for the rest
of their lives. Immunosuppression, however, may make patients vulnerable to
infections and cancers, the second and third leading causes of death after lung
been few studies in the field of lung transplantation to identify what is most
effective and works best. The U.S. Food and Drug Administration (FDA) has so
far not approved specific immunosuppressive drugs
or drug regimens
pertaining to lung transplant either.
Details of the Study
team from the University of Maryland School of Medicine (UMSOM) has developed a
new epidemiological analysis of lung transplant data in the United States that
focuses on regimens that would prevent the body's immune system from attacking
the transplanted lung. They have also been able to identify a drug combination
which appears to have the potential to extend patient survival considerably.
Iacono, the Hamish S. and Christine C. Osborne Distinguished Professor in
Advanced Pulmonary Care at UMSOM, Medical Director of the Lung Health Program
at the University of Maryland Medical Center is the lead author of the study.
He says, "We postulated that an
infrequently used regimen may make a difference in outcome,"
and added, "What we found could improve survival of
lung transplant patients on a larger scale."
The team used
the database of 9,000 lung transplant patients maintained by the United Network
for Organ Sharing (UNOS), patients were categorized by their immunosuppression
regimen and then survival rates were compared.
Why Sirolimus? Sirolimus
, an immunosuppressive drug
from the class of drugs called
cell cycle inhibitors, was singled out. Sirolimus was selected on the basis of
a few small, long-term studies that found markedly improved survival,
diminished chronic rejection incidence, and improved in lung function in those
patients who took it.
also compared the outcomes of Sirolimus with its counterpart Mycophenolate
Mofetil (MMF), a very commonly used cell cycle inhibitor. "According to our study,
sirolimus appears to offer a survival advantage of almost two years over MMF,"
said the first author Marniker Wijesinha, a UMSOM post-doctoral fellow. "The survival improvement with sirolimus was
driven by fewer deaths from the top three causes: chronic rejection,
infections, and cancer," he added.
Drug Combination of Sirolimus and Tacrolimus
another immunosuppressant, which is presently used in majority of lung
transplant recipients, was commonly used for all the patients of the study as
well. Talking about the immunosuppressive regimen followed and how it was
altered in this study, Dr. Wijesinha said, "The
typical regimen consists of three drugs: tacrolimus, a cell cycle inhibitor, and
steroids (prednisone). The variable in this study was the cell cycle
The median survival linked to the Sirolimus plus
Tacrolimus combination (8.9 years) was better than the MMF plus Tacrolimus (7.1
Almost 5,800 patients, the majority
from the database, were given the MMF plus Tacrolimus combination, which in
practice has become the standard immunosuppression after lung transplant. A
little over 200 patients received the Sirolimus plus Tacrolimus
Sirolimus, however, has a
shortcoming as it interferes with the wound
, which could potentially be life-threatening
if the drug
is administered in the early days following the transplant surgery. Hence, it
is recommended that Prophylactic Sirolimus maintenance therapy
started three to 12 months after surgery. This delay in Sirolimus initiation
has been accounted for by the research team allowing no scope for false
an optional addition to the maintenance therapy, which is used in almost over
half of the transplant centers in the United States, was also considered by the
research team. Induction therapy involves administering a high dose of
immunosuppression to patients for a short duration around three to 14 days, at
the time of transplantation. Drugs like basiliximab, daclizumab, alemtuzumab,
or antithymocyte globulin are used during the therapy.
group that was given the Sirolimus plus Tacrolimus for maintenance therapy,
without induction therapy emerged as the one with the highest survival among
all combinations that were tried.
The Dean of
UMSOM and University Executive Vice President for Medical Affairs and also the
John Z. and Akiko K. Bowers Distinguished Professor, Dr. E. Albert Reece said, "This study illustrates the value of
searching through large databases to discern patterns and practices that may not
be immediately obvious, but can have a major impact on patient care."
also mentioned, "Further studies of
patients undergoing lung transplantation are needed to confirm the findings
associated with sirolimus, but this research is a great start."
the limitations of the study and what is required further, Dr. Wijesinha said, "A particularly useful direction for a
future study would be to investigate the optimal dosages of sirolimus and
tacrolimus in lung transplant patients (which may vary according to patient
characteristics). Our study, unfortunately, could not do this because there
were no data on this."
and his team from UMSOM have begun to apply their findings from the study to
their standard treatment regimen followed for lung transplant recipients.
The team has
switched to the Sirolimus plus Tacrolimus combination to help in the
long-term prevention of chronic rejection.
- Survival Associated With Sirolimus Plus Tacrolimus Maintenance Without Induction Therapy Compared With Standard Immunosuppression After Lung Transplant - (http://dx.doi.org/10.1001/jamanetworkopen.2019.10297)