

AJRCCM Feb 2000

Idiopathic Pulmonary fibrosis-predictors of survival

●Dyspnea score(1,6)● CRP score (2)●Composite physiologic index (3,4)●Change in PFTs [FVC,DLCO,P(A-a)O2] (5,6)●Walk test - 6 min walk (7)

- modified [ timed walk test-(8) ] distance/velocity to desaturate1)Schwartz et al,1994; 2)Watters et al,1986; 3)Wells et al,2003; 4)

Latsi et al,2003;5) Flaherty et al,2003; 6)Collard etal,2003; 7) Lama et al,2003 ;8) Hallstrand et al,2005

Longstanding “Awareness”●Currently available treatment

regimen “ineffective”

●Myth or fact?

Idiopathic Pulmonary Fibrosis Treatment

Idiopathic Pulmonary FibrosisRole of Pilot Studies

“Pilot” Studies – Initial study following an anecdotal observation

RetrospectiveCase Reports/Series

Prospective Data Gathering

Observations: provocative, positive, suggestive

Concepts, Hypothesis

Further Clinical Studies (Prospective)

Idiopathic Pulmonary Fibrosis: TreatmentRole of Pilot Studies

“Pilot” Studies with Positive Observations

Prospective Clinical Studies

Open LabelPhase II

Randomized Control Trials (RCT)

Positive Data

Proof of Concept Phase II

Idiopathic Pulmonary Fibrosis: TreatmentPilot Studies Evolution to Clinical Trials

Well Designed, Phase III RCT

Endpoints for Improved Outcome

Positive 1° Endpoint

Clinical Relevance and Significance

Positive Data

Evidence

Negative 2° and Negative Signals in Subgroups, Exploratory Analysis

Negative 1° Endpoint

Positive 2° and Positive Signals in

Subgroups &/or Exploratory Analyses No Evidence for Treatment

Idiopathic Pulmonary Fibrosis: Treatment

Pilot Studies → Evolution to Clinical Studies

●Prednisone Azathioprine Prednisone + Azathioprine

Treatment Pilot Further Studies Current Status 1/2007

●Colchicine Douglas 1993

Retrospective Douglas 1997

No evidence for clinical benefit

RCT Prospective Douglas 1998

●N-acetyl Cysteine (NAC)

Behr et al. 1997

Multicenter,DBRCT, IFIGENIA (Europe) prednisone + AZA + NAC vs pred + AZA

FVC and DLCO better with adjunct NAC compared to pred+AZA : ? New standard of care ..need further studies

Winterbauer et al. 1978

Double blind RCT, placebo controlled. Raghu et al 1999

Prednisone + Azathioprine “Std of care”, guided by Int’l Consensus 2000 despite no evidence

Idiopathic Pulmonary Fibrosis: TreatmentPilot Studies → Evolution to Clinical Trials

Treatment Pilot Further Studies Current Status 4/2007

●Pirfenidone Raghu et al. 1999

Phase II double-blind RCT. Azuma et al. 2005.

Phase III completed in Japan;ongoing western world

●Etanercept Niden et al. ATS 2002

Proof of concept, DBRCT, placebo controlled trial

Results presented Raghu :CHEST,11/05 ERS,9/06

Ziesche et al. 1999

Multicenter, double-blind, RCT (DBRCT), placebo controlled GIPF-001 (phase III) Raghu et al. 2004.

DBRCT phase III survival studies completed

●-interferon

●Anticoagulation Kubo et al,CHEST 05(RCT) needed

? Treatment roleNeed further studies

High Dose N-acetylcysteine in Idiopathic Pulmonary Fibrosis: the IFIGENIA-Trial*

●Multinational, double-blind, randomized, placebo-controlled, parallel-group trial

●Prednisone + Azathioprine + NAC vs. Prednisone + Azathioprine

* Maurits Demedts et al NEJM 2005


-0.3

-0.2

-0.1

0

0.1Baseline Endpoint 6m

Endpoint12m

Lite

rs

NACPlacebo

NAC (n=)Placebo (n=)

8075

6360

5551

Primary endpoint : VC (L)

P = 0.02



NAC (n=)Placebo (n=)

7974

5859

4847

-1

-0.5

0

0.5Baseline Endpoint 6m Endpoint 12m

mm

ol/m

in/k

Paa

NACPlacebo

Primary endpoint : DLCO (mmol/min/kPa)

P= 0.003


Survival within one year

NAC PlaceboMortality 9% (7/80) 11% (8/75)Time to death 144* (46-276 days) 71 (57-132)

* Median (quartiles)

Idiopathic Pulmonary Fibrosis: Results of the European Trial (IFIGENIA STUDY)* Prednisone plus Azathioprine +/- N-Acetyl Cysteine (NAC)

*M.Demedts et al,NEJM,2005

* Demedts et al NEJM 2005; 353: 229-42

NAC Placebo

AEn

322

6665334331

n8072

6665333331

Patient%

100 90

8886444441

AEn

303

1261

10 565544

n7567

125110565544

Patient%

100 89

1371

13 787755

Total number of patientsTotal AE

Blood alkaline phos increasedBlood lactate dehydrogenase inc.Back painRespiratory failureBone marrow toxicityEdemaHeadacheAstheniaInfluenza like illnessMuscle crampTremor

Adverse Events (AE) Occurring in at least 5% of Patients

P=0.03


* Demedts et al NEJM,2005

Conclusions●Therapy with NAC 600 mg TID added to prednisone and

azathioprine, preserves VC and DLCO in IPF better than prednisone and azathioprine (standard therapy)

Idiopathic Pulmonary FibrosisTreatment with Antifibrotic Agents

Am J Respir Crit Care Med 1999; 159:1061-9

Idiopathic Pulmonary FibrosisTreatment with Pirfenidone

Idiopathic Pulmonary Fibrosis (IPF)Treatment with Pirfenidone in IPF

Open label, Phase 2, Compassionate Use Study (UWMC, Seattle, WA)(Raghu et al,AJRCCM 1999)

Raghu G et al. AJRCCM 1999

● Arata Azuma, MD (Tokyo)● Toshihiro Nukiwa, MD (Sendai)● Eiyasuu Tsuboi, MD (Tokyo)● Moritaka Suga, MD (Kumamoto)● Shosaku Abe, MD (Sapporo)● Koichiro-Nakata, MD (Tokyo)

Idiopathic Pulmonary Fibrosis:Treatment with Pirfenidone (prospective,double blind placebo

controlled,clinical trial in Japan)*

*Sponsor: Shionogi & Co., Ltd. Osaka, JapanAzuma et al,AJRCCM,2005

● Yoshio Taguchi, MD (Tenri)● Sonoko Nagai, MD (Kyoto)● Harumi Itoh, MD (Fukui)● Motoharu Ohi, MD (Osaka)● Atsuhiko Sato, MD (Kyoto)● Shoji Kudoh, MD (Tokyo)

● Ganesh Raghu, MD (Seattle, WA, USA)

Pirfenidone: Treatment for IPFDouble-Blind, Placebo Controlled Clinical Trial in Japan*

I. Primary Endpoint●Lowest SpO2 during 6MET higher in the

subset of pirfenidone group of patients completing the 6 minute walk at 6 months (p=0.0069), 9 months (p=0.0305)- a positive trend(p =0.07) was seen in

all the patients in the pirfenidone group(full analysis set)

Results

Azuma et al. AJRCCM (2005)

Pirfenidone treatment in IPF : Current Status(April 2007)

● Experimental anti fibrotic agent

● Only available for use in patients enrolled/participating in clinical studies and not for routine use in patients

● Phase III study began last Nov 2005 in Japan- results announced as a press release by Shionogi(Dec 21st 2006)

indicates a positive study(final results for scientific review awaited)

● Phase III study in North America and Europe just begun ● Until results of these studies are available for the scientific

community,unknown if effective for IPF

A Randomized Placebo-Controlled Trial Assessing the Efficacy and Safety of Etanercept in Patients with Idiopathic

Pulmonary Fibrosis

Data presented at CHEST : Nov,2005 and at ERS,Sep,2006

G Raghu*,1 JA Lasky,2 U Costabel*,3 KK Brown*,4 V Cottin,5 RM du Bois*,6 M Thomeer,7 J Utz*,8 L McDermott9

1University of Washington Medical Center, Seattle, WA 2Tulane University Medical Center , New Orleans, LA 3Ruhrlandklinik Essen-Heidhausen, Essen, Germany 4National Jewish Center, Denver, CO 5Center for Orphan Lung Diseases, Lyon, France 6Royal Brompton Hospital, London, UK, 7Universitaire Ziekenhuizen KULeuven, Leuven, Belgium 8Mayo Clinic, Rochester, MN 9Wyeth Research, Collegeville, PA Sponsor: Wyeth Research

*Consultants/Advisors

Proof of Concept Study : Etanercept in IPF(data presented Raghu et al CHEST NOV,05 and ERS Sept,06)

● 48 week, double-blind, placebo-controlled, randomized, parallel, multi-center international study – 88 IPF patients enrolled

– 85 in efficacy population, 87 in safety population– Primary comparison between groups: Baseline versus 48

weeks, LOCF

Placebo 2x/week S/C

Etanercept 25 mg 2x/week S/CScreen

48 weeks4 weeks

Proof of Concept Study : Etanercept in IPF(data presented at CHEST NOV,05 and ERS Sep.06)

Conclusions●Efficacy

– Primary and Secondary Endpoints not met– Trend in favor of etanercept for

– Multiple physiologic endpoints – Functional measures (6MWD, QoL)

– Post Hoc Analyses– Trend toward improved progression-free

survival– Highest treatment differences for tertile of

patients with entry FVC < 57%●Safety

– No significant difference in the overall incidence of adverse event, serious adverse events or infections between treatment groups

BUILD 1*

●A double-blind randomized placebo controlled multicenter study to assess the efficacy, tolerability, and safety of bosentan in patients with idiopathic pulmonary fibrosis (IPF)

* Sponsor : Actelion

BUILD 1 : Bosentan did not improve 6MWD up to 12 months (Primary Endpoint) (data presented at ATS* and

ERS meeting 5/06 and 9/06) : King*,Behr,Brown,Dubois** and Raghu)

All treated patients Placebon = 83

Bosentann = 71

Baseline (m) Mean (SD) Median

372 (74)387

375 (92)397

Month 12* (m) Mean (SD) Median

338 (162)369

323 (164)390

Change from baseline (m) Mean (SD) Median

-34 (127)-9

-52 (121)-23

Treatment effect Mean (SE) Median p-value (Mann-Whitney U-test)

-18 (20)-170.226

*Or earlier if premature discontinuation

BUILD 1 Predefined Population: In biopsy proven IPF, Bosentan delayed time to disease progression

or death (data presented at ATS*/ERS** meetings, 5 and 9/06:

King*,Behr,Brown,Dubois** and Raghu )

p=0.009

100908070

605040302010

00 3 6 9 12 15

Months treatment50 47 42 36 24 0

Placebo 49 47 42 41 22 0 Bosentan

Patients at risk

Placebo

Bosentan

Patients without event (%)

BUILD 1: Summary and Conclusions data presented at ATS* and ERS** meetings 5 and 9/06 :

(King*,Behr,Brown,Dubois** and Raghu )

– Bosentan did not improve the primary endpoint of 6MWD

– Bosentan showed a trend to delayed time to disease progression or death

– In the predefined population with biopsy proven IPF, treatment effect was more pronounced

– Bosentan was well tolerated, with no unexpected adverse events

– These promising results will be investigated in a larger study (BUILD 3)

BUILD 1 : Dyspnea & QoL Conclusions of Results(Raghu et al,ERS Sep.06)

● QoL in IPF patients is severely compromised at baseline● Treatment with bosentan resulted in significant QoL

improvements at month 6; favorable trend observed at month 12

● Bosentan improved the overall well-being of IPF patients, especially in the biopsy-proven IPF subpopulation

● These results concur with the observed delay in time to death or disease progression in the bosentan group1

● Results will be further investigated in the long-term morbidity/mortality BUILD 3 study

1du Bois RM, et al. Bosentan in IPF patients, BUILD 1 study [poster]. Presented at ERS; Munich, Germany; 4 September 2006.

Idiopathic Pulmonary Fibrosis:Anticoagulant Therapy*

●Prospective randomized study in Japan●56 IPF patients●Randomization:

– Prednisolone alone or– Prednisolone plus oral warfarin in the

outpatient setting and low molecular weight heparin in hospitalized patients with progressive respiratory failure

●Overall survival and hospitalization-free periods were assessed

* Kubo et al. Chest 2005; 128:1475-82


* Kubo et al. Chest 2005; 128:1475-82

P=0.049

P=0.3

● Poorly design study● Decision/Need for hospitalisation arbitrary ● All hospitalisations may not have had true acute

exacerbations .● Differential drop outs


Limitations

* Kubo et al. Chest 2005; 128:1475-82

IPF: Treatment with -Interferon

Does it work ?

IPF: Treatment with -Interferon

Raghu et al, NEJM , 2004; 350:125-133

INSPIRE

● Large multicenter trial designed to determine if IFN- provides survival benefits in patients with mild-to-moderate IPF

●Tested signals of survival benefits from post hoc analysis in an earlier phase III trial that failed to show benefits on primary composite outcome of progression-free survival(Raghu et al. N Engl J Med. 2004;350:125-133.)

Raghu G. Eur Respir J. 2006;28:463-465.

INSPIRE

● Study Terminated on March 05 2007*

●No survival benefits associated with Interferon-gamma

* InterMune press Release.

Insights from Recent Clinical Trials


Idiopathic Pulmonary Fibrosis

Clinical Course

* Martinez et al. AIM 2005; 142:963-7

New Insights on Disease Progression From Recent Clinical Trials

●Rapid decline of respiratory status precedes death in otherwise stable patients

●Remarkable stability without treatment in many patients

●Importance of acute exacerbations●Very low mortality during 1-yr follow-up in

patients with well-established IPF●Trials with true placebo-arm may be possible

based on observed stability without treatment


● No differences in chosen primary endpoints between treatment groups– interferon (Raghu et al. data presented ATS 2000)– interferon (Raghu et al. NEJM 2004;InterMune press release March 2007)– Pirfenidone (Azuma et al. AJRCCM 2005)– Etanercept (Raghu et al. Chest Meeting Nov 05 and ERS meeting Sep 06)– Bosentan (King et al. ATS, May 23, 2006)

● N-acetylcysteine (NAC) added to prednisone and azathioprine preserved VC and DLCO better than prednisone + azathioprine (Demedts et al. NEJM 2005)

● Pirfenidone improves VC (Shionogi Press Release,Dec 06)

Idiopathic Pulmonary Fibrosis (Mild/Moderate):Treatment

1999 yr →

Ongoing MulticenterTrials in IPF(2007--)

Phase III ●Pirfenidone ●Bosentan (BUILD III) ●Others (?)

Phase I ●Antibody against TGF●Others (?)

The Future of Therapy for Lung Fibrosis: Next Steps

Phase II ● Imitanib●Zilueton ●Others(?)

Multicenter Clinical trials in IPF : (Aug 2007-- )Ongoing, just started and/or to begin

Phase III ● Pirfenidone (CAPACITY;PIPF-004 and-006)● (Bosentan (BUILD III) ● Prednisone-NAC-AZA(PANTHER,NIH)● Others (?)

Phase I ● Antibody against TGF● Others (?)

The Future of Therapy for Lung Fibrosis: Next Steps

Phase II ● Imitanib

● Zilueton(?)● Phosphodiesterase inhibitor(STEP-IPF,NIH) ● Others(?)

Percieved* time line of concurrent/new IPF multicenter clinical studies: yr 2007----

2007 2008 2009 20112010 2012

BUILD III

CAPACITY :PIPF 004

OTHERS ------ ? ----------------------??

CAPACITY :PIPF 006

NIH PANTHER (anticipated to begin 8/07-- )

(pred-Aza-NAC)

NIH STEP-IPF (anticipated to begin 6-7/07-- )

IPF TreatmentIn pursuit of evidence based decisions*

●Many ongoing or planned phase I, II, and III trials now underway may need to amend/modify protocols based on the significance of the results of phase III trials that will become available during the initial or mid stages of ongoing studies.

*Raghu G. Eur Respir J. 2006;28:463-465.

Idiopathic Pulmonary Fibrosis (IPF): TreatmentChallenges for New, multicenter, clinical trials: Yr 1999

Theoretic goals and realities (Yr 1999Theoretic goals and realities (Yr 1999))

Years

Specific new Rx

Functional impairment

Survival

• rate of progressionrate of progression• Improved functionImproved function• Better quality of lifeBetter quality of life• Prolong survivalProlong survival

Current Standard of Care?

●Prednisone + azathioprine has evolved as apparent “standard of care,” supplemented by other currently available prescription and over-the-counter medicines

●Subjective perceptions of patients and physicians based on signals from trials drive decisions, rather than grade A clinical trial evidence


●Current standard of care: longstanding variability“Conventional” approaches

●Treatment deferred to worsening stages– Lone corticosteroids followed by adjunct

immunosuppression●“New guidelines” (Joint ATS/ERS Statement yr 2000)

– Prednisone plus azathioprine●Not based on scientific evidence

Idiopathic Pulmonary Fibrosis (Mild/Moderate)

Treatment

Standard of Care: Call to Action

●Clinical investigators must clarify current standard of care by providing new evidence

●Current chaotic and poor standard of care must be replaced

●Well-designed clinical trials will separate myth from facts and provide solid evidence to inform clinical decisions


● clarify current standard of care

● improve standard of care

●Placebo control protocols for different stages of disease status(mild-moderate disease when diagnosed ; advanced stages)

●Revise existing international consensus statement for management of IPF

●Based on scientific evidence

Idiopathic Pulmonary Fibrosis Treatment : Immediate needs(absolute)

What Can We Do Now for Our Patients With IPF ?* - an evidence based approach

● No further harm/minimize iatrogenic problems● Interpret new data based on small nos. of patients with caution● Encourage patients to enroll in well-designed clinical trials● For those unwilling, unable, or ineligible to participate in trials,

provide option for conservative follow-up with “no specific medication” other than oxygen supplementation

● Provide the best supportive care possible based on clinical and physiological needs

● Monitor clinical course regularly; undertake appropriate diagnostic and therapeutic intervention for complications

● Consider lung transplantation in a timely manner for eligible patients

*Raghu G. Eur Respir J. 2006;28:463-465.

●Maximally suppress disease progression●Avoid potential complications●Identify deterioration●Lung transplantation in selected patients●Clinical trials

Idiopathic Pulmonary Fibrosis Therapy

Current Goals

Idiopathic Pulmonary Fibrosis: Treatment

●Very advanced endstages– Unable to walk a few steps because of

profound dyspnea and O2 desaturation despite supplemental oxygen use

– Unable to perform PFTs (hold breath for DLco)

●Palliative, comfort measures

Idiopathic Pulmonary fibrosis Treatment options*

● No specific treatment other than supportive care

● Upfront Clinical trials

● Clinical trials at deterioration

● Lung transplantation at the earliest decline

● Prompt diagnostic and treatment interventions for complications

● Preventive measures : avoid exposures to fibrogenic factors (environmental, antireflux)

● Prednisone plus azathioprine plus NAC? * personal approach

Idiopathic Pulmonary FibrosisTreatment: Suggested Approach*

IPF - Established Dx (Clinical, UIP)

? Ongoing clinical trials for initial Rx

Discuss prognosis, treatment options (introduce lung Tx)Baseline PFTs , HRCT, CBC, Chemistry, ABG, O2 sat walking,(echocardiogram?)

Yes No

Encourage patientsto participate

Oral Prednisone + azathioprine (2-3 mg/kg/d, not > 200 mg/day)40 mg/day x 15 d

20 mg/day x 3 mo

* Personal

(+/-NAC 600 mg tid)

Oral prednisone + azathioprine (+/-NAC)

3 month, 6 month f/u visits with PFTs, O2 sat during walk

6 months assess for:

Worse Stable Improve

Continue Rx

Blood test 15 d x 2, monthly x 3

Decrease prednisone 10-20 mg/d

* Personal


Worse (3-6 months after initial Rx)

LungTx

* Personal

? Superimposed problems Secondary to IPF

Appropriate Dx/Rx Discuss options

Clinicaltrials

Rx based onanecdotal experience

and/or new data

• Follow-up 3 monthly with FVC, DLCO, SpO2 during walk, blood tests• 6-12 month PFTs:

•Improvement in FVC, DLCO, (predicts survival)•Deterioration (dismal prognosis, comfort care)•Stable

• 12 month echocardiogram• HRCT/CT 12 months, yearly (earlier if new, superimposed nodule/mass)

Monitoring


Ganesh Raghu, MD, FCCP, FACP

Documents

Transcript of Ganesh Raghu, MD, FCCP, FACP