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Jonathan B. Orens, MD
Associate Professor of Medicine,
Division of Pulmonary and Critical Care Medicine
The Johns Hopkins School of Medicine
Medical Director, Lung Transplantation Program
Johns Hopkins Hospital
Baltimore, Maryland
Transplantation of the lungs became an acceptable therapeutic
option for patients with end-stage lung and pulmonary
vascular disease in 1981, following the first successful
human heartlung transplantation performed for a patient
with primary pulmonary hypertension.1,2
At the time no other efficacious therapy was available
and the transplantation was performed as an experimental
“last ditch” life-saving procedure. Since
then, both single and double lung transplantation has
become part of the routine armamentarium to treat patients
with pulmonary arterial hypertension (PAH) when all other
measures fail. For highly selected patients, lung transplantation
offers the possibility of improved survival and functional
status.1,3-5
However, despite major strides in the field of lung transplantation,
numerous shortcomings are still associated with this procedure,
including lack of available donor lungs, need for lifelong
immunosuppression, acute and chronic allograft rejection,
infection, and extremely high costs of the procedure and
posttransplantation care. Furthermore, since the time
of that first heart-lung transplantation, treatment options
for patients with PAH have changed dramatically. Both
calcium channel blockers and intravenous epoprostenol
have shown proven benefit and in many cases provide adequate
treatment to prevent or prolong the need for transplantation.6-12
Recently agents such as endothelin antagonists and sildenafil
have been added to the medication armamentarium, further
broadening therapeutic options. Indeed, lung transplantation
has moved from a primary treatment for pulmonary hypertension
to a therapy that complements the current medical options
to prolong life and improve quality of life.
Candidate Selection for Transplantation
Appropriate candidates for lung transplantation have end-stage
lung disease without concomitant illness that would adversely
affect their survival following transplantation. In selecting
candidates for this procedure it is important to consider
the severity of the patient’s illness as it relates
to projected survival without transplantation, coexisting
medical problems, and the financial cost of the procedure.
Although assessing projected survival without transplantation
is difficult, it is extremely important with regard to
selecting the appropriate timing for lung transplantation,
since waiting periods for lung transplants now average
1.5 to 2 years. Although there are ongoing efforts to
change the strategy for donor lung allocation, currently
in the United States the priority for obtaining a lung
transplant is based solely on the time accrued on the
waiting list, after matching for ABO blood type and body
size. This is unlike that for other solid organ transplants,
where consideration is given to the severity of the recipient’s
disease. Therefore, in order to select the appropriate
time to list patients for this procedure, one must carefully
consider the candidate’s projected survival against
the waiting period for transplantation.
Table
1 - Indications for Lung Transplantation in Pulmonary
Arterial Hypertension.
New
York Heart Association functional class III or
IV
Mean right atrial pressure =10 mm Hg
Mean pulmonary arterial pressure =50 mm Hg
Cardiac index =2.0 L/min/m2
Failure of medical therapy in the setting of:
WHO class III or IV symptoms
Mean right atrial pressure =10
mm Hg
Mean pulmonary arterial pressure
>50 mm
Hg
Cardiac index < 2.0 L/min/m2
WHO
= World Health Organization
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In order to assure some consistency across transplant centers,
international guidelines have been published that are used
by many centers to select lung transplant candidates.13
These criteria are also used by most insurance carriers
for coverage purposes. Although these guidelines were proposed
to develop standards across centers, individual programs
continue to use their own selection criteria, which vary
from center to center. Thus, a candidate who is unacceptable
at one program may be considered acceptable elsewhere. The
guidelines for patients with primary pulmonary hypertension
are outlined in Table 1.
There are both absolute and relative contraindications
to transplantation (Table 2). It
is important to note that the criteria used for inclusion
and exclusion are general guidelines to help select potential
candidates. In special circumstances, individual patients
may be accepted for transplantation even if they do not
meet all of the criteria in these guidelines.
Table
2 - Contraindications to Lung Transplantation
Relative
contraindications
Age:
> 65 for single lung transplantation
> 60 for bilateral single
lung transplantation
> 55 for heart and lung transplantation
Psychosocial instability
Mechanical ventilation
Chest wall deformity
Asymptomatic osteoporosis
History of substance abuse
Weight outside of acceptable range (morbid obesity
or severely malnourished)
Prednisone use >20 mg/day or 40 mg every other
day
Bilateral pleurodesis (for cardio-pulmonary bypass
candidates)
Absolute contraindications
HIV infection
Bone marrow failure
Cirrhosis of liver or active hepatitis B or C
infection
Chronic renal failure (creatinine clearance <50
mL/min)
Malignancy precluding long-term survival
Other life-limiting conditions
Active tobacco smoking or other substance abuse
Significant coronary artery or peripheral vascular
disease
Impaired left heart function unless considered
for heart-lung transplant
Severe symptomatic osteoporosis
Sputum growing antibiotic panresistant bacteria
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Timing of Lung Transplantation
Although many patients may improve or remain stable with
medical therapy for several years, at some point this therapy
may fail, requiring lung transplantation as the only life-sustaining
option. Because of the long waiting periods for lung transplantation
in the United States, and the unpredictable response to
medical therapy, deciding when to refer these patients for
transplant remains a clinical conundrum. Patients who remain
stable or improve with medical therapy should not be prematurely
exposed to the risks of surgery and long-term immunosuppression.
However, some patients may be observed during medical therapy
too long, ultimately being referred for transplantation
too late to survive the waiting period for a transplant.
Additionally, some patients may be referred late enough
in their course to have developed additional problems, such
as malnutrition and renal insufficiency, placing them at
higher risk for surgery.
Carefully monitoring the response to medical therapy
at regular intervals is crucial to assess whether the
treatment remains effective. For those in whom all forms
of medical therapy fail, transplantation should be offered
before the patient becomes too ill to enjoy a successful
outcome. Lung transplantation should be considered for
patients with PAH in whom therapy with vasodilators fails.
Because of the long waiting period for lung transplantation,
and the unpredictable rate of decline for some patients,
many centers advocate listing patients for transplantation
as soon as the diagnosis of PAH is established, while
others recommend that listing should occur when and if
there is failure of medical therapy (ie, vasodilators
and anticoagulation). Accordingly, the overall clinical
picture must be assessed for each patient in order to
allow ample waiting time for this potential life-saving
therapy. Thus it is left to the treating physician and
transplant specialist to make some predictions regarding
an individual patient’s survival with medical therapy.
Resting hemodynamics, 6-minute walk or shuttle test
results, and functional class (eg, World Health Organization)
status have each been demonstrated to predict survival
in PAH.14-17 Anticoagulation
with warfarin, calcium channel blockers, and long-term
epoprostenol have each been documented to improve survival
in PAH,8,18-20
and response to these therapies must be considered in
relation to the timing of transplantation. Since the prognosis
for patients with PAH may change continuously in response
to treatment, pretreatment survival predictions using
baseline static measurements, such as functional class,
are of little value in determining the need for transplantation.
Initiation of epoprostenol may dramatically improve symptoms
and prognosis, potentially postponing or obviating the
need for lung transplantation.10
Indeed, vasodilator responders with PAH have a 90% to
95% 5-year survival when initiated on oral calcium channel
blocker therapy and therefore are generally not initially
listed for lung transplantation.8
Unfortunately, the vast majority of patients with PAH
(75% to 85 %) are nonresponders, and without therapy face
a 5-year survival of less than 40%. It is this latter
group that should be considered for continuous intravenous
epoprostenol therapy and listing for lung transplantation.
Aalthough long-term data with epoprostenol are limited,
improved 5-year, or 50 month (50% to 60%) survival, has
been reported.19,20
Thus, the potential effect of epoprostenol on survival
must be considered when evaluating patients for lung transplantation.
At our center, we generally begin the evaluation process
for lung transplantation when WHO class III symptoms develop.
If there are no significant contraindications for transplantation,
these patients are listed and symptoms are monitored while
time is accrued on the waiting list. If symptoms stabilize
during medical therapy, these patients are removed from
the active list; reactivation occurs if medical therapy
begins to fail.
Effect of Epoprostenol on Timing
of Lung Transplantation for PAH
Improvement in symptoms and survival with continuous infusion
epoprostenol has had a significant impact on the timing
of lung transplantation.10,11,21
Treatment with this therapy may result in three potential
clinical responses. (1) A few patients experience no significant
improvement, and in this group medical therapy is considered
to have failed. In these individuals, transplantation
is the only viable life-sustaining option. These patients
are usually maintained on epoprostenol in the hope that
their disease will stabilize until transplantation. (2)
Another potential response, and fortunately the most likely
(occurring in >90% of patients), is improvement with
epoprostenol with a demonstrable reduction of at least
one point in WHO symptom class within the first 3 to 6
months. However, some patients develop a recurrence of
symptoms despite further increases in their epoprostenol
dose and require further consideration for transplantation.
These patients will have benefited from epoprostenol in
the short term by deferring the immediate need for lung
transplantation.10 (3) Some
patients develop a substantial and long-lasting (years)
benefit from epoprostenol, and lung transplantation will
be deferred indefinitely.
Deciding where an individual patient lies within these
three groups at an isolated point in time can be a challenge
clinically. Serial assessment of functional status together
with direct measurement of hemodynamics allows one to
best determine the response to therapy. For those who
are good long-term responders to epoprostenol, it remains
unclear how long the benefit may hold, as the longest
survival time of a patient receiving epoprostenol is now
well over 10 years. However, it is important to remember
that if one waits too long, until functional status markedly
declines and hemodynamics begin to fail, the patient may
become too sick for a successful transplant.
Type of Transplant
The operation of choice for primary pulmonary hypertension
remains controversial. Combined heart-lung transplantation,22
single lung transplantation23-25
and double lung transplantation10,25
have all been performed successfully. However, combined
heart-lung transplantation is rarely necessary for PAH,
since the right ventricle tends to recover function relatively
quickly following either single or double lung transplantation.25
Given the success of single and double lung transplantation,
coupled with the limited supply of heart-lung donor blocks,
single and double lung transplantation has almost completely
replaced heart-lung transplantation for PAH in the United
States.
Whether one should offer single or double lung transplantation
for PAH is not clear, as there are pros and cons for each
approach. Single lung transplantation is a less invasive
and shorter surgical procedure, allows two recipients
to be served from a single donor, and the waiting periods
are shorter than for double lung transplants. However,
the most recent International Society for Heart and Lung
Transplantation (ISHLT) registry data show a slight long-term
survival advantage for patients with double lung transplants
(all diseases combined) compared to single lung transplants,
although the difference is not statistically significant
for patients with PAH.26
There is, however, one important potential problem with
single lung transplants for pulmonary hypertension that
has influenced many programs to favor double lung transplantation.
With single lung transplantation, blood preferentially
flows in the pulmonary circuit toward the new lung; little
flow goes to the native lung because of the severe pulmonary
vascular disease. If the new lung develops infection or
rejection, a severe shunt can develop, causing profound
hypoxemia and making management extremely difficult.27
Immunosuppression
Following lung transplantation, recipients must receive
lifelong immunosuppression to prevent allograft rejection.
Unfortunately, numerous side effects are associated with
these medications. The major consequence of long-term
immunosuppression
is an increased rate of infection. Following transplantation
there is an increased risk for bacterial, viral (particularly
cytomegalovirus), and fungal infections.28,29
The risk of infection relates inversely to the time from
the transplant procedure. 28,29
This is due in part to both mechanical factors and the
intensity of immunosuppression.28,30
Although the risk of infection decreases as the amount
of immunosuppression is reduced over time, the risk never
returns to that of normal individuals.
Other risks of immunosuppression relate specifically
to each drug. Most centers use a triple-drug-based regimen
including cyclosporine (Neoral) or tacrolimus (Prograf),
with azathioprine (Imuran) or mycophenolate mophetil (CellCept)
and prednisone. Both cyclosporine and tacrolimus may induce
hypertension and nephrotoxicity, while azathioprine and
mycophenolate produce leukopenia. Long-term corticosteroid
use is associated with a litany of problems, including
osteoporosis, skin bruising, hyperglycemia, cataracts,
and myopathy. In addition to these problems, long-term
immunosuppression is associated with an increased risk
of cancer, particularly post-transplant lymphoproliferative
disorder, which has been reported at a rate of around
6% following thoracic organ transplantations.31
Lung Transplantation Outcomes
Survival
The success of lung transplantation can be measured according
to several criteria, including survival, physiologic function,
quality of life, and cost benefit. According to 2003 US
Scientific Registry data, overall survival following lung
transplantation is currently 77.4% at 1 year and 42.5%
at 5 years.32 Lung transplant
recipients with PAH do not fare as well, however, having
a 1-year survival of 72%, with much of this mortality
due to perioperative deaths.32
The 5-year survival is 37%.32
Figure 1 shows survival outcome by disease
in patients from the United Network for Organ Sharing
(UNOS)/ISHLT registry (data analysis through 2001).
A number of factors are responsible for early mortality
(0 to 30 days). These include infection (23.5%), primary
graft failure (30.5%), cardiovascular factors (11.5%),
acute rejection (4.9%), bronchiolitis (0.5%), technical
factors (8.3%), and other causes (20.5%).33
The factors responsible for late mortality differ from
those for early mortality. Over the long term, chronic
allograft rejection, manifested pathologically as obliterative
bronchiolitis, is the single most important factor limiting
the overall success of lung transplantation. Obliterative
bronchiolitis occurs in at least 40% of patients by 2
years and in up to 70% by 5 years,34
and it is the cause of death in 50% of those affected.
Other causes of late mortality include infection, malignancy,
and other comorbidities. Prior to the development of epoprostenol,
transplantation provided a survival advantage for patients
with PAH when comparing transplant survival with data
from the National Institutes of Health primary pulmonary
hypertension registry.25
At this point, however, it makes little sense to compare
the outcome of lung transplantation with that of medical
therapy. Lung transplantation should be utilized only
for patients in whom medical therapy fails.
Functional Outcomes of Transplantation
Functional outcomes have been analyzed by the International
Society for Heart and Lung Transplantation registry report.35
At 3 years post transplant, 89.6% of recipients reported
no activity limitations, 9.3% were able to perform activity
with some assistance, and 1% required total assistance.
Despite the functional improvements achieved with transplantation,
only a minority of patients (29.1%) were working full
time by 3 years post transplant. A majority of patients
(54.8%) required repeat hospitalization in the first year
of follow-up, although in the third postoperative year
this fell to 38.2%. The most common reason for repeat
hospitalization was allograft rejection and infection.
Quality of Life Following Transplantation
Despite widespread use of lung transplantation as a therapeutic
modality, few published studies assess quality of life
in recipients of this procedure. Gross and colleagues36
documented overall improvement in quality of life following
lung transplantation assessed by the Medical Outcomes
Health Survey (MOS)-20 health profile. Over the long term,
the benefit persists except in those patients who develop
chronic rejection. Although significant benefits in exercise
tolerance, pulmonary function, and quality of life exist
following lung transplantation, only a minority of patients
return to work on a full-time basis. The reasons why so
few recipients return to work are not well known. Following
transplantation the majority of patients reach functional
levels that should not limit their physical ability to
work in a variety of occupations. It is true, however,
that many transplant recipients are unable to work because
of financial constraints. For some the choice of returning
to work means giving up disability insurance benefits
that cover their long-term medications and post-transplant
medical care.
Cost of Lung Transplantation
The financial cost of lung transplantation is not trivial.
In fact, the high cost has been a motivating factor for
Medicare and other third party payers to offer reimbursement
for this procedure only to approved centers of excellence.
Ramsey et al37 outlined the
overall costs of lung transplantation for the University
of Washington Medical Center. The average charges for
the procedure and immediate postoperative care were $164,989
(median $152,071). The post-transplant average monthly
charges during the first 6 months were $16,628; in the
second 6 months they were $5,440, but fell to $4,525 thereafter.
This compared to the average monthly charges for patients
on the waiting list of $3,395. Although these figures
come from a single center, they do not differ substantially
from reports of other centers.38,39
Summary
All potential lung transplantation candidates with PAH
should be considered for treatment with epoprostenol where
available. In the United States, patients should be listed
for transplantation at initiation of therapy; the response
to epoprostenol should be reviewed at regular intervals
and dosage increased as tolerated. Patients who respond
well should be removed from the transplant list and monitored
for continued responsiveness. For those in whom medical
therapy fails, lung transplantation remains a viable option.
Despite the potential for improved survival and function,
this procedure is associated with several limitations.
These include the lack of available donor lungs, the morbidity
and mortality associated with the surgery, high financial
cost, lifelong need for immunosuppression, and the risk
of infection and rejection. Research is under way to develop
better methods for organ tolerance without the need for
potent, nonspecific immunosuppression. Potential candidates
for lung transplantation should be referred to transplant
centers early to maximize their chance for survival.
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