A plain-language introduction to CLAD

Chronic lung allograft dysfunction (CLAD)

Plain-language explanation of terms. An allograft is an organ that is transplanted from one person to another. After a lung transplant, the donor lung is the allograft.

Plain-language explanation of terms. FEV1 is the forced expiratory volume in one second: the volume of air that a person can blow out in the first second of a forceful breath. It is measured by a breathing test called spirometry.

• CLAD stands for chronic lung allograft dysfunction. A 2026 review abstract describes it as the fibrotic manifestation of chronic rejection and a major barrier to long-term survival after lung transplantation. Fibrotic means that scar-like tissue forms.

  Records: CLAD: translating basic science to clinical practice (paper, abstract only); Molecular endotypes of CLAD (proposed framework) (endotype, abstract only)

• The same abstract describes CLAD as the final common pathway of diverse alloimmune injuries, augmented by non-alloimmune insults. Alloimmune means an immune reaction against tissue from another person.

  Records: CLAD: translating basic science to clinical practice (paper, abstract only)

• The 2019 consensus report of the International Society for Heart and Lung Transplantation (ISHLT) defined CLAD. As restated in an open-access 2026 study, the definition is a sustained loss of at least 20 percent in FEV1 from the post-transplant baseline, after other identifiable causes such as infection, airway complications or pleural effusion have been excluded and treated. The consensus text itself was not opened for this site.

  Records: Spirometry: FEV1 decline from baseline in the ISHLT 2019 CLAD definition (diagnostic, secondary text read); Chronic lung allograft dysfunction: Definition, diagnostic criteria, and approaches to treatment: A consensus report from the Pulmonary Council of the ISHLT (paper, metadata only)

• According to the introduction of an open-access 2026 study, the 2019 consensus introduced four states, Potential, Possible, Probable and Definite CLAD, based on the degree and persistence of the fall in FEV1. In that study, in a cohort of 482 recipients, Possible CLAD was the earliest state independently associated with increased mortality.

  Records: ISHLT 2019 CLAD states: Potential, Possible, Probable and Definite (stage, secondary text read); Prognostic validation of the 2019 International Society for Heart and Lung Transplantation chronic lung allograft dysfunction states in lung allograft recipients (paper, abstract only)

• An open-access 2020 review lists severity stages 0 to 4 by current FEV1 relative to baseline: stage 0 is above 80 percent of baseline and stage 4 is 35 percent or below.

  Records: CLAD stages 0 to 4 by FEV1 relative to baseline (stage, secondary text read); Chronic lung allograft dysfunction post-lung transplantation: The era of bronchiolitis obliterans syndrome and restrictive allograft syndrome (paper, secondary text read)

BOS and RAS: the two main forms

Plain-language explanation of terms. A phenotype is a form of a disease as it appears in a patient, judged from signs such as breathing tests and scans.

Plain-language explanation of terms. Obstructive means that air flows out of the lungs with difficulty. Restrictive means that the lungs hold less air than expected.

• BOS stands for bronchiolitis obliterans syndrome. In the 2019 ISHLT phenotype scheme, as tabulated in an open-access review, BOS is the phenotype with obstructive findings (FEV1/FVC below 0.7) and without the restrictive findings or the computed tomography (CT) findings that define RAS.

  Records: Bronchiolitis obliterans syndrome (BOS) (phenotype, secondary text read); Chronic lung allograft dysfunction post-lung transplantation: The era of bronchiolitis obliterans syndrome and restrictive allograft syndrome (paper, secondary text read)

• An open-access 2020 review describes BOS as a disease in which the small airways are affected by chronic inflammation and obliterative fibrosis, while the peripheral lung tissue remains relatively intact.

  Records: Bronchiolitis obliterans syndrome (BOS) (phenotype, secondary text read); Bronchiolitis obliterans syndrome and restrictive allograft syndrome after lung transplantation: why are there two distinct forms of chronic lung allograft dysfunction? (paper, abstract only)

• RAS stands for restrictive allograft syndrome. In the 2019 scheme it is the phenotype with restrictive findings (a decline in total lung capacity of at least 10 percent from baseline) together with parenchymal opacities or pleural thickening on CT, without obstruction.

  Records: Restrictive allograft syndrome (RAS) (phenotype, secondary text read); Chronic lung allograft dysfunction post-lung transplantation: The era of bronchiolitis obliterans syndrome and restrictive allograft syndrome (paper, secondary text read)

• The same 2020 review characterises RAS as a diffuse fibrotic process across the airway, pleura, septum, alveoli and vasculature, in contrast to the airway-centred process of BOS. RAS was described as a distinct form in 2011, and a companion consensus report in 2019 gave an update.

  Records: Restrictive allograft syndrome (RAS) (phenotype, secondary text read); Bronchiolitis obliterans syndrome and restrictive allograft syndrome after lung transplantation: why are there two distinct forms of chronic lung allograft dysfunction? (paper, abstract only); Restrictive allograft syndrome (RAS): A novel form of chronic lung allograft dysfunction (paper, metadata only); Chronic lung allograft dysfunction: Definition and update of restrictive allograft syndrome: A consensus report from the Pulmonary Council of the ISHLT (paper, metadata only)

• The mixed phenotype has obstruction, restriction and CT abnormalities together. The undefined phenotype covers presentations that meet the CLAD criteria but do not fit BOS, RAS or mixed. A 2026 study adds a separate unclassifiable category for presentations that the current criteria do not cover.

  Records: Mixed phenotype (phenotype, secondary text read); Undefined phenotype (phenotype, secondary text read); Phenotyping of chronic lung allograft dysfunction in the ScanCLAD study (paper, abstract only)

• Lung function testing alone cannot always identify the exact phenotype, and adjudicators agreed poorly on phenotype in one single-lung cohort.

  Records: Clinical CLAD phenotypes are hard to assign reproducibly (bottleneck, abstract only); Spirometry: FEV1 decline from baseline in the ISHLT 2019 CLAD definition (diagnostic, secondary text read)

ALAD and BLAD: the period before CLAD

Plain-language explanation of terms. ALAD stands for acute lung allograft dysfunction. BLAD stands for baseline lung allograft dysfunction.

• A 2026 review abstract recognises ALAD as a heterogeneous syndrome of acute lung function decline, and describes it as an opportunity to characterise graft injury before irreversible fibrosis develops. The abstract gives no diagnostic criteria, thresholds or timing, and none are stated here.

  Records: Acute lung allograft dysfunction (ALAD) (stage, abstract only); CLAD: translating basic science to clinical practice (paper, abstract only)

• A 2025 review that draws on two ISHLT expert groups states that the definitions and real significance of ALAD and BLAD are not yet fully established and that many uncertainties remain.

  Records: The ABC of transplant: ALAD, BLAD, and CLAD: definition and significance (paper, abstract only); Definitions and prognosis of ALAD and BLAD are not settled (bottleneck, abstract only)

• The introduction of an open-access 2026 study notes that baseline allograft dysfunction, defined by a subnormal baseline FEV1, may predispose to earlier or more severe CLAD progression.

  Records: Prognostic validation of the 2019 International Society for Heart and Lung Transplantation chronic lung allograft dysfunction states in lung allograft recipients (paper, abstract only); Spirometry: FEV1 decline from baseline in the ISHLT 2019 CLAD definition (diagnostic, secondary text read)

• ISHLT consensus documents on ALAD and on BLAD were published in 2026, but only their titles are indexed in PubMed, so they could not be read for this site.

  Records: Definitions and prognosis of ALAD and BLAD are not settled (bottleneck, abstract only)

Endotypes: classifying CLAD by its biology

Plain-language explanation of terms. An endotype is a subtype of a disease that is defined by its underlying biological mechanism, rather than by how the disease looks or by one test result.

• The 2026 review by Burman and colleagues proposes a shift from the clinical phenotypes BOS and RAS toward biologically defined endotypes, which the authors suggest may better predict progression and response to treatment. The abstract describes no validated endotype scheme, so the endotype record carries the status proposed.

  Records: Molecular endotypes of CLAD (proposed framework) (endotype, abstract only); CLAD: translating basic science to clinical practice (paper, abstract only)

• The same abstract names pathways involved in CLAD: cytotoxic and senescent T cells, humoral (antibody-mediated) immunity, innate immune activation, dysfunction of the airway lining, aspiration and dysbiosis (an unhealthy balance of microbes). Each is a proposed framework taken from the abstract only.

  Records: Cytotoxic and senescent T cells (mechanism, abstract only); Humoral (antibody-mediated) alloimmunity (mechanism, abstract only); Innate immune activation (mechanism, abstract only); Airway epithelial dysfunction (mechanism, abstract only); Aspiration (mechanism, abstract only); Microbial dysbiosis (mechanism, abstract only)

• A Leuven transcriptomic atlas reports two transcriptomic endotypes from 128 explant samples, validated across four datasets according to its abstract, plus a 26-gene panel. Endotype frameworks come from small or single-centre studies and have not been validated across centres.

  Records: A transcriptomic atlas of chronic lung allograft dysfunction. (paper, abstract only); No validated molecular endotype scheme exists for CLAD (bottleneck, abstract only)

What is not yet settled

• These open problems are recorded on this site as proposed bottlenecks. They are pending review and are not established conclusions.

• No therapy of proven benefit for established CLAD

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

  Verification status: Abstract only

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

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

  Verification status: Abstract only

• Clinical CLAD phenotypes are hard to assign reproducibly

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

  Verification status: Abstract only

• No validated molecular endotype scheme exists for CLAD

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

  Verification status: Abstract only

• Definitions and prognosis of ALAD and BLAD are not settled

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

  Verification status: Abstract only