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)

• Pulmonary alveolar proteinosis across the clinical spectrum

  Pulmonary alveolar proteinosis (PAP) is a rare lung disease in which surfactant-rich material accumulates within alveoli, causing cough, exertional dyspnoea, fatigue and sometimes severe hypoxaemia. It ranges from incidental imaging abnormalities to progressive respiratory failure and can resemble pneumonia, pulmonary oedema or fibrotic interstitial lung disease.

  In most adults, PAP is autoimmune: antibodies neutralise granulocyte-macrophage colony-stimulating factor (GM-CSF), impairing alveolar macrophage function and surfactant clearance. Genetic CSF2RA deficiency and secondary forms linked to haematological malignancy, immunodeficiency or inhalational injury broaden the differential and affect treatment.

  Severity does not track neatly with the amount of material seen on CT. Some people remain stable for years, while others develop exercise limitation, resting hypoxaemia and recurrent infection. Fever requires assessment for secondary infection.

  Diagnosis combines exposure and medical history, pulmonary function testing, high-resolution CT and selected laboratory or bronchoscopic findings. Care should be matched to physiology and subtype, with Australian access pathways considered alongside the clinical evidence.

  Surfactant biology and the limits of the label

  Alveolar proteinosis describes a pathological pattern rather than one disease. PAS-positive surfactant material in alveoli or lavage fluid supports the pattern but does not establish an autoimmune cause. Infection, malignancy, oedema and drug reactions must also be considered.

  Congenital disease usually involves biallelic CSF2RA variants, preventing normal GM-CSF receptor signalling. Secondary disease may follow haematological disorders, immune deficiency or certain inhalational exposures. These mechanisms differ from adult autoimmune disease and should shape investigation.

  Adult autoimmune PAP often includes CD4 lymphopenia and a tendency to respiratory infection. CSF-2RA autoantibody testing can support the diagnosis when available, although access and interpretation vary. A negative antibody test does not exclude every form.

  Recognising the variable phenotype

  The common presentation is gradually increasing breathlessness on exertion, persistent cough, fatigue and reduced exercise tolerance. Resting hypoxaemia may develop later. Fever, purulent sputum or a new infiltrate should trigger evaluation for infection rather than presumed disease activity.

  Functional assessment often provides more useful severity information than CT burden. SpO2, oxygen needs, six-minute walk distance, FVC and diffusing capacity establish a baseline and detect decline. Sudden deterioration should also prompt review for infection, embolism, cardiac disease or another lung condition.

  Australian environmental exposures require careful interpretation. Bushfire smoke affecting Canberra, Sydney, Melbourne and Perth can worsen wheeze and exercise tolerance, but does not establish a secondary cause of PAP. Occupational dusts in mining, construction and manufacturing deserve documentation because they can cause other lung diseases with a similar appearance.

  Practical recommendations for suspected disease

  Begin with a careful exposure history, medication review, full examination and physiological staging. HRCT may show geographic ground-glass opacity with interlobular septal thickening, often called a crazy-paving pattern, but this is not specific. Compare previous imaging and consider the distribution of opacity.

  Bronchoscopy with bronchoalveolar lavage (BAL) can provide cytology, microbiology and evidence of PAS-positive material. Milky lavage fluid is characteristic yet not pathognomonic. BAL is not mandatory when the diagnosis is secure, and significant hypoxaemia calls for planning with oxygen support and an experienced procedural team.

  • Record resting SpO2, exertional desaturation, oxygen prescription, FVC, DLCO and six-minute walk distance at baseline and follow-up.
  • Compare current HRCT with earlier scans and obtain a pattern review before labelling the disease active.
  • Send BAL for cell counts, cytology, microbiology and appropriate staining, with results coordinated through the respiratory team.
  • Investigate the subtype with blood count, HIV testing, relevant autoimmune or malignancy studies, and CSF-2RA antibody or genetic testing when indicated.

  These findings should be reconciled in a multidisciplinary meeting involving respiratory medicine, radiology, pathology and, where needed, infectious disease or haematology. Unstable hypoxaemia requires immediate care for infection or another emergency, not a delayed diagnostic pathway.

  Matching treatment to severity and subtype

  Stable patients with mild symptoms and preserved oxygenation may be observed. Smoking and vaping cessation, exercise within tolerance, vaccination and rapid treatment of respiratory infection reduce risk. Worsening physiology should trigger reassessment rather than indefinite surveillance.

  Whole-lung lavage is established care for clinically significant hypoxaemia or progressive disease. It requires large-volume saline instillation and drainage under specialist anaesthesia and intensive-care support. Complications include infection, bronchospasm, pneumothorax, cardiovascular instability and transient respiratory deterioration.

  Inhaled GM-CSF can reduce disease activity and the need for lavage in selected autoimmune disease. Response varies, while genetic or secondary disease may require a different strategy. Australian access is uneven, so specialists may need to consider hospital formulary supply, a clinical trial or the Special Access Scheme when the patient meets its eligibility criteria.

  Secondary disease requires treatment of the underlying malignancy, immune deficiency or exposure. Immunosuppression is not routine for autoimmune PAP. Lung transplantation is rarely required, usually only after irreversible advanced fibrosis and failure of available disease-directed therapy.

  Australian pathways, equity and long-term care

  Definitive assessment and lavage are concentrated in tertiary respiratory services in Sydney, Melbourne, Brisbane, Adelaide and Perth. People in regional, rural and remote areas may face long travel, repeated admissions and limited access to procedural follow-up. Telehealth can coordinate review, but it cannot replace bronchoscopy or lavage.

  Clinical care operates within Commonwealth medicine regulation and state and territory health law. The TGA assesses therapeutic goods, while the PBS subsidises eligible listed medicines; both are separate from Medicare rebates for consultations and diagnostic services. Rare-disease products are not automatically funded, and access through a hospital formulary, clinical trial or Special Access Scheme requires specialist documentation.

  Equitable follow-up should address transport, remote living, smoking, work exposures and vaccination. Aboriginal and Torres Strait Islander patients need timely, culturally safe respiratory assessment, with liaison and transfer arranged where distance would otherwise delay BAL or treatment review.

  Long-term plans should identify the responsible respiratory service, monitoring schedule and threshold for urgent reassessment. For unexplained hypoxaemia with compatible CT findings, the next step is referral to a respiratory physician experienced in PAP, with imaging, oxygen readings and blood results sent before review.

  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)