Small-airways disease and bronchiolitis obliterans

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Small-airways disease is a physiological and radiological description, not one diagnosis. The bronchioles may be inflamed, plugged, compressed or fibrosed in asthma, COPD, infection, hypersensitivity, aspiration and occupational or autoimmune disease. Constrictive bronchiolitis specifically narrows the airway wall concentrically, causing expiratory flow limitation and patchy gas trapping. Because small airways contribute little resistance until disease is widespread, symptoms and expiratory CT abnormalities may precede a striking FEV1 reduction.

Clinical context is decisive. In a lung transplant recipient, serial decline from the individual's best post-transplant FEV1 can signal chronic lung allograft dysfunction but infection, acute rejection, anastomotic disease and other causes must be excluded by the transplant team. After allogeneic stem-cell transplantation, bronchiolitis obliterans may be a pulmonary manifestation of chronic graft-versus-host disease. Outside transplantation, a careful exposure, autoimmune, infection and medicine history may reveal an inhalational or systemic cause.

The older term 'bronchiolitis obliterans organising pneumonia' creates avoidable confusion. Cryptogenic organising pneumonia is an alveolar and distal-airspace organising process that often appears as patchy consolidation and behaves differently from constrictive bronchiolitis. Do not call constrictive bronchiolitis BOOP, and do not apply an organising-pneumonia corticosteroid expectation to fixed bronchiolar fibrosis.

Key points

Small airways are bronchioles below the resolution of routine imaging; substantial disease can exist before conventional spirometry becomes clearly abnormal.
Bronchiolitis obliterans, or constrictive bronchiolitis, is fibrotic narrowing and obliteration of small airways that usually produces progressive, relatively fixed airflow obstruction.
Important contexts include lung transplantation, allogeneic haematopoietic stem-cell transplantation, connective-tissue disease, severe inhalational injury, selected infections and drug or immune-mediated injury.
After lung transplantation, an obstructive chronic allograft dysfunction phenotype is termed bronchiolitis obliterans syndrome when defined clinically without requiring surgical histology.
Symptoms are often insidious exertional breathlessness and dry cough; examination may be normal or reveal wheeze, crackles or inspiratory squeaks.
Expiratory HRCT may show mosaic attenuation and air trapping, but these findings are not specific and require inspiratory comparison, adequate expiration and clinical context.
Small-airway indices from spirometry can be suggestive but are variable and should not independently diagnose bronchiolitis obliterans.
Exclude reversible asthma, COPD, bronchiectasis, infection and central airway disease; a poor bronchodilator response does not by itself establish bronchiolar fibrosis.
Treatment is cause-specific and evidence is limited. Transplant immunosuppression changes belong to the transplant centre; there is no universal community corticosteroid regimen.
Selected post-lung-transplant patients may receive long-term azithromycin, but ECG, liver, hearing, drug-interaction, NTM and antimicrobial-resistance safeguards are essential.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Transplant-related injury

Chronic rejection after lung transplantation and immune injury after stem-cell transplantation can scar and obliterate small bronchioles.

Toxic inhalation

Smoke, nitrogen oxides, flavouring chemicals and other occupational or accidental exposures directly injure bronchiolar epithelium, with the final risk shaped by exposure and individual susceptibility.

Post-infective bronchiolitis

Severe viral or bacterial lower-respiratory infection can leave fixed small-airway narrowing, especially after childhood disease, and its contribution is interpreted alongside the other recognised causes.

Autoimmune and inflammatory disease

Rheumatoid arthritis, inflammatory bowel disease and selected medicines can cause constrictive bronchiolitis through immune-mediated injury, especially when other respiratory vulnerabilities are present.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Bronchiolar epithelial injury
An immune, toxic or infectious insult damages non-cartilaginous conducting airways smaller than conventional spirometry can localise.
2
Inflammation and repair
Submucosal inflammation activates fibroblasts and extracellular-matrix deposition around the bronchiolar lumen, which helps produce the characteristic physiological impairment.
3
Concentric narrowing
Fibrous scarring constricts or obliterates small airways, producing patchy fixed expiratory obstruction, which helps produce the characteristic physiological impairment.
4
Regional air trapping
Affected lung empties poorly during expiration, causing mosaic attenuation, hyperinflation and ventilation-perfusion mismatch, contributing to the resulting loss of respiratory reserve.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Post-lung-transplant BOS patternRed flag

A sustained fall from the best post-transplant expiratory function with new obstruction may represent BOS, but transplant specialists must exclude infection, acute rejection, airway stenosis and restrictive allograft dysfunction.

Post-HSCT bronchiolitis obliteransRed flag

Progressive dry cough, wheeze or exertional dyspnoea with fixed obstruction in a person with allogeneic transplantation and chronic graft-versus-host features should prompt urgent haematology-respiratory review.

Exposure-related constrictive bronchiolitis

Persistent breathlessness and airflow limitation after a well-documented major inhalational event or repeated occupational aerosol exposure requires detailed agent chronology, occupational assessment and removal from further harmful exposure.

Autoimmune-associated bronchiolitis

Rheumatoid arthritis, Sjögren syndrome or another connective-tissue disease may accompany bronchiolar obstruction, sometimes with bronchiectasis or interstitial disease that changes imaging and treatment decisions.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Serial quality-assured spirometry with bronchodilator testingFirst step
Why
Confirm obstruction, trajectory and degree of reversibility.
Interpretation and limitations
Compare with personal baseline, especially after transplantation. Fixed obstruction supports but does not prove constrictive bronchiolitis; a rapid fall demands exclusion of infection and transplant complications rather than routine outpatient observation.
02
Lung volumes and gas transfer
Why
Characterise gas trapping and competing parenchymal or vascular disease.
Interpretation and limitations
Raised residual volume can support air trapping, while reduced gas transfer may reflect emphysema, vascular or interstitial disease. Normal conventional measures do not exclude early patchy small-airway disease.
03
Paired inspiratory and expiratory high-resolution CT
Why
Demonstrate regional air trapping and identify structural alternatives.
Interpretation and limitations
Mosaic attenuation that accentuates on expiration supports small-airway obstruction; inspect vessel calibre, bronchiectasis, emphysema, infiltrates and technical expiratory effort because vascular disease and poor expiration can mimic the pattern.
04
Sputum culture including targeted mycobacterial studies
Why
Exclude infection before immunosuppression changes or chronic macrolide use.
Interpretation and limitations
Request routine, fungal or mycobacterial testing according to host and imaging. NTM disease must be excluded before macrolide monotherapy because resistance can compromise future definitive treatment.
05
Transplant-centre graft assessment
Why
Distinguish chronic dysfunction from rejection, infection and airway complications.
Interpretation and limitations
The centre may use serial physiology, CT, bronchoscopy, lavage, biopsy and donor-specific or other tests. No single community test establishes BOS or justifies altering immunosuppression.
06
Exposure, autoimmune and medicine evaluation
Why
Identify a cause outside the transplant setting.
Interpretation and limitations
Timeline fumes, flavouring or industrial aerosols, infections and drugs; examine for connective-tissue disease and order targeted serology only when clinically supported. Causation should not rest on an isolated antibody.
07
Multidisciplinary radiology and pathology review
Why
Resolve discordant cases and decide whether tissue is justified.
Interpretation and limitations
Surgical biopsy can miss patchy disease and carries risk; reserve it for cases where expert clinicoradiological review cannot answer a management-changing question through safer means.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Asthma

Variable symptoms and objective reversibility favour asthma, whereas constrictive bronchiolitis typically causes persistent obstruction and expiratory air trapping.

COPD

Smoking or occupational exposure with emphysema and diffuse obstruction suggests COPD, though toxic bronchiolitis may overlap.

Organising pneumonia

Organising pneumonia fills distal air spaces with granulation tissue and commonly causes consolidation rather than primary fixed bronchiolar obliteration.

Hypersensitivity pneumonitis

Antigen-linked centrilobular inflammation, ground-glass change and systemic exposure pattern distinguish HP, although it also affects small airways.

Tracheobronchomalacia

Dynamic central-airway collapse produces expiratory symptoms and flow limitation visible on dynamic CT or bronchoscopy rather than peripheral mosaic disease alone.

Additional chapter-specific clues

Acute mimic or complicationRed flag

Fever, purulent sputum, pleuritic pain, rapid hypoxaemia or abrupt functional loss suggests infection, embolism, pneumothorax or acute transplant complication rather than slow bronchiolar fibrosis alone.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01SuspectConfirm a bronchiolar patternFirst stepProgressive breathlessness or cough accompanies unexplained fixed obstruction or expiratory air trapping.

1Construct a timeline of transplantation, infection, inhalational exposure, autoimmune disease and medicines, noting onset relative to each potential insult.
2Repeat quality-assured spirometry with bronchodilator and obtain volumes, gas transfer and paired inspiratory-expiratory CT where clinically justified.
3Exclude asthma, COPD, bronchiectasis, central airway obstruction, infection, vascular disease and organising pneumonia using the pattern rather than one small-airway index.
4Refer for specialist multidisciplinary review and reserve invasive tissue sampling for a specific question likely to alter treatment.

02TransplantEscalate declining allograft functionEscalationA lung or stem-cell transplant recipient develops new symptoms or sustained FEV1 decline.

1Contact the relevant transplant or haematology centre promptly, providing serial spirometry, oxygenation, symptoms, infection exposure and current immunosuppression.
2Assess urgently for infection and acute physiological danger while the centre coordinates CT, bronchoscopy, rejection evaluation or graft-versus-host assessment.
3Do not independently increase, reduce or stop immunosuppression; implement only the centre's cause-specific plan with prophylaxis and interaction review.
4Follow serial physiology and functional trajectory, recording the individual's best baseline and the agreed threshold for re-contact or admission.

03SupportPreserve function and prevent injuryConstrictive bronchiolitis is probable or confirmed after specialist assessment.

1Remove ongoing occupational or inhalational exposure and provide tobacco-dependence care, vaccination and infection-prevention advice appropriate to immune state.
2Trial inhaled bronchodilator only with a defined symptom or function endpoint; offer pulmonary rehabilitation and assess oxygen needs using national criteria.
3Treat the underlying transplant, autoimmune or inflammatory cause through its specialist team, acknowledging that established fibrotic obstruction may not reverse.
4Discuss prognosis, work impact, advance planning and transplant referral where appropriate, while continuing active symptom and exacerbation care.

04MacrolideUse azithromycin with safeguardsA transplant specialist recommends long-term azithromycin for a defined BOS indication.

1Confirm the indication and outcome measure, then review cardiac history, QT-prolonging medicines, hearing or balance problems, liver function and gastrointestinal risk.
2Obtain ECG and appropriate sputum mycobacterial assessment before monotherapy; current or suspected NTM disease requires specialist microbiology management instead.
3Use the centre-approved regimen and counsel on adverse effects, interactions and antimicrobial resistance, documenting the intended trial or prevention duration.
4Repeat ECG and liver tests after initiation and at guideline intervals, stopping or revising treatment for QT prolongation, toxicity or absent agreed benefit.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Provide immunomodulatory macrolide treatment in selected bronchiolitis obliterans syndrome after lung transplantation.

Azithromycin for selected post-lung-transplant BOS

A BTS-supported specialist regimen is 250 mg orally three times weekly for prevention, or 250 mg on alternate days for a defined treatment trial.

This is specialist and often off-label care, not a universal regimen for all constrictive bronchiolitis. Check ECG, QT interactions, liver tests, hearing, gastrointestinal effects, sputum and NTM risk; counsel about antimicrobial resistance.

Relieve a reversible bronchomotor component or improve symptoms despite predominantly fixed bronchiolar obstruction.

Inhaled long-acting bronchodilator trial

Use one locally selected licensed inhaler at its device-specific adult maintenance dose after observing technique and documenting a baseline endpoint.

Response is not guaranteed and non-response should prevent indefinite device accumulation. Check for beta2-agonist cardiac effects, antimuscarinic urinary or ocular effects and duplicate ingredients; it does not treat fibrotic obliteration.

Treat rejection or graft-versus-host mechanisms when the specialist assessment supports immune-mediated active disease.

Specialist transplant immunosuppression adjustment

Use only the transplant centre's individualised regimen, drug levels and taper schedule; there is no safe universal community dose.

Never change treatment from spirometry alone. Infection, nephrotoxicity, cytopenia, metabolic toxicity, malignancy and major interactions require centre-led monitoring; established fibrosis may not improve despite greater immunosuppression.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Progressive fixed obstruction

Ongoing scarring reduces expiratory flow and exercise capacity and may become irreversible before diagnosis, creating an additional need for recognition and targeted treatment.

Respiratory failure

Extensive air trapping and ventilation-perfusion mismatch can cause chronic hypoxaemia and later ventilatory failure, particularly when baseline cardiopulmonary reserve is limited.

Recurrent infection

Poorly ventilated obstructed regions retain mucus and promote repeated bacterial infection and further inflammation, with severity determined by its extent and the patient's underlying reserve.

Transplant graft failure

In lung recipients, bronchiolitis obliterans syndrome may represent progressive chronic allograft dysfunction and threaten graft survival.

Treatment toxicity

Evidence-limited immune treatment can add infection and systemic harm without reliably reversing established fibrotic narrowing, creating an additional need for recognition and targeted treatment.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Trend quality-assured FEV1 against the individual's stable baseline, particularly after transplantation, and escalate a sustained or rapid decline through the centre-specific plan.
Record dyspnoea, cough, oxygen saturation, exercise capacity, exacerbations, infections, admissions and work or daily-function loss alongside physiology.
For immunosuppressed patients monitor infection symptoms, blood counts, renal and liver function, drug levels and interactions according to the transplant or haematology protocol.
For long-term azithromycin repeat liver tests and ECG after initiation and periodically under BTS guidance, while asking about hearing, balance, gastrointestinal effects and resistance.
Repeat CT only when a clinical or physiological change will alter management; serial radiation cannot replace spirometry and structured functional follow-up.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Expiration reveals hidden disease

Affected lobules remain relatively lucent on expiration while normal lung increases attenuation. Paired images are therefore more informative than inspiratory CT alone for regional gas trapping.

Mosaic has two mechanisms

Patchy attenuation may reflect airway gas trapping or perfusion heterogeneity. Expiratory change, vessel calibre and the broader physiological pattern help separate them.

BO is not BOOP

Constrictive bronchiolitis narrows bronchioles and causes fixed obstruction; organising pneumonia fills distal airspaces and usually produces infiltrates. The terminology predicts different investigations and treatment expectations.

The baseline is personal

After lung transplantation, comparison with the patient's best stable post-transplant function is more meaningful than a population predicted value when detecting allograft decline.

Biopsy can miss the target

Constrictive bronchiolitis is patchy, so even surgical tissue may be non-diagnostic. Expert clinicoradiological and physiological synthesis can be more useful than pursuing histology at any cost.

11Common pitfallsFrequent interpretation and management errors.

01
Calling every low mid-expiratory flow measurement small-airways disease despite otherwise normal, high-quality physiology.
02
Using inspiratory CT alone and missing or overcalling expiratory air trapping.
03
Diagnosing BOS from falling FEV1 without urgently excluding infection, acute rejection and airway complications.
04
Confusing constrictive bronchiolitis with cryptogenic organising pneumonia because of the obsolete term BOOP.
05
Starting long-term azithromycin without ECG, interaction, liver, hearing, sputum and NTM safeguards.
06
Escalating immunosuppression outside the transplant team when established fibrotic disease or infection may explain decline.