Timely Topics in I have nothing to disclose! Pulmonary Medicine - - PDF document

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Timely Topics in Pulmonary Medicine

Lorriana Leard, MD

Associate Professor of Clinical Medicine Chief of Clinical Operations UCSF Pulmonary, Critical Care, Allergy & Sleep Medicine Lorriana.Leard@ucsf.edu

Disclosures

I have nothing to disclose!

Overview

Ø Cases with new management strategies that

you might face in practice….or just want to know about….

Case of Shortness of Breath

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Case of Shortness of Breath

57 year old man presents with mild dyspnea on exertion x 2 month, no cough

Ø PMH: GERD Ø Meds: Omeprazole 40mg daily Ø SH: lifetime non-smoker, pharmacist Ø FH: no family history of lung disease

Case of Shortness of Breath

PE: 114/73 HR 70 RR 16 O2 Sat 96% RA (93% walking) Inspiratory crackles at both bases Normal cardiac exam, no JVD, no edema No clubbing, joint deformities, rashes

Case of Shortness of Breath What is next best step in management?

A.

Lasix

B.

Levofloxacin

C.

PPD

D.

HRCT scan

E.

Echocardiogram

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CXR is Not Useful for Differentiating ILD’s

HP CTD- ILD IPF NSIP

Case of Shortness of Breath

FVC 5.10 (83%) FEV1 4.42 (90%) FEV1 / FVC 0.87 TLC 7.40 (88%) DLCO 23.41 (57%)

HRCT Scan

Ø ILD protocol ◆ Inspiratory plus expiratory images ◆ Prone as well as supine

Specific HRCT Findings

Ø Honeycombing Ø Reticulation Ø Ground Glass Opacities Ø Traction Bronchiectasis Ø Air trapping Ø Nodules Ø Emphysema

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HRCTs are essential in ILD

• Pattern of abnormality on HRCT scan may

suggest a specific ILD

• HRCT findings guide subsequent diagnostic

tests

• HRCT findings may be sufficient for diagnosis

Case of Shortness of Breath Case of Shortness of Breath Case of Shortness of Breath

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Case of Shortness of Breath Case of Shortness of Breath Case of Shortness of Breath What is the best thing to tell a patient at this point?

A.

Prednisone at 1 mg/kg should be started to try to reverse this disease.

B.

There is no available treatment. Most patients live 3-5 years from time of diagnosis.

C.

You should be seen by a specialist and your case discussed with a multidisciplinary team before any treatment is started.

D.

You should have a lung biopsy to establish the diagnosis.

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Multidisciplinary Approach to Diagnosis

1 2 3 4 5 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Step Assessment Method Information Provided 1 Individual HRCT 2 Individual HRCT, clinical data 3 Discussion (clinician & radiologist) HRCT, clinical data 4 Individual (clinician, radiologist & pathologist) HRCT, clinical data, SLB 5 Discussion HRCT, clinical data, SLB

Modified from: Flaherty KR, et al. AJRCCM. 2004;170:904 -9 10.

ILD Classification

Pulmonary Fibrosis

Exposure-related:

• Occupational
• Environmental
• Avocational
• Medication

Idiopathic interstitial pneumonia (IIP) Connective tissue disease:

• Scleroderma
• Rheum arthritis
• Sjogrens
• MCTD
• Dermatomyositis

Other:

• Sarcoidosis
• Vasculitis/Diffuse alveolar

hemorrhage

• Langherhans cell

histiocytosis

• Lymphagioleiomyomatosis
• Pulmonary alveolar

proteinosis

• Eosinophilic pneumonias
• Neurofibromatosis

Idiopathic pulmonary fibrosis (IPF) Desquamative interstitial pneumonia (DIP) Acute interstitial pneumonia (AIP) Nonspecific interstitial pneumonia (NSIP) Respiratory bronchiolitis interstitial lung dis. (RBILD) Cryptogenic organizing pneumonia (COP) Lymphocytic interstitial pneumonia (LIP)

Don’t stop with a diagnosis of “Pulmonary Fibrosis”

ØReasons for a specific diagnosis: ◆ Many forms are treatable ◆ Treatment depends on the diagnosis ◆ Prognosis varies ◆ Eligibility for clinical trials

Differentiating Diseases Predicts Prognosis

Bjoraker et al, AJRCCM ‘98

1950-90’s: Lumpers 2000: Splitters

DIP /IPF

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Case of Shortness of Breath Idiopathic Pulmonary Fibrosis

Ø Average survival from

diagnosis: 2.5-3 years

Ø Afflicts men more than

women

Ø No apparent race or

ethnic predilection

Ø Path: UIP pattern Ø HRCT: subpleural, basila

r predominant reticulation, honeycombing, and traction bronchiectasis

What do you recommend?

A.

Prednisone, Azathioprine and N- Acetylcysteine (NAC)

B.

Nintenadib

C.

Pirfenidone

D.

Palliative care consultation as there is no treatment for this disease

E.

B or C

Systematic Review / Meta-Analysis

Canestaro WJ, et. al. CHEST 2016; 149(3):756-766

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Systematic Review / Meta- Analysis Conclusions

Ø Pirfenidone and Nintedanib ◆ are first treatments shown to slow rate of

disease progression (FVC decline)

◆ Long term mortality impact not clear

ASCEND

King et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary

• fibrosis. NEJM 2014;370:2083

ASCEND

Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis

◆ Performed in response to an FDA request for

an additional trial to support approval

◆ Designed to enrich subjects for disease

progression (as measured by change in FVC)

• King. NEJM 2014;370:2083

ASCEND: Study design

Ø Enrolled 555 highly-selected patients with IPF Ø Randomized to pirfenidone or placebo x 52 wks IPF

n = 555

Pirfenidone

n = 278

Placebo

n = 277

52 wks 1°: FVC 2°: 6MWT distance; PFS; dyspnea; death

• King. NEJM 2014;370:2083

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ASCEND: Subjects

Baseline Pirfenidone (n=278) Placebo (n=277) Age, years 68 68 Male sex 80% 77% FVC 68% 69% DLCO 44% 44% 6MWT distance 415 421 Dyspnea (UCSD) 34 37 Definite UIP HRCT 96% 95%

• King. NEJM 2014;370:2083

ASCEND: 1° Endpoint

• King. NEJM 2014;370:2083

Relative difference = 45% P value < 0.001

INPULSIS

Richeldi et al. Efficacy and safety of nintedanib in idiopathic pulmonary

• fibrosis. NEJM 2014;370:2071

INPULSIS: Study design

Ø Enrolled 1066 patients with IPF/likely IPF Ø Randomized (3:2) to nintedanib/placebo for

52 wks

IPF

n = 1066

nintedanib

n = 638

Placebo

n = 423

52 wks 1°: FVC 2°: acute exacerbation; QOL; death

Richeldi NEJM 2014;370:2071

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INPULSIS: Subjects

Baseline INPULSIS 1 INPULSIS II

Nintedanib Placebo Nintedani b Placebo

Age, years 67 67 66 67 Male sex 81% 80% 78% 78% FVC 80% 81% 80% 82% DLCO 48% 48% 47% 46% Oxygen sat 96% 96% 96% 96% SGRQ score 40 40 40 39

Richeldi NEJM 2014;370:2071

INPULSIS: 1° Endpoint

Mean difference 109.9 (71.3, 148.6) P value < 0.001

Richeldi NEJM 2014;370:2071

ILD Summary

Ø Don’t stop at “pulmonary fibrosis” Ø History is essential Ø HRCT scans are a key diagnostic tool Ø The diagnosis of ILD should be made using a

multidisciplinary approach

Ø Treatment depends on the specific type of ILD ◆ there are now 2 treatments available for IPF

But what about when the disease still does progress..

Ø And now a word about Lung Transplant…

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Lung Transplant for IPF

§ Should be

considered in all patients < 70 years

§ 50-60% 5 year

survival after transplant

Bjoraker et al, AJRCCM ‘98, Neurohr et al, Transplant International, ‘10

Lung Transplant

Ø ECLS / ECMO supports patients

to LT

Ø Ex vivo perfusion systems

support donor lungs to LT

Case of Recurrent Pneumonia

Case of Recurrent Pneumonia

Ø 31 year old man originally from Mexico

prevents for evaluation.

◆ history of recurrent pneumonias from a young

age.

◆ hospitalized 4 times in the past 3 years Ø His chief complaint is dyspnea and cough

productive of brown mucous, and chest pain. He can walk about 3 blocks. He's limited by dyspnea, fatigue and palpations.

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Case of Recurrent Pneumonia

Ø VS: BP 129/79 HR 90 T 36.7°C RR 20

SpO2 97% BMI 18.6 kg/m2

Ø Chronically ill appearing, cachectic, and frail Ø No sinus tenderness, No LAD Ø RRR, S1 and S2 present Ø Lungs with rhonchi bilaterally, prolonged

expiratory phase, reduced air movement

Ø Digital clubbing

CXR

Spirometry

11/19/14 BMI 18.6 FVC 1.69 (36%) FEV1 0.98 (25%) FEV1/FVC 57.76 Sputum:

• AFB Culture negative x 3

What is next best step to establish the diagnosis?

A.

Sweat Chloride Test

B.

CF PCR for common mutations

C.

A1AT genotype

D.

Bronchoscopy

E.

Echocardiogram

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Case Diagnostic testing

Ø Sweat Chloride = 79 [Normal <40 mmol/L] Ø CF PCR for common mutations ◆ Heterozygous for the delF508 mutation Ø CFTR Full Gene Sequence Analysis ◆ One copy F508del ◆ One copy G551S

Mortality Rates in Hispanic and Non-Hispanic CF Patients

Buu et. al. CHEST 2016; 149(2):380-389

He is wondering if there is any CFTR specific therapy. What do you tell him?

A.

Ivacaftor is likely to improve lung function and quality of life.

B.

No genotype specific therapy is available

• utside of a clinical trial.

C.

Sorry, nothing is available. Gene therapy has not panned out as we had hoped.

Modulation of CFTR defects

Pittman J et. al. CHEST 2015; 148 ( 2 ): 533 - 542

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Ivacaftor

Ø Multicenter Double-blind RCT Ø Patients with cystic fibrosis and the G551D

mutation on at least one allele

◆ Increase in FEV1 (p < 0.0001) ◆ Decrease in sweat chloride (p < 0.0001) ◆ Decrease in pulmonary exacerbation rate (p =

0.0003)

◆ Increase in CFQ-R score (p < 0.001), ◆ Increase in weight (p < 0.0001) from baseline.

Accurso FJ et al. N Engl J Med 2010;363:1991-2003.

Ivacaftor

Ø Approved in 2012 for use in patients >6 years

with CF who have at least 1 G551D mutation in the CFTR gene

Ø Feb 2014, FDA approved Ivacaftor for 8

mutations

◆ G551D, G178R, S549N, S549R, G551S,

G1244E, S1251N, S1255P and G1349D

Modulation of CFTR defects

Pittman J et. al. CHEST 2015; 148 ( 2 ): 533 - 542

Lumacaftor / Ivacaftor

Ø TRAFFIC and TRANSPORT trials ◆ 2 phase 3, multinational, RCT, ◆ lumacaftor AND ivacaftor were given orally 2x

per day for 24 weeks

✦ Increase in FEV1 ✦ Decrease in pulmonary exacerbation rate ✦ Increase in BMI Wainwright CE et al. N Engl J Med 2015;373:220-231.

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Lumacaftor / Ivacaftor

Wainwright CE et al. N Engl J Med 2015;373:220-231.

Lumacaftor/Ivacaftor

Ø July 2015: FDA approved Lumacaftor /

ivacaftor for CF patients homozygous for F508del

Case Spirometry

11/19/14 2/25/15 6/4/15 7/8/15 BMI 18.6 20.4 20.6 20.6 FVC 1.69 (36%) 2.26 2.66 2.71 (58%) FEV1 0.98 (25%) 1.21 1.39 1.46 (36%) FEV1/FVC 57.76 53.51 52.19 53.85

Ivacaftor

The Future of CF Treatment

Pittman J et. al. CHEST 2015; 148 ( 2 ): 533 - 542

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CF Take Home Points

Ø Sweat Chloride testing for screening Ø If CF Common mutations panel is

inconclusive, consider CFTR Full Gene Sequence Analysis

Ø Small molecules that alter mutant CFTR

function are now available, depending on genotype

Ø New therapies bring the possibility of

prevention of CF lung disease!

Case of the Chronic Cough Case of the Chronic Cough

Ø 68 year old woman c/o cough x 13 years ◆ Coughs 6-7x per day for 15 minutes ◆ Remembers that in 2003 she started coughing

at work --remembers because she tried to refrain from coughing when talking on the phone

◆ Coughs during day / not at night ◆ No post nasal drip ◆ No shortness of breath with sports

COUGH

Ø #1 Reason people see a doctor (10-40% visits) Ø > 30 million visit per year Ø Pub Med search for cough: 43,570 Ø For “Chronic cough”: 3,152 Ø Most frequent complaint of patients seeking

advice from pulmonary physicians

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Cough…

Syncope Urinary Incontinence Rib fractures Gastro esophageal reflux Emesis Incontinence Fatigue Sleep Disturbances

And the Complications!

Problems with Managing Cough

Ø Frustration: ◆ Difficult to identify the etiology ◆ Very little evidence from RCTs ◆ Rarely eliminate the cough Ø Fear: ◆ Of missing more serious disease

Classification of Cough

Acute Subacute Chronic <3 weeks 3-8 Weeks > 8 weeks

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Case of the Chronic Cough

Ø Empiric trials of intranasal steroids /intranasal

atrovent

Ø Evaluation of her vocal cords /sinuses by

• tolaryngology

Ø Allergy testing without a trigger identified Ø PFTs and trials of treatment with various inhalers Ø 24 hour pH: normal Ø Empiric medical treatment for GERD Ø Behavior modifications including elevating the HOB Ø Chest CT scans = Normal Ø Bronchoscopy = no endobronchial lesions noted

? = Further work-up

24 hour pH probe Swallow evaluation Chest CT Bronchoscopy Sputum analysis Echocardiogram GERD Vocal cords / Aspiration Masses / ILD / Emphysema Endobronchial lesions, Infection, Eosinophilia Nocardia, AFB, Fungi Heart disease

What interventions could be recommended to try to manage this Unexplained Chronic Cough?

A.

Azithromycin

B.

Omeprazole

C.

Gabapentin

D.

Morphine

The “Difficult to Treat” Cough

Gibson P , et. al. CHEST 2016; 149(1):27-44

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Lung Cancer Screening

Case of the Smoker

55 y.o. man with 40 pk-yr smoking history and no other PMH, comes to see you because his best friend just died of Lung Cancer. He has no

• symptoms. He asks

Ø What he can do to prevent dying from Lung

Cancer?

Ø What do you recommend?

Photo From: www.ehow.com

Case of the Smoker

What do you recommend?

• A. Chest X-ray
• B. Sputum Cytology
• C. Low Dose Chest CT scan
• D. Smoking Cessation
• E. C and D

N Engl J Med. 2011;365:395-409.

53,454 randomized to annual CXR vs. CT scans

National Lung Screening Trial

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National Lung Screening Trial

Ø Age 55 - 74 years Ø History of cigarette smoking > 30 pk yrs Ø If former smokers, quit within 15 years

Exclusions:

Ø Prior diagnosis of lung cancer Ø Chest CT within 18 months Ø Hemoptysis Ø Unexplained weight loss

N Engl J Med. 2011;365:395-409.

Results of NLST

N Engl J Med. 2011;365:395-409.

Ø20% Reduction in Lung Ca mortality Ø6% Reduction in all cause mortality ØARR = 0.46% ØNNS = 217

N Engl J Med. 2011;365:395-409.

Risks of Lung Cancer Screening with LDCT?

Ø False-positive results: benign nodules Ø Futile detection of small aggressive

tumors or indolent disease

Ø Complications from diagnostic work-up Ø Anxiety of test findings Ø Radiation exposure Ø Cost

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Radiation Risk

Background radiation dose 3 mSv/yr Background radiation dose in Denver 5 mSv/yr 25 cross-country airplane flights 1 mSv Standard chest CT 6 mSv Low dose chest CT 1.5 mSv Tc-99m sestamibi 1 day stress/rest 12 mSv

But is it cost effective?

Targeting of low-dose CT screening according to the risk of lung-cancer death, may be more effective.

Kovalchik SA et al. N Engl J Med 2013;369:245-254.

CMS

Ø At-risk patients 55 to 77 years of age Ø CMS covers a distinct visit for formal shared

decision making using dedicated evidence- based decision aids

Ø CMS set specific criteria for radiologists and

imaging centers and required use of a standardized nodule-identification- and- reporting system and data collection

Chin J, et. al. N Engl J Med. 2015;372: 2083-2085.

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Conclusions: Lung Cancer Screening Today

Ø LDCT can detect early stage lung cancers Ø Has high "false positive" rate leading to

additional testing (serial imaging àinvasive procedures)

Ø Decreases lung cancer mortality by 20% and

all cause mortality by 6.7% in 1 large RCT

Ø Counsel patients on risks / benefits Ø Need more widely accepted prediction model

Timely Topics in Pulmonary Medicine

Ø IPF= 2 treatments now available that can slow

progression.

Ø CF = Small molecules can modify CFTR gene

defects, may one day prevent disease

Ø Chronic Cough, Unexplained = consider trial

• f gabapentin

Ø Lung Cancer Screening = should be done

with smoking cessation program, prediction models may soon help guide screening

Thank you!

Ø Questions