Kind

Bottlenecks

Open problems that limit progress.

• Bottleneck

  Definitions and prognosis of ALAD and BLAD are not settled

  Evidence: proposed bottleneck; synthesis of abstract-level sources; pending approval

  The early window before CLAD is the focus of new definitions, but reviews state that their definitions and significance are not yet fully established.

• Bottleneck

  Biomarker findings are hard to validate and generalise across centres

  Evidence: proposed bottleneck; synthesis of abstract-level sources; pending approval

  Prognostic markers often perform differently between cohorts or centres, and translation into routine diagnostic tests is described as a barrier.

• Bottleneck

  Clinical CLAD phenotypes are hard to assign reproducibly

  Evidence: proposed bottleneck; synthesis of abstract-level sources; pending approval

  Adjudicators agreed poorly on phenotype in one single lung cohort, and reviews state that lung function alone cannot always identify the exact phenotype.

• Bottleneck

  CLAD is recognised late and no biomarker is validated for early warning

  Evidence: proposed bottleneck; synthesis of abstract-level sources; pending approval

  CLAD is defined by persistent lung function decline, and none of the many proposed blood, lavage or tissue biomarkers is universally accepted in practice.

• Bottleneck

  No therapy of proven benefit for established CLAD

  Evidence: proposed bottleneck; synthesis of abstract-level sources; pending approval

  No treatment has shown clear benefit for established CLAD in randomised trials, and guideline authors call for high-quality trials.

• Bottleneck

  No validated molecular endotype scheme exists for CLAD

  Evidence: proposed bottleneck; synthesis of abstract-level sources; pending approval

  Endotype frameworks are proposed from small or single-centre studies and have not been validated across centres.

• Bottleneck

  Pulmonary antibody-mediated rejection has dismal outcomes and no established treatment platform

  Evidence: proposed bottleneck; synthesis of abstract-level sources; pending approval

  The 2026 ISHLT statement reports a 2-year survival of only 20 percent for pulmonary AMR and calls better treatments a critical unmet need.

• Bottleneck

  Human tissue studies are small and raw human sequence data are often not open

  Evidence: proposed bottleneck; synthesis of abstract-level sources; pending approval

  Many mechanistic human studies use a handful of explants, and several public GEO series state that raw human sequence files were withheld or put under controlled access.

• Bottleneck

  Unclear endpoints and heterogeneous patients hinder CLAD trials

  Evidence: proposed bottleneck; synthesis of abstract-level sources; pending approval

  An ISHLT consensus states that lung transplant trials have been hindered by unclear endpoints, and a preprint proposes trajectory classes for trial enrichment.

• Bottleneck

  CLAD care and measurement vary between centres

  Evidence: proposed bottleneck; synthesis of abstract-level sources; pending approval

  Surveys report persistent variation in prevention and treatment and incomplete access to some measurements, which limits comparative evidence.