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)

• The Role of Macrolides in Managing Bronchiolitis Obliterans

  Bronchiolitis obliterans is a serious small-airway disorder in which persistent inflammation and fibrotic narrowing progressively limit airflow. Once established, the damage can be difficult to reverse, making early recognition and careful long-term management especially important. The condition may follow lung transplantation, hematopoietic stem-cell transplantation, inhalational injury, severe infection, or autoimmune disease.

  Macrolide antibiotics such as azithromycin and clarithromycin have attracted attention because their potential value extends beyond antimicrobial activity. They may reduce neutrophilic inflammation, alter cytokine signaling, and influence airway mucus production. This makes them relevant to bronchiolitis obliterans syndrome, particularly after lung transplantation, although their benefits are not uniform across all patients.

  Respiratory specialists evaluating this subject will also consider the wider scientific and clinical setting represented by the APSR 2022 logo, a congress identity associated with discussion of advances in pulmonary medicine and healthcare research.

  Why this disease is difficult

  Bronchiolitis obliterans affects the smallest conducting airways, where conventional imaging can initially appear unremarkable. Symptoms may begin with exertional breathlessness, dry cough, wheezing, or a gradual decline in exercise tolerance. Serial spirometry is often more informative than a single test, because a persistent fall in forced expiratory volume can signal evolving airway injury.

  In transplant recipients, the condition is commonly discussed as bronchiolitis obliterans syndrome, a clinical phenotype defined by a sustained reduction in lung function after excluding other causes. Infection, acute rejection, gastroesophageal reflux, airway stenosis, medication toxicity, and poor treatment adherence can produce similar changes. Correctly identifying the dominant process is essential before adding or continuing long-term macrolide therapy.

  How macrolides may work

  Macrolides have immunomodulatory properties that may be relevant when neutrophilic inflammation contributes to airway damage. Azithromycin, for example, can influence inflammatory-cell recruitment, reduce selected pro-inflammatory mediators, and improve mucociliary function in some chronic airway disorders. These effects are separate from its ability to inhibit bacterial protein synthesis.

  The response appears to depend on disease phenotype. Patients with neutrophil-predominant airway inflammation may benefit more than those with advanced, fixed fibrosis. Macrolides cannot reliably reopen scarred bronchioles, and they should not be described as a cure. Their most realistic role is as part of a broader strategy that may slow functional decline, reduce inflammation, or help preserve a transplant recipient’s lung function.

  What clinical evidence shows

  Studies of azithromycin in lung-transplant populations have reported improved or stabilized spirometric measures in selected patients, particularly when treatment begins early in the course of bronchiolitis obliterans syndrome. Some research also suggests a preventive effect when azithromycin is started after transplantation, although study designs, dosing schedules, and patient populations differ.

  Evidence remains mixed because bronchiolitis obliterans is biologically diverse and difficult to study in large randomized trials. Improvements in forced expiratory volume do not always translate into better survival or freedom from progression. A clinical decision should therefore combine lung-function trends with symptoms, bronchoscopy findings, infection history, imaging, and the patient’s overall transplant status.

  Clinical situation	Potential rationale for a macrolide	Important limitation
  Early decline after lung transplantation	May address neutrophilic inflammation and preserve spirometry	Other causes of graft dysfunction must be excluded
  Established bronchiolitis obliterans syndrome	Could stabilize function in a responsive inflammatory phenotype	Limited value when fibrosis is advanced
  Suspected respiratory infection	Provides antimicrobial activity against selected organisms	Empirical use may mask resistant or atypical infection
  Long-term preventive therapy	May reduce inflammatory airway injury in carefully selected recipients	Resistance, drug interactions, and cardiac effects require monitoring
  Hematopoietic stem-cell transplant complications	May be considered within specialist-directed protocols	Evidence is less consistent and disease mechanisms vary

  Selecting patients and timing

  The strongest clinical rationale generally exists when spirometry shows a new, persistent decline and evaluation suggests an inflammatory airway process. In lung-transplant care, specialists may consider azithromycin after assessing infection, rejection, reflux, aspiration, and adherence. Some centers use a trial of therapy with repeat pulmonary-function testing to determine whether a meaningful response occurs.

  Treatment should be individualized rather than automatically prescribed for every patient with obstructive physiology. A stable patient with advanced fixed obstruction may gain little, while someone with early inflammatory changes may have a greater opportunity for preserved function. Decisions should also account for microbiology results, concurrent immunosuppression, renal and hepatic status, and the patient’s risk of adverse effects.

  Safety and monitoring

  Long-term macrolide treatment can prolong the QT interval and increase the risk of serious ventricular arrhythmias, particularly in patients with cardiac disease, electrolyte abnormalities, bradycardia, or other QT-prolonging medicines. A baseline medication review and, when appropriate, electrocardiography can reduce avoidable risk. Liver injury, gastrointestinal symptoms, hearing changes, and vestibular effects are additional considerations.

  Drug interactions are especially important in transplant medicine. Clarithromycin can substantially affect cytochrome P450 metabolism and raise concentrations of calcineurin inhibitors such as tacrolimus and cyclosporine. Azithromycin generally has fewer interactions, but it is not interaction-free. Periodic review of liver tests, hearing symptoms, electrocardiographic risk, immunosuppressant levels, and respiratory cultures is prudent.

  Macrolide resistance is another major concern. Prolonged exposure can select resistant bacteria and may complicate future treatment of respiratory infections. Before extended therapy, clinicians should consider sputum or bronchoalveolar-lavage cultures when clinically indicated, including assessment for nontuberculous mycobacteria. Macrolide monotherapy should be avoided when it could promote resistance in an undiagnosed mycobacterial infection.

  Practical recommendations for clinical teams

  A safe approach combines specialist judgment with objective follow-up. The following principles can support decision-making:

  • Confirm a sustained change in lung function and investigate infection, rejection, reflux, aspiration, and structural airway disease.
  • Define the treatment goal, such as stabilizing spirometry, reducing inflammatory activity, or preventing post-transplant decline.
  • Review the electrocardiogram, medication list, liver function, hearing history, and risk of antimicrobial resistance before prescribing.
  • Use repeat spirometry and symptom assessment to determine whether treatment is producing a meaningful response.
  • Reassess the need for continued therapy rather than allowing an indefinite prescription without a documented benefit.

  Macrolides should sit within a multimodal plan that may include optimization of immunosuppression, infection prevention, reflux management, pulmonary rehabilitation, vaccination, airway-clearance measures, and evaluation for advanced therapies. In progressive disease, referral to a transplant or specialized airway-disorders team should not be delayed while waiting for a medication response.

  The clinical value of macrolides is greatest when their anti-inflammatory potential is matched to the right phenotype and balanced against long-term toxicity. Clinicians and congress participants can help refine this role by sharing outcomes, standardizing response measures, and supporting better research in distinct bronchiolitis obliterans populations. Apply these principles in multidisciplinary respiratory practice, and review every prolonged macrolide course against measurable benefit and patient safety.

  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)