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Disclosures Lung transplantation in occupational None and - - PDF document

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2/28/2017 Disclosures Lung transplantation in occupational None and environmental lung diseases Jonathan Singer, MD MS Assistant Professor of Medicine UCSF Lung Transplant Program Division of Pulmonary, Critical Care, Allergy, and Sleep

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Lung transplantation in occupational and environmental lung diseases

Jonathan Singer, MD MS Assistant Professor of Medicine UCSF Lung Transplant Program Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine

Disclosures

  • None

A bit of history

  • 1963: James Hardy performs first LTx
  • Patient: Jail inmate; PMH: lung CA, chronic renal insufficiency
  • Survived 18 days
  • 1963‐83: 40 more attempts at LTx
  • Most survived < 2wks
  • 1983: FDA approves cyclosporin for renal tx
  • Joel Cooper performs LTx on a 58yo w/ Idiopathic Pulmonary

Fibrosis (lower doses of prednisone)

  • Survives 8 years; dies of renal failure

2016

  • JHLT. 2016 Oct; 35(10): 1149-1205
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Survival is improving

2016

  • JHLT. 2016 Oct; 35(10): 1149-1205

Me Median an sur survival (y (years): 1990 990‐1998 998: 4. 4.2; Condit nditiona

  • nal=7.1;

1999 999‐2008 008: 6. 6.1; Condit nditiona

  • nal=8.4;

2009 009‐6/20 2014: 14: NA NA; Condit nditiona

  • nal=NA

Indications for Lung Transplantation

  • Pulmonary Vascular Disease
  • Idiopathic pulmonary

arterial hypertension

  • Pulmonary hypertension

secondary to systemic disease

  • Eisenmenger’s syndrome
  • Suppurative Disease
  • Cystic Fibrosis
  • Bronchiectasis
  • Obstructive Lung Disease
  • CO

COPD

  • Alpha‐1‐antitrypsin deficiency
  • Br

Bron

  • nch

chio iolitis litis obl

  • bliterans

ns

  • Restrictive Lung Disease
  • Idiopathic pulmonary fibrosis
  • Fibrosis secondary to

connective tissue disorders

  • Sarcoidosis
  • Eosinophilic granuloma
  • Lymphangioleiomyomatosis
  • Oc

Occupa upati tion

  • nal di

disea sease

  • Hyp

Hypersensitivit ensitivity pneu pneumonitis itis

Indications by Year

2016

  • JHLT. 2016 Oct; 35(10): 1149-1205

Eligibility Considerations

  • Severe debilitation due to

pulmonary disease

  • Currently on maximal

medical management

  • Limited life expectancy

(<2 years)

  • No concurrent severe

medical issues/systemic disease

  • Strong psychosocial support

and coping skills

  • No current nicotine or

substance abuse

  • Physical rehabilitation

potential

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2/28/2017 3

Listing: The Lung Allocation Score

  • < 5/05: Seniority based
  • Rapidly progressive diseases (IPF, PAH) disadvantaged
  • 5/05: Lung Allocation Score (LAS)
  • Urgency based model using clinical variables
  • Weighted model to predict “transplant benefit”
  • Waitlist urgency: P(death) within 1 year on waitlist
  • Post‐Tx survival: P(survival) in days during 1st post‐tx yr
  • 0 ‐ 100
  • Blood type
  • Size

The “Transplant Window”

TOO EARLY TRANSPLANT WINDOW TOO LATE

TIME

2 YEARS

CLINICAL STATUS

“Too late” is a moving target

Hoopes CW. J Thorac Cardiovasc Surg. 2013

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Transplant type based on underlying disease

  • Single:
  • Pulmonary fibrosis
  • Emphysema
  • Double:
  • Cystic fibrosis
  • Bronchiectasis
  • Pulmonary hypertension
  • Heart‐Lung: CHD with Eisenmenger’s
  • Unique clinical characteristics with pulmonary HTN

Single lung transplantation

  • Initially only offered for ILD and COPD
  • now 50/50 single/double
  • Maximizes donor pool, since one donor may

benefit 2 recipients

  • Technically easier than double lung
  • Contraindicated in CF, and other suppurative

lung disease

  • Use in pulmonary HTN remains controversial

Case 1. Something stinks…

HPI

  • 55 yo woman; symptoms begin in 2011 with dry cough
  • 2012: Progressive SOB with periods of sudden worsening.
  • Diagnosed with pneumonia; multiple rounds of antibiotics

did not help

  • Diagnosed with asthma  oral steroids steroids provided

relief for up to weeks

  • 6/2012 Initiated on oxygen, CT chest showed possible

fibrosis

PMH Meds Asthma Albuterol, singulair SH Works as a floor manager in a local casino; flooding 5 years ago with heavy damage to the carpet which covers concrete floors ROS None PE: 37.5 110/70 70 16 86% RA RRR Dry inspiratory crackles No rashes, joint swelling

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Studies

  • Autoimmune serologies

negative

Spirometry FEV1 1.15 (38%) FVC 1.24 (36%) TLC 2.71 (45%) DLCO 5.6 (24%)

Expiratory

Interstitial Lung Disease

  • “Interstitium” is a potential

space between the epithelial and endothelial basement membrane

  • Interstitial lung disease occurs

when there is inflammation or fibrosis in this space

Interstitial lung disease

ILD of known etiology (HP, drugs, collagen‐vascular) Idiopathic Interstitial Pneumonia (IIP) Granulomatous ILD(Sarcoidosis)

Other

(eosinophilic pneumonia, LM, HX etc.)

Chronic fibrosing Smoking related Acute/subacute IPF NSIP RBILD DIP AIP COP

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Differential Diagnosis

Collagen Vascular Disease/Autoimmune

  • Antisynthetase syndrome (Jo‐1, PL‐7, PL‐12, EJ, OJ,

SRP, Mi‐2, Ku), also MDA‐5

  • Rheumatoid arthritis (higher proportion of UIP)
  • SLE (greater prevalence of ILD than appreciated in

the literature)

  • Systemic sclerosis (diffuse more associated with

ILD; limited more with PAH)

  • Mixed connective tissue disease
  • Sjogren’s
  • Vasculitidies: granulomatous polyangiitis

Idiopathic

  • IPF
  • NSIP
  • COP
  • AIP (Hamman‐Rich Syndrome)
  • RBILD
  • DIP
  • LIP
  • PPFE
  • Unclassifiable

Environmental

  • Hypersensitivity pneumonitis (avian, molds,

isocyonates, other organic dusts)

  • Pneumoconioses (silicosis, asbestosis, berryliosis,

coal miner’s lung disease) Medications

  • TNF‐alpha inhibitors (eternacept, infliximab,

adalimumab)

  • Chemotherapy drugs: bleomycin, busulfan, etc.
  • Amiodarone
  • Methotrexate
  • Sirolimus/everolimus
  • NSAIDS, antibiotics (eosinophilic)

Other

  • Eosinophilic pneumonia: idiopathic, parasitic
  • Sarcoidosis
  • Lymphangioleiomyomatosus (LAM)
  • Pulmonary langerhans cell histiocytosis
  • Lymphangitic carcinomatosis
  • Pulmonary alveolar proteinosis

Return to Case 1. Diagnosis Return to Case 1. Diagnosis Hypersensitivity pneumonitis from workplace mold exposure

Hypersensitivity pneumonitis

  • Allergic reaction to inhaled organic dust, fungus,

molds, or chemicals

  • Many names, depending on exposure
  • Bird fancier’s lung, farmer’s lung, hot tub lung,

Woodman’s disease, etc…

  • Avian antigen most likely to cause fibrosis
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Clinical course

  • Stopped working, started prednisone and cellcept
  • Over 6 months 2LPM  10LPM at rest, 15LPM w/

exertion

  • Listed for transplant 3/12/2013
  • 4/30/13: underwent bilateral lung transplantation
  • n central veno‐arterial ECMO support
  • 22 day recovery period
  • Remains well today with stable allograft function

Transplant for Group D “Restrictive” 2000 ‐2013 N = 8692

Source: UNOS

HP, 147 Scleroderma, 121 Sarcoidosis, 285 Pulmonary Fibrosis‐other, 1090 IPF, 5679 Other, 1370 HP Scleroderma Sarcoidosis Pulmonary Fibrosis‐other IPF Other

Hypersensitivity pneumonitis

  • Likely under recognized

indication

  • National registry: <1%
  • UCSF: 8% (31 of 222)
  • 31 cases of HP
  • 8 (26%) dx made after

transplant

Kern RM. CHEST. 2014

Survival is excellent

Kern RM. CHEST. 2014 Va Variable HR 95% CI CI P Multivariate HP Diagnosis 0.25 0.08‐0.6 0.008 Age 1.03 0.99‐1.08 0.091 Bilateral Tx 0.33 0.17‐0.65 0.001 Male 1.05 0.50‐2.02 0.987 BMI 1.08 1.01‐1.16 0.026 Treated for Rejection 0.73 0.35‐1.52 0.404

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Case 2. Between a rock and a hard place

HPI

  • 44yo male moved to US from Mexico in late 2012.
  • 2013: Spontaneous pneumothorax , hospitalized 19 days, TB excluded
  • 2014: DOE, wheezing  diagnosed with asthma
  • 2014‐15: multiple ER visits for SOB  prednisone bursts and antibiotics
  • Oct 2015: CT chest showed “mild” pleural/paratracheal thickening and

mediastinal adenopathy

  • Bronchoscopy negative for cancer/tuberculosis
  • Jan 2016: second pneumothorax
  • Feb 2016: started on 2LPM of oxygen, stopped working

PMH Meds

  • Asthma

Albuterol, pulmicort, combivent, singulair SH Lives with his wife and 3 children in Fresno, on disability Life long non‐smoker Worked in stone grinding and sculpting work in Mexico (cantera) for 18yrs

  • Inconsistent PPE use
  • Stopped working when he moved to the U.S.

PE: 37.5 105/70 118 36 82% on RA  93% 3LPM Thin Tachycardi, loud P2 Expiratory wheezes and rhonchi upper lung zones > lower + clubbing

Spirometry FEV1 0.71 (19%) FVC 2.47 (53%) FEV1/FVC 0.29 DLCO 11.6 (33%)

Diagnosis: Progressive massive fibrosis from silica inhalation

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2/28/2017 9

Diagnosis: Progressive massive fibrosis from silica inhalation

  • Inhaled crystalline silica
  • Free radical generation
  • Direct toxicity to pneumocytes and alveolar macrophages
  • Inflammation ‐> Fibrosis

Clinical course

  • 9/22/16: seen in UCSF transplant clinic, decompensated right

heart failure, saturating 65% on 5LPM

  • Admit to ICU: initiate dobutamine, diuresis, BiPAP, rapid

completion of transplant workup

  • 10/4/16 Listed for transplant
  • Progressive hypoxia/hypercarbia over next 1 week

(7.33/83/62) ‐> tracheostomy and mechanical ventilation

  • 10/9 Progressive right heart failure, impending death, accept high

risk donor

Clinical course

  • Prepping chest for surgery: tachycardic to 170s with

hypotension

  • crash median sternotomy with cardiac massage and

emergent central VA ECMO.

  • Right ventricle football size and purple
  • 1 hour of manual cardiac massage, repeated

defibrillation

  • Patient expired

Lung transplant for silicosis is rare

  • Before 2011, 4 case reports and 2

case series

  • U.S. national transplant registry for
  • ccupational lung diseases and

silicosis from 2005‐2010

  • 37 cases (0.5% of 8129 transplants)
  • Silicosis: 17
  • Pneumoconioses NOS: 7
  • Coal workers pneumoconiosis: 6
  • Asbestosis: 2
  • Berylliosis: 1
  • Survival equivalent to non‐
  • ccupational lung diseases.
  • ? Non‐silicosis occupational lung

disease

  • Singer. Occ Med (London). 2012
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Outbreaks of silicosis

  • Kramer. CHEST. 2012

Survival in silicosis vs IPF

  • 2006‐ 2013
  • Tx for silicosis vs IPF
  • 17 subjects, up to 80 months of

follow up

  • Rosengarten. Am J Ind Med. 2017

Follow up on outcomes in the U.S.

  • May 2005 – Sept 2013
  • Of 7,273 transplants
  • Silicosis: 24
  • Non‐silicosis: 29
  • Hayes. Lung. 2015

Here we go again

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  • Blackley. MMWR. 2016; Blackley. Am J Ind Med. 2016

What about after lung transplantation? What about after lung transplantation?

  • Risk of infection
  • Impacts return to certain jobs
  • Farming to teaching
  • Impacts avocation
  • Impacts places of residence
  • Can disease recur in the allograft?
  • Air pollution and allograft failure

Case 3. It’s confusing.

  • 26 yo, 18 months post‐transplant for cystic fibrosis
  • Had been doing well. Working part time, enjoyed hiking with friends in

East Bay hills

  • Self‐report of transient R arm paralysis and loss of sensation and aphasia

that resolved T 36.8 BP 142/80 HR 96 RR 16 Sa02 98% RA Gen: Lying in bed, eyes closed Neck: No JVD Cor: Borderline tachy, regular rhythm, no murmurs Pulm: CTAB GI: S/NT/ND +BS Neuro: A&O x4, non‐focal exam

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MRI Brain Brain biopsy performed Diagnosis: Invasive Aspergillosis What about after lung transplantation?

  • Risk of infection
  • Impacts return to certain jobs
  • Farming to teaching
  • Impacts avocation
  • Impacts places of residence
  • Can disease recur in the allograft?
  • Air pollution and allograft failure
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Diseases known to recur

  • Sarcoidosis
  • Lymphangioleiomatosis (LAM)
  • Pulmonary Langerhans cell histiocytosis (PLCH)
  • Ta

Talc gr granulo ulomatos

  • sis

is

  • Diffuse panbronchiolitis
  • Pul

Pulmonary

  • nary alv

alveolar pr proteinosis sis (PAP) P)

  • Desquamative interstitial pneumonitis (DIP)
  • Gi

Gian ant cell cell inte terstitial titial pneumo pneumonia ia (Har (Hard me metal/C l/Cobalt alt lung ung di disease ase)

  • Alpha‐1 antitrypsin deficiency‐related emphysema
  • Bronchoalveolar carcinoma

Recurrence of HP after transplant: 6‐10%

Kern RM. CHEST. 2014

CT: air trapping; bronchoscopy: BAL 24% L, CD4:CD8 0.7, biopsy with subepithelial granuloma CT: air trapping; bronchoscopy: BAL 29%L, CD4:CD8 0.7, biopsies with multiple granulomas

Transbronchial lung biopsy showing granuloma composed of histiocytes, multinucleate giant cells and lymphocytes.

What about after lung transplantation?

  • Risk of infection
  • Impacts return to certain jobs
  • Farming to teaching
  • Impacts avocation
  • Impacts places of residence
  • Can disease recur in the allograft?
  • Air pollution and allograft failure

Chronic rejection is common

2016

  • JHLT. 2016 Oct; 35(10): 1149-1205
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Chronic Lung Allograft Syndrome: Bronchiolitis obliterans

Causes of death by time

2016

  • JHLT. 2016 Oct; 35(10): 1149-1205

Air pollution and CLAD

Belgium: Nawrot. Thorax. 2011 Canada: Bhinder. Am J Transplant. 2014 Europe: Ruttens. ERJ. 2017

MOC Questions

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  • Q1. Of the following, which single test best

distinguishes hypersensitivity pneumonitis from idiopathic pulmonary fibrosis?

  • 1. CT chest with and without expiratory images
  • 2. Positive IgE antibody to suspected antigen
  • 3. CBC with differential
  • 4. Pulmonary function testing with diffusing capacity
  • Q2. How does silica cause pulmonary fibrosis?
  • 1. Inhaled amorphous silica dust triggers an

exuberant allergic reaction, leading to fibrosis

  • 2. Inhaled crystaline silica dust generates an

exuberant allergic reaction, leading to fibrosis

  • 3. Inhaled amorphous silica dust generates free

radicals and inflammation, leading to fibrosis

  • 4. Inhaled crystaline silica dust generates free

radicals and inflammation, leading to fibrosis

  • Q3. Up to what percentage of lung transplants are

performed for occupational and environmentally‐ caused lung diseases?

  • 1. 1%
  • 2. 5%
  • 3. 10%
  • 4. 20%

Thank you.