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CLAD, Pulmonary GVHD Have Similar Clinical Traits, Research Needs


Fine-tuning clinical phenotypes and identifying effective treatments remain challenging in chronic lung allograft dysfunction (CLAD) after lung transplantation and chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem-cell transplantation.

A recent review gives a novel perspective on the similarities between pulmonary chronic graft-versus-host disease (cGVHD) and chronic lung allograft dysfunction (CLAD) and informs where more research is needed.

Although allogeneic hematopoietic stem-cell transplantation (HSCT) is a potentially life-saving treatment for patients with hematological conditions, cGVHD can limit long-term survival post transplant. Similarly, long-term survival following lung transplantation can be limited by CLAD.

Most organs can be affected by cGVHD, which occurs in an estimated 30% to 70% of patients after HSCT. Pulmonary complications of cGVHD, potentially including bronchiolitis obliterans syndrome and forms of restrictive interstitial lung disease (ILD), can have a significant impact on morbidity and mortality after HSCT.

Lung transplantation is a well-established option for patients with end-stage lung disease, but despite progress in transplant donor selection and surgical and aftercare management, CLAD still remains a complication—affecting about 50% of transplant recipients within 5 years of their operation. Bronchiolitis obliterans syndrome and restrictive allograft syndrome, which typically involves ILD, are the 2 main clinical types of CLAD. A third subtype is a combination of the features of the 2 main types.

Post-HSCT pulmonary cGVHD and CLAD after lung transplantation have similar underlying immunopathology leading to pulmonary fibrosis and structural lung remodeling, although more research has been done on CLAD due to its prevalence and mortality rates. The present study’s authors argue that a better understanding of both conditions is necessary to diagnose them early and improve treatments and outcomes.

Immunosuppressive regimens are typically used to treat cGVHD and CLAD, but those also come with risks and have thus far struggled to prevent and treat both conditions. Overly aggressive immunosuppressive therapy can also lead to a reduction in the potentially curative graft-versus-host effect meant to occur after HSCT for hematological conditions. Immunosuppressive regimens also increase a patient’s risk of infection when used in any context, including cGVHD or CLAD. More in-depth research on the underlying mechanisms of both conditions could help clarify the causes of disease onset and progression, allowing for more strategic treatment of at-risk patients.

Bronchiolitis obliterans syndrome is the only condition technically recognized as pulmonary cGVHD, and there are significant similarities between bronchiolitis obliterans syndrome seen after HSCT and after lung transplantation. Despite varying clinical backgrounds or triggers, they have similar processes of tissue remodeling and gene expression of fibrosis-related genes.

Progressive obstructive airflow limitation, assessed by pulmonary function tests (PFTs) such as spirometry, is the main clinical diagnosis tool for bronchiolitis obliterans syndrome. However, the authors highlight difficulties with this methodology, including the potential for missing the clinical features until the disease is advanced because bronchiolitis obliterans syndrome is a small airways disease. Increased screening frequency and estimating PFT trajectories may help in this regard.

ILD after lung transplantation has long been considered a potential complication, and restrictive allograft syndrome has been recognized as a separate entity since 2010. The umbrella term CLAD was introduced to cover both obstructive (bronchiolitis obliterans syndrome) and restrictive (restrictive allograft syndrome) lung allograft dysfunction. However, in pulmonary cGVHD, there is no official recognition of a restrictive phenotype. This, the authors note, is a significant gap that needs to be addressed to provide clear clinical guidance on diagnosis and management.

A chest CT can reveal manifestations of restrictive allograft syndrome in patients with CLAD, revealing features like ground-glass opacities and signs of tissue fibrosis. CT imaging could also prove useful in identifying ILD in restrictive pulmonary cGVHD, considering the 2 conditions show comparable radiological findings.

Effective therapies for prevention and treatment of CLAD represent an unmet need for patients undergoing lung transplant, and more research is necessary to determine effective treatments and improve long-term patient survival. Current options have varied efficacy, and the adverse effects of currently available options directed against immune response limit their use.

In pulmonary cGVHD, the need for effective therapies is even more urgent. Given its rarity, lack of guidelines, and the potentially multisystemic nature of GVHD overall, it is challenging to pinpoint the best therapy options. Preemptive immunosuppressant therapy, an option in CLAD, is not suggested in cGVHD after HSCT due to the risk of hematological relapse from immune response suppression. And even though several new therapies are under investigation, this represents another area where more research is warranted.

Overall, the study authors conclude that each entity could benefit from research on the other, considering the similarities between their mechanisms and clinical characteristics.

“Research efforts should focus on identifying common targets for prevention and treatment, which are an urgent unmet need and might equally benefit both entities, to further improve quality of life and long-term survival after allogeneic HSCT and lung transplantation,” they concluded.


Bos S, Beeckmans H, Vanstapel A, et al. Pulmonary graft-versus-host disease and chronic lung allograft dysfunction: two sides of the same coin? Lancet Respir Med. Published online May 2, 2022. doi:10.1016/S2213-2600(22)00001-7

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