Speaker's Highlight

• Don Sin University of British Columbia, St. Paul Hospital (Canada)
  Kenneth R. Chapman Toronto General Hospital Research Institute (Canada)
• Parameswaran Nair McMaster University (Canada)
  Carolyn Calfee UCSF (U.S.A.)
• Gregory P. Downey University of Colorado School of Medicine (U.S.A.)
  David A. Schwartz University of Colorado School of Medicine (U.S.A.)
• Neil Schluger Tuberculosis Control Branch, California Department of Public Health (U.S.A.)
  Nick Kim Critical Care & Sleep Medicine, University of California San Diego (U.S.A.)
• Nicola Hananiah Baylor College of Medicine (U.S.A.)
  Jae-Joon Yim Seoul National University College of Medicine (Republic of Korea)
• Koichiro Asano Tokai University School of Medicine (Japan)
  Diahn-Warng Perng Taipei Veterans General Hospital (Taiwan)
• Konstantinos Kostikas University of Ioannina (Greece)
  Karin Klooster University Medical Center Groningen (Kingdom of the Netherlands)

• Non-invasive biomarkers for acute rejection after lung transplant

  Lung transplantation can restore breathing capacity and extend survival, yet acute cellular or antibody-mediated rejection remains a serious threat. The process may begin before patients notice breathlessness, cough, fever, or a measurable decline in daily function. Earlier detection could give clinicians more time to confirm the cause and adjust immunosuppression.

  Routine surveillance still relies heavily on spirometry, imaging, laboratory testing, bronchoscopy, and transbronchial biopsy. Biopsy provides valuable tissue evidence, but it is invasive, carries procedural risks, and may miss patchy disease. Non-invasive biomarkers are therefore being studied as repeatable signals that can support clinical decisions without requiring tissue at every visit.

  For a respiratory medicine community such as APSR and KATRD, the central issue is practical: which markers can detect rejection early, distinguish it from infection or environmental injury, and fit into long-term follow-up? No single test has solved these problems, but several complementary approaches are moving toward clinical use.

  Why early detection matters

  Acute rejection may reduce lung function before radiographic changes become obvious. A falling forced expiratory volume in one second (FEV1), especially when confirmed across several measurements, can be an important warning. Home spirometry adds frequent observations between clinic appointments and may reveal a gradual pattern that a quarterly test would overlook.

  Symptoms and lung function are not specific to rejection. Respiratory infection, airway complications, medication toxicity, fluid overload, and exposure to pollutants can produce similar findings. Research on air pollution effects is especially relevant because particulate matter and ozone can increase airway inflammation and complicate interpretation of biomarker results.

  Signals from breath and exhaled air

  Fractional exhaled nitric oxide, or FeNO, reflects nitric oxide production in inflamed airways. It is simple to measure and widely available in respiratory practice, but its value after transplantation is still being defined. Elevated readings may reflect eosinophilic inflammation, infection, inhaled corticosteroid changes, or other airway processes rather than rejection alone.

  Exhaled volatile organic compounds offer a broader chemical profile. Gas chromatography, electronic noses, and machine-learning models may identify patterns associated with immune activation or graft injury. Exhaled breath condensate is another area of interest because it can contain inflammatory mediators and oxidative stress markers. These techniques remain sensitive to sampling conditions, diet, smoking exposure, equipment, and the lack of universally accepted thresholds.

  Blood-based biomarkers and graft injury

  Donor-derived cell-free DNA (dd-cfDNA) is released into the recipient’s bloodstream when transplanted lung cells are damaged. A rising fraction can indicate allograft injury and may appear before a major FEV1 decline. Its appeal lies in the ability to obtain serial blood samples with limited burden, making it suitable for surveillance and for monitoring response after treatment.

  The central limitation is biological specificity. Infection, ischemia-reperfusion injury, airway damage, and other forms of graft stress can also increase dd-cfDNA. Results must therefore be interpreted alongside symptoms, imaging, microbiology, lung function, and immunosuppressive drug levels. Peripheral blood gene-expression profiles and immune-cell signatures may add information by describing the host response rather than cell damage alone.

  Biomarker approach	Main strength	Important limitation	Likely clinical role
  Home spirometry	Frequent, inexpensive functional monitoring	Poor specificity and variable technique	Early warning between visits
  dd-cfDNA	Direct signal of graft-cell injury	Can rise with infection or other damage	Risk assessment and treatment monitoring
  FeNO	Fast, non-invasive airway inflammation measure	Confounded by infection and steroid therapy	Adjunct for selected airway inflammation
  Exhaled VOCs	Potentially broad disease fingerprint	Technology and validation remain inconsistent	Future classification and screening
  Blood gene-expression panels	Captures systemic immune activity	Complex interpretation and limited standardization	Rejection-risk stratification

  Combining biomarkers improves interpretation

  A multimodal strategy is more promising than relying on one abnormal result. For example, a sustained fall in home FEV1 accompanied by rising dd-cfDNA may justify accelerated imaging, infection testing, or bronchoscopy. A stable FEV1 with an isolated biomarker change may call for repeat sampling and clinical review rather than immediate escalation of immunosuppression.

  Digital monitoring can strengthen this approach. Connected spirometers, symptom diaries, oxygen saturation, activity data, and medication records create a longitudinal picture of graft health. Algorithms may detect subtle deviations from an individual baseline, but they require carefully curated datasets and external validation across transplant centers, devices, ethnic groups, and immunosuppression protocols.

  Separating rejection from infection

  The most difficult diagnostic problem is overlap. Acute rejection and respiratory infection can both cause cough, hypoxemia, infiltrates, inflammatory biomarker changes, and declining spirometry. Treating presumed rejection without excluding infection may worsen an underlying pathogen, while delaying anti-rejection therapy can allow irreversible graft injury.

  Biomarker panels should therefore be evaluated for clinical discrimination, not simply statistical association. Useful studies need clear definitions of rejection, systematic infection testing, repeated measurements, and outcomes such as treatment response or later chronic lung allograft dysfunction. A marker that predicts poor outcomes but cannot distinguish the cause of injury may still be valuable for triage, but it should not be presented as a stand-alone diagnostic test.

  Moving from research to routine care

  Before adoption, non-invasive assays need standardized collection methods, validated cutoffs, turnaround times suitable for clinical practice, and evidence that their use improves patient outcomes. Cost, laboratory capacity, insurance coverage, and access to home monitoring also influence whether a promising test can work outside a specialist research center.

  Patient education is equally important. Transplant recipients should understand that a biomarker is a warning signal, not a final diagnosis. Consistent home spirometry technique, prompt reporting of symptoms, and adherence to sampling schedules can improve data quality. Clinicians should document each patient’s baseline and assess trends rather than reacting to a single isolated value.

  Practical priorities for transplant programs

  • Pair home spirometry with clear thresholds for repeat testing and clinical contact.
  • Interpret dd-cfDNA alongside infection studies, imaging, lung function, and treatment history.
  • Use standardized protocols for breath collection, blood sampling, and laboratory analysis.
  • Build longitudinal databases that connect biomarker changes with biopsy results and outcomes.
  • Explain test limitations so patients understand when confirmatory procedures remain necessary.

  The next phase of transplant biomarker research should focus on integrated, patient-specific monitoring rather than a search for one perfect assay. Combining functional data, graft-injury markers, immune signatures, and clinical context may reduce unnecessary biopsies while preserving diagnostic safety.

  Respiratory specialists, transplant teams, researchers, and patients can help accelerate progress by participating in prospective validation studies and using consistent monitoring pathways. Turning early biological signals into timely, evidence-based action could protect graft function and improve long-term outcomes after lung transplantation.

  Richard Russell Nuffield Department of Clinical Medicine, University of Oxford (United Kingdom)
• Mona Bafadhel King’s College London (United Kingdom)
  David Jackson Guy’s and St Thomas’ Hospital, King’s College London (United Kingdom)
• James Chalmers University of Dundee (United Kingdom)
  David Price University of Aberdeen (United Kingdom)