20/03/15 1 Keuhkonsiirto PAH ja sidekudossairauspotilailla

20/03/15 Sidonnaisuuteni kaupalliseen
yritykseen (ky) viimeisten 2 v aikana
Keuhkonsiirto PAH ja
sidekudossairauspotilailla
Maija Halme
HYKS / Keuhkosairauksien klinikka
20.3.2015 SKLY / Kuopio
ISHLT: A consensus document for the
selection of lung transplant candidates:
2014 update
Absolute contraindications
•  recent history of malignancy
•  untreatable significant dysfunction of another major organ (e.g heart,
liver, kidney or brain) unless combined organ tx can be performed
•  uncorrected atherosclerotic disease with suspected or confirmed
end–organ ischemia or dysfunction and / or coronary artery disease
not amenable to revascularization
•  acute medical instability, including, but not limited to, acute sepsis,
myocardial infarction, and liver failure
•  uncorrectable bleeding diathesis
•  chronic infection with highly virulent and / or resistant microbes that
are poorly controlled pre-tx
•  evidence of active M. tuberculosis infection
ISHLT: A consensus document for the
selection of lung transplant candidates:
2014 update
Sidonnaisuuden laatu
Ky 1
Ky 2
Saanut ky:lta apurahan
-
-
Omistan ky:n osakkeita
-
-
Saanut ky:lta palkkaa/palkkion
-
-
Suunnitellut koulutustilaisuuden ja saanut
ky:lta palkkion
Bayer, BI, GSK,
Intermune, MSD
Osallistunut kongressiin ky:n osittain tai
kokonaan maksamana
Bayer, GSK,
NordicInfu Care,
Olympus, Pfizer,
Takeda
Osallistunut ky:n hallintoelinten toimintaan
-
-
Olen työsuhteessa ky:een
-
-
Vastaanottanut muuta tukea ky:lta
-
-
ISHLT: A consensus document for the
selection of lung transplant candidates:
2014 update
Absolute contraindications, cont.
•  significant chest wall or spinal deformity expected to cause severe
restriction after tx
•  class II or III obesity (BMI > 35.0 kg/m2)
•  current non-adherence or a history of repeated or prolonged
episodes of non-adherence to medical therapy
•  psychiatric or psychologic conditions associated with inability to
cooperate
•  absence of an adequate or reliable social support system
•  severily limited functional status with poor rehabilitation potential
•  substance abuse or dependance (e.g alcohol, tobacco, marijuana,
or other illicit substances)
ISHLT: A consensus document for the
selection of lung transplant candidates:
2014 update
Relative contraindications
Relative contraindications, cont.
•  age > 65 years in association with low physiologic reserve and or
other relative contraindications
•  class I obesity (BMI 30.0-34.9 kg/m2), particularly truncal obesity
•  progressive or severe malnutrition
•  severe, symptomatic osteoporosis
•  extensive prior chest surgery with lung resection
•  mechanical ventilation and / or extracorporeal life support
•  colonization or infection with highly resistant or virulent bacteria,
fungi, and certain strains of mycobacteria
•  lung tx in candidates with hepatitis B or C should be performed in
centers with experienced hepatology units
•  lung tx in HIV-positive candidates (controlled disease with
undetectable HIV-RNA, and compliant on combined anti-retroviral
therapy) should be performed in centers with expertise
•  patients infected with Burkholderia cenocepacia / gladioli and multidrug resistant M abscessus should be evaluated by centers with
significant experience
•  atherosclerotic disease burden sufficient to put the candidate at risk
for end-organ disease after lung tx
•  diabetes, systemic hypertension, epilepsy, central venous
obstruction, peptic ulcer disease, gastroesophageal reflux should be
optimally treated before tx
1 20/03/15 ISHLT: A consensus document for the
selection of lung transplant candidates:
2014 update
ISHLT: A consensus document for the
selection of lung transplant candidates:
2014 update
Pulmonary vascular disease:
Timing of transplant listing
Pulmonary vascular disease:
Timing of referral
•  NYHA functional class III or IV symptoms during escalating therapy
•  rapidly progressive disease (assuming weight and rehabilitation
concerns not present)
•  use of parenteral targeted PAH therapy regardless of symptoms or
NYHA functional class
•  known or suspected pulmonary veno-occlusive disease (PVOD) or
pulmonary capillary hemangiomatosis
•  NYHA functional class III or IV despite a trial of at least 3 months of
combination therapy including prostanoids
•  cardiac index of < 2 l/min/m2
•  mean right atrial pressure of > 15 mmHg
•  6-minute walk test of < 350 m
•  development of significant hemoptysis, pericardial effusion, or signs
of progressive right heart failure (renal insufficiency, increasing
bilirubin, BNP, or recurrent ascites)
ISHLT: A consensus document for the
selection of lung transplant candidates:
2014 update
ISHLT: A consensus document for the
selection of lung transplant candidates:
2014 update
Interstitial lung disease:
Timing of referral
Interstitial lung disease :
Timing of transplant listing
•  histopathologic or radiographic evidence of UIP or fibrosing NSIP,
regardless of lung function
•  abnormal lung function: FVC < 80% predicted or diffusion capacity
(DLCO) < 40 % predicted
•  any dyspnea or functional limitation attributable to lung disease
•  any oxygen requirement, even if only during exertion
•  for inflammatory interstitial lung disease (ILD), failure to improve
dyspnea, oxygen requirement, and / or lung function after a clinically
indicated trial of medical therapy
•  decline in FVC > 10% during 6 months of follow-up
•  decline in DLCO > 15% during 6 months of follow-up
•  desaturation to < 88% or distance < 250 m on 6MWT or > 50 m
decline in 6MWT over 6-month period
•  PH on right heart catheterization or 2-dimensional echocardiography
•  hospitalization because of respiratory decline, pneumothorax, or
acute exacerbation
Does the presence of CTD modify survival in
patients with pulmonary fibrosis?
Interstitial lung disease:
special considerations
324 cases of CTD-ILD and 2209 cases of IPF (follow-up 2.3 y)
ILD severe enough to warrant consideration to lung tx may
be associated with collagen vascular diseases such as
scleroderma and rheumatoid arthritis.
Data regarding specific predictors of prognosis in this setting
is limited.
If the lung disease has not responded to appropriate
treatment and there are no extrapulmonary contraindications
to tx, it is reasonable to use similar guidelines to those
proposed for idiopathic ILD.
ISHLT 2015
RA (65%)
SSc (14%)
misc. (19%)
median surv.
6.6 y
8.8 y
5.6 y
IPF
3.1 y
Navaratham V et al
Resp Med 2011
2 20/03/15 Survival and quality of life in rheumatoid arthritis–
associated interstitial lung disease after lung
transplantation
NON-IPF ILD and lung tx
Patients with non-IPF ILD (including sarcoidosis and scleroderma)
should be evaluated for lung tx if disease progression occurs in the
context of advanced patients with FVCs less than 50% or those with
hypoxemia (pO2 < 55 mmHg) at rest and/or ”out of proportion”
pulmonary hypertension (mPAP > 35 mmHg or mPAP > 25 mmHg + CI
< 2.0 l/min/m2)
Gottlieb J
ERS Monograph 2011 pp 332-340
In scleroderma, significant extrapulmonary disease (especially kidney
and esophageal) should also be excluded
Gottlies J
Curr Opin Pulm Med 2014; 20: 457-462
Figure 1 Kaplan – Meier survival curves
1 year after lung transplantation.
RA-ILD, rheumatoid arthritis –
associated interstitial lung disease; SScILD, scleroderma-associated interstitial
lung disease;
IPF, idiopathic pulmonary fibrosis.
”In RA-ILD patients, lung tx appears to
result in a significant improvement in QoL
with regard to respiratory symptoms”
(SF-36, SGRQ)
n=10
n= 17
n= 53
Yazdani A et al:
The Journal of Heart and Lung Transplantation, Volume 33, Issue 5, 2014, 514 - 520
Indications for lung and heart-lung transplantations in Finland
Adult Lung Transplants
Major Indications by Year (Number)
2014
JHLT. 2014 Oct; 33(10): 1009-1024
For some retransplants, diagnosis other than
retransplant was reported, so the total number of
retransplants may be greater.
Indication
SL
DL
HL
Total
Fibrosis
11
72 (+5)
1
84 (+5)
Emphysema (α1AT)
4 (+2)
32
0
36 (+2)
COPD
3
27
2
32
CHD
1
1
19
21
PAH
2
8 (+1)
9
19 (+1)
CTEPH
3
1
3
7
Cystic fibrosis
0
13 (+1) +1 lobar
0
14 (+1)
Bronchiectasis
0
4
0
4
LAM
0
6
0
6
Cardiomyopathy
0
0
4
4
PVOD
0
4 (+3)
0
4 (+3)
ARDS / DAD
0
5 (+1) +1 lobar
0
6 (+1)
Occupational
0
2
0
2
Bronchiolitis (obstr./constr.)
0
2 + 1 lobar
0
3
24 (+2)
177 (+11) +3 lobar 38
242 (+13)
31.12.2014
Indications for lung and heart-lung transplantations in Finland
Indication
SL
DL
HL
Total
Fibrosis
11
72 (+5)
1
84 (+5)
Emphysema (α1AT)
4 (+2)
32
0
36 (+2)
COPD
3
27
2
32
CHD
1
1
19
21
PAH
2
8 (+1)
9
19 (+1)
CTEPH
3
1
3
7
Cystic fibrosis
0
13 (+1) +1 lobar
0
14 (+1)
Bronchiectasis
0
4
0
4
LAM
0
6
0
6
Cardiomyopathy
0
0
4
4
PVOD
0
4 (+3)
0
4 (+3)
0
5 (+1) +1 lobar
0
6 (+1)
Occupational
0
2
0
2
Bronchiolitis (obstr./constr.)
0
2 + 1 lobar
0
3
24 (+2)
177 (+11) +3 lobar 38
30
lobar
25
3
HL
38
15
DL
188
10
SL
26
20
5
0
14
2013
2012
2011
2010
2009
2008
2007
2006
2005
2004
2003
2002
2001
2000
2099
1998
1997
1996
1995
1994
1993
1992
1991
1990
1989
1988
19
ARDS / DAD
Lung and heart-lung transplantations in
Finland 1988 – 2014 (n = 255)
year
242 (+13)
31.12.2014
3 20/03/15 IPF (73) ja sidekudossairauteen liittyvä ILD (11)
keuhkon- ja sydänkeuhkosiirtojen indikaationa
Suomessa
30
25
ILD:
polymyosiitti (1)
nivelreuma (2)
MCTD (2)
skleroderma (2)
SLE (4)
20
15
10
5
0
14
2013
2012
2011
2010
2009
2008
2007
2006
2005
2004
2003
2002
2001
2000
2099
1998
1997
1996
1995
1994
1993
1992
1991
1990
1989
1988
19
Nathan S Chest 2015
PAH & survival
Pulmonaaliarteriahypertension
( = PAH) yleisimmät etiologiat
•  Idiopaattinen PAH (IPAH) 39-61%
•  Sidekudossairauksiin liittyvä PAH 11-28%
•  Synnynnäiseen sydänvikaan liittyvä PAH 10-20%
•  Portopulmonaalinen PAH 5-10%
Hoeper & Gibbs 2014
Pulmonary hypertension and transplantation
ESC/ERJ guidelines 2009
The worst prognosis is seen in patients
with PVOD and pulmonary capillary
haemangiomatosis (PCH)
because of the lack of effective medical
treatments.
Those patients should be listed for
transplantation at diagnosis.
McLaughlin et al 2006
Factors associated with increased mortality
(US Registry to EValuate EArly and Longterm PAH disease management, REVEAL)
• 
• 
• 
• 
• 
functional class NYHA IV
male gender with age > 60 years
increased PVR
PAH associated with portal hypertension
family history of PAH
4 20/03/15 Additional factors associated with increased
mortality (REVEAL)
•  functional class NYHA III
•  increased mean right atrial pressure
•  decreased resting systolic blood pressure or an elevated
heart rate
•  decreased 6MWT
•  increased BNP
•  PAH associated with connective tissue disease (CTD)
•  renal insufficiency
•  presence of pericardial effusion
•  decreased DLCO
Matala diffuusiokapasiteetti
PAH-potilaalla
Muista!
•  veno-oklusiivinen tauti (PVOD)
•  emfyseeman ja keuhkofibroosin kombinaatio
•  systeemiseen skleroosiin liittyvä PAH
Huonompi prognoosi kuin IPAH-potilailla
Diffuusiokapasiteetti
•  PAH potilailla alentunut
•  sidekudostautia sairastavilla PAH-potilailla
matalampi kuin esim. synnynnäiseen
sydänvikaan liittyvässä PAH:ssa
•  matala DLCO
–  itsenäinen riskitekijä
mortaliteettiriskianalyyseissä
A subgroup of patients presenting with a DLCO
arbitrarily defined as < 45% predicted who have
significantly poorer survival compared with patients
with DLCO > 45% predicted
•  older than general PAH population
•  more likely to have history of smoking
•  significantly higher mortality
features just linked to age or different type of
pulmonary vasculopathy?
Trip P et al ERJ 2013
Updated Treatment
Algorithm of
Pulmonary Arterial
Hypertension
HYKS: spesifistä lääkehoitoa
saavat potilaat (2000 - )
100%
APAH
90%
IPAH
80%
CTEPH
n = 25 (11)
n = 24 (12)
n = 23 (9)
70%
60%
50%
40%
30%
20%
10%
0%
0
Galiè N et al
JACC 2013
1
68%
2
3
48%
4
5
34%
6
NIH
(Alonzo 1991)
5 20/03/15 PAH ja keuhkonsiirto
•  Leikkaustyyppi
–  sydänkeuhkosiirto (HL): nykyään vain tietyt synnynnäistä
sydänvikaa sairastavat potilaat
–  yhden keuhkon siirto (SL)
–  kahden keuhkon siirto (DL)
•  yleisin leikkaustyyppi nykyään
•  vähemmän välittömän postop.vaiheen riskitilanteita SL
verrattuna
•  parhaimmat pitkäaikaistulokset
Galie N et al
JACC 2013
•  Suurentunut riski kuolla leikkausjonossa (vrt LAS) →”siltana”
keuhkonsiirtoon tarvittaessa
–  ECMO tai eteisseptostomia
Indications for lung and heart-lung transplantations in Finland
PAH ja keuhkonsiirto, tulokset
•  hemodynamiikka / sydämen oikean puolen
dysfunktio korjautuu nopeasti leikkauksen
jälkeen
•  käytössä ollut spesifinen vasodilatoiva
hoito pystytään yleensä lopettamaan
leikkauksen yhteydessä
•  riski suurentunut primaarille graftin
dysfunktiolle ja (BOS:lle)
Indication
SL
DL
HL
Total
Fibrosis
11
72 (+5)
1
84 (+5)
Emphysema (α1AT)
4 (+2)
32
0
36 (+2)
COPD
3
27
2
32
CHD
1
1
19
21
PAH
2
8 (+1)
9
19 (+1)
CTEPH
3
1
3
7
Cystic fibrosis
0
13 (+1) +1 lobar
0
14 (+1)
Bronchiectasis
0
4
0
4
LAM
0
6
0
6
Cardiomyopathy
0
0
4
4
PVOD
0
4 (+3)
0
4 (+3)
ARDS / DAD
0
5 (+1) +1 lobar
0
6 (+1)
Occupational
0
2
0
2
Bronchiolitis (obstr./constr.)
0
2 + 1 lobar
0
3
24 (+2)
177 (+11) +3 lobar 38
242 (+13)
31.12.2014
IPAH, PVOD ja CTEPH keuhkon- ja
sydänkeuhkosiirtojen indikaationa Suomessa
www.ISHLT.org/ registries
30
25
”In 1991 11.8% of all lung transplants were
for idiopathic PAH
vs only 2.7% in 2011”
20
15
10
5
0
14
2013
2012
2011
2010
2009
2008
2007
2006
2005
2004
2003
2002
2001
2000
2099
1998
1997
1996
1995
1994
1993
1992
1991
1990
1989
1988
19
iloprosti inh.
sildenafiili
bosentaani
treprostiniili
ambrisentaani
riosikvaatti
masitentaani
6 20/03/15 Adult Lung Transplants
DL Gra' survival by diagnosis Kaplan-Meier Survival by Diagnosis
(Transplants: January 1990 – June 2012)
100% 90% 80% 70% 60% 50% IPF (n=76) 40% A1A (n=30) 30% COPD (n=26) 20% PAH (n=8) 10% CF (n=14) All pair-wise comparisons with CF
were significant at p < 0.0001
Alpha-1 vs. COPD: p < 0.0001
Alpha-1 vs. IPF: p < 0.0001
COPD vs. IPF: p < 0.001
IPF vs. IPAH: p = 0.0362
0% 0 2 4 6 8 10 Years 2014
JHLT. 2014 Oct; 33(10): 1009-1024
Systeemisessä skleroosissa
United Network for Organ
Sharing Registry (UNOS)
•  of the 20 135 patients transplanted between
1987 and 2011, 142 had the diagnosis of
scleroderma
•  PAH:n prevalenssi 5-10%
•  ILD:n prevalenssi ~ 40%
•  the outcome of patients with scleroderma
were similar to that of other patients
Launay D et al 2014
DePasquale E et al
JHLT 2014
Proposed systemic sclerosis contraindications
Proposed systemic sclerosis contraindications
Working group on heart/lung tx in systemic sclerosis
of the French network on PH
Working group on heart/lung tx in systemic sclerosis
of the French network on PH
•  Uncontrolled active inflammatory myopathy; progressive myopathy;
myopathy with diaphragm involvement
•  Digital ulcers:
–  > 1 severe episode / year despite optimal treatment
–  active digital ulcer: temporary contraindication
•  Gastrointestinal:
–  oesophageal stricture
–  active and severe upper gastrointestinal ulcerations despite optimal treatment,
including proton pump inhibitors and prokinetics
–  high grade dysplasia in a Barett´s esophagus
–  gastroparesis [abnormal gastric emptying (< 25% clearance at 90 min postingestion)] despite medical treatment
–  chronic gastrointestinal bleeding with or without anaemia
–  symptomatic involvement of the small intestine, such as malabsorption and
pseudo-obstruction
–  colorectal involvement with pseudo-obstruction, and/or diverticulitis
and/
Launay D et al
or perforation
Presse Med 2014
•  Heart:
–  conduction abnormalities and/or rhythm disturbances (symptomatic
bradycardia, ventricular and atrial tachycardia): these must be
managed prior to lung tx (implantation of a pacemaker, where
appropriate) but are not a contraindication if heart tx is considered
•  Kidney
–  renal function should have been stable for 3 months except in the
case of acute functional renal failure related to right ventricle
dysfunction
–  interval < 3 years between systemic sclerosis renal crisis and heart /
lung tx
–  increased risk of scleroderma renal crisis
a. diffuse systemic sclerosis evolving for less than 3 years since the first
non-Raynaud sign / symptom
b. rapidly progressive and severe cutaneous involvement: progression of
the cutaneous involvement characterised by an increase of more than
25% in Rodnan score within 6 to 12 months
Launay D et al
c. corticosteroids > 15 mg prednisone (or equivalent) /day
Presse Med 2014
7 20/03/15 J Heart Lung Transplant
2015; 34: 1-15
8