Transplant

Question 1

Chronic lung allograft dysfunction

Answer 1

CLAD encompasses a range of pathologies that cause a transplanted lung to not achieve or maintain normal function.

Manifests as airflow restriction and/or obstruction and is predominantly a result of chronic rejection.

Three distinct phenotypes: bronchiolitis obliterans, neutrophilic reversible allograft dysfunction, and restrictive allograft syndrome.

CLAD is poorly responsive to treatment once diagnosed.

There is a lower long term survival of pulmonary transplant patients compared to recipients of other solid organ transplants, due to constant exposure to the external environment (i.e. infection, air pollution), potential for aspiration, susceptibility to ischemia reperfusion injury-mediated graft dysfunction and the organ’s propensity to contain abundant lymphoid tissue.

Factors including acute rejection, primary graft dysfunction, respiratory infections and gastroesophageal reflux disease have been shown to predispose lung transplant patients to the development of CLAD.

Question 2

Bronchiolitis Obliterans syndrome

Answer 2

description

• characterized by a new, fixed airflow obstruction after either lung transplant or allogeneic hematopoietic stem cell transplant (HSCT), ?in the setting of CGVHD
• typically develops within 2 years of the procedure
• associated with increased morbidity and mortality. Occurs in 4-6% of allogeneic HSCT recipients and up to 14% of pts with chronic GVHD
• bronchiolitis obliterans syndrome is closely linked to chronic graft-vs-host disease (GVHD)

diagnosis

• diagnosis based on the presence of obstructive lung disease on PFTs. FEV1/FVC <0.7, FEV1 <75%, and either HRCT evidence of air trapping or residual volume >120% without concurrent resp infection. Exclude other causes of resp obstruction (asthma, infxn, smoking). A decrease in FEV1 may occur before the onset of obstructive lung disease.

treatment

• initial treatment of overt BOS includes the FAM regimen (fluticason bd, azithro 250 thrice weekly, montelukast 10mg daily) + systemic corticosteroid. This recommendation is based on non-randomised studies
• second line CGVHD (used in addition to corticosteroids): calcineurin inhibitors (tac, ciclo), ibrutinib (which is FDA approved), extracorporeal photophoresis, JAK inhibitors, mycophenolate mofetil, rituximab, mTOR inhibitors, TKI’s. But there is not data for comparison of 2nd-line options
• Prolonged use of azithromycin not recommended after resolution of Bronchiolitis Obliterans, given the increased risk of relapse in high risk patients.
• azithro use as prophylaxis in pts undergoing HSCT is associated with increased relapse in high risk pts so not recommmended
• however, BOS is usu irreversible despite immunosuppressive (high dose corticosteroids) treatment, which also have significant morbidity effects (e.g. infections) [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(19)30256-X/fulltext?rss=yes ; also have pdf]

Macrolides (azithro) and Bronchiolitis Obliterans syndrome

• macrolides have immunomodulatory and anti-inflammatory properties for which they are broadly used in the management of several chronic respiratory diseases.
• Prev RCT demonstrates azithromycin prophylaxis improved bronchiolitis obliterans syndrome–free survival among patients who had undergone a lung transplant with a significant reduction in bronchiolitis obliterans syndrome prevalence after 2 years.
• ALLOZITHRO study (RCT phase 3) showed that in pts who received early (from time of conditioning) prophylactic azithromycin prior to HSCT, had worse airflow decline–free survival after 2 years (estimated) (33% vs 41% placebo grp), worse overall survival (56% vs 70% placebo grp), worse haematological relapse (33% vs 22% placebo). No difference in incidence of acute or chronic GVHD betwn the grps. 13 months after recruitment, there was an unexpected imbalance in the number of severe hematological relapses. Trial was terminted due to safety concerns. From this study, FDA now advises that the risk of azithro exposure post HSCT exeed the benefits. Prophylactic azithro isn’t recommended in pts undergoing HSCT - 2017 JAMA, Effect of azithro on survival after HSCT https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5817485/ ;;; FDA statement https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-increased-risk-cancer-relapse-long-term-use-azithromycin-zithromax-zmax-antibiotic