Pulmonary Alveolar Proteinosis

Slide 1 · Pulmonary Alveolar Proteinosis

Surfactant clearance failure • Mechanisms • Morphology • Clinical correlation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Explain normal surfactant clearance and the function of GM-CSF signalling.

Distinguish autoimmune, secondary and hereditary forms of PAP.

Recognise characteristic alveolar morphology and clinical consequences.

Integrate a contemporary diagnostic and treatment approach.

Slide 3 · What the term PAP describes

A rare pulmonary syndrome of abnormal surfactant accumulation.

Material collects in alveolar and bronchiolar airspaces.

Deficient alveolar macrophage clearance is the central mechanism.

Distinct aetiologies converge on similar microscopic findings.

Alveolar spaces

Retained surfactant

Schematic — not a clinical or histologic specimen

Slide 4 · The disease is primarily an airspace-filling process

The hallmark material lies inside alveoli, not predominantly within septa.

Alveolar walls may remain relatively intact.

Extensive material can produce confluent areas of consolidation.

Alveolar spaces

Retained surfactant

Schematic — not a clinical or histologic specimen

Slide 5 · Surfactant clearance: The homeostatic requirement

Surfactant normally resides along the alveolar air–liquid interface.

Continuous turnover requires removal and catabolism of material.

Alveolar macrophages are essential to surfactant catabolism.

Surfactant in alveolus

Alveolar macrophage

Catabolism / clearance

Slide 6 · GM-CSF supports alveolar macrophage maturation

Granulocyte–macrophage colony-stimulating factor (GM-CSF) is a regulatory cytokine.

GM-CSF signalling permits terminal alveolar macrophage differentiation.

This specialised macrophage state is required for efficient surfactant disposal.

GM-CSF signal

Terminal macrophage maturation

Surfactant catabolism

Slide 7 · The central failure in PAP

Deficient GM-CSF signalling compromises macrophage function.

Inefficient degradation allows surfactant to accumulate over time.

Airspace occupancy increases while inflammation can remain minimal.

GM-CSF signalling deficit

Impaired macrophage clearance

Surfactant accumulation

Alveolar filling

Slide 8 · Why accumulation does not require hypersecretion

PAP is best understood as impaired clearance of alveolar surfactant.

Production–clearance imbalance can occur without primary overproduction.

This distinction explains why therapy may target material removal or macrophage function.

Normal balance

Surfactant turnover

Functional macrophage removal

PAP

Clearance insufficient

Airspace material accumulates

Slide 9 · Three groups in the Robbins classification

Autoimmune PAP: Neutralising anti–GM-CSF autoantibodies.

Secondary PAP: Acquired conditions associated with impaired macrophage function.

Congenital/hereditary PAP: Extremely rare signalling defects.

AUTOIMMUNE

Neutralising antibodies

GM-CSF signal blocked

SECONDARY

Associated disorder

Macrophage function impaired

HEREDITARY

Inherited pathway defect

GM-CSF pathway disrupted

Slide 10 · Autoimmune PAP is the dominant form

Autoimmune PAP at 90% of PAP cases.

The typical onset is during adulthood.

No familial predisposition is expected in the usual autoimmune form.

Slide 11 · Neutralising antibodies interrupt a cytokine signal

Autoantibodies bind GM-CSF and neutralise its activity.

The resulting signalling deficiency affects alveolar macrophages.

Loss of terminal differentiation reduces surfactant clearance.

Anti–GM-CSF antibodies

Neutralised GM-CSF

Immature/dysfunctional macrophage

Surfactant retention

Slide 12 · Evidence supporting GM-CSF dependence

GM-CSF knockout in mice produces PAP-like disease.

GM-CSF replacement reverses the phenotype in this experimental model.

Mechanistic animal findings support the role of signalling loss in PAP.

Slide 13 · Secondary PAP has heterogeneous associations

Secondary cases are uncommon relative to autoimmune PAP.

A related systemic or inhalational disorder is usually identifiable.

The mechanism of macrophage impairment can differ across disorders.

Slide 14 · Hematopoietic disease and malignancy

Hematopoietic disorders can be associated with secondary PAP.

Malignancies are included among described associations.

The diagnostic search should consider the broader clinical context.

Slide 15 · Immunodeficiency as a PAP context

Immunodeficiency disorders can coexist with PAP.

Dysfunctional macrophage maturation or activity is proposed.

Infections can also complicate the PAP course, requiring careful attribution.

Slide 16 · Inhalational diseases associated with PAP

Acute silicosis and other inhalational syndromes are associated with secondary PAP.

An exposure history can reveal an otherwise hidden cause.

The precise downstream defect may not be established.

Slide 17 · Lysinuric protein intolerance is another association

This inherited amino-acid metabolic disorder among secondary-PAP associations.

The clinical association broadens the differential beyond autoimmune disease.

Its presence does not imply autoantibody-mediated GM-CSF neutralisation.

Slide 18 · Mechanism in secondary PAP: A cautious model

GM-CSF-dependent differentiation or downstream macrophage function may be affected.

The precise link is not known for all associated disorders.

Robbins characterises some of these proposed connections as speculative.

Associated disorder / exposure

Possible maturation / function defect

Reduced surfactant clearance

PAP morphology

Slide 19 · Hereditary GM-CSF signalling deficiency

An extremely rare form presents in early life.

Loss-of-function variants may affect GM-CSF or receptor genes.

The pathway failure produces abnormal surfactant clearance.

Inherited signalling defect

Insufficient GM-CSF receptor pathway

Macrophage dysfunction

Alveolar material

Slide 20 · The three groups converge on one phenotype

Different proximal causes share reduced effective alveolar macrophage activity.

Histologic deposits can look essentially the same.

Aetiologic classification therefore requires evidence beyond morphology.

AUTOIMMUNE

Neutralising antibodies

GM-CSF signal blocked

SECONDARY

Associated disorder

Macrophage function impaired

HEREDITARY

Inherited pathway defect

GM-CSF pathway disrupted

Slide 21 · Modern nomenclature distinguishes additional entities

The 2024 ERS scheme separates hereditary GM-CSF-receptor PAP from congenital surfactant dysfunction.

The supplied Robbins section uses a broader “congenital” label for rare signalling-associated PAP.

These should not be treated as synonymous molecular diagnoses.

Hereditary PAP

GM-CSF signalling defect

CSF2RA / CSF2RB in ERS algorithm

Congenital surfactant disorders

Surfactant protein/trafficking defect

Separate molecular work-up

Slide 22 · Gross lung changes

Deposits can cause focal-to-confluent lung consolidation.

The lungs may become markedly enlarged and heavy.

The change reflects accumulation of material in many airspaces.

Slide 23 · Low-power architecture: Packed alveoli

Widespread alveolar lumina contain extracellular material.

Accumulation may involve contiguous fields of lung.

The architectural framework can remain preserved despite filling.

Alveolar spaces

Retained surfactant

Schematic — not a clinical or histologic specimen

Slide 24 · High-power morphology: Eosinophilic precipitate

Intra-alveolar deposits are pink and relatively homogeneous on H&E.

The material may appear dense, amorphous or granular.

Surfactant proteins and lipids account for its composition.

Alveolar spaces

Retained surfactant

Schematic — not a clinical or histologic specimen

Slide 25 · Periodic acid–Schiff positivity

The alveolar precipitate is periodic acid–Schiff (PAS) positive.

This is a useful tissue clue for surfactant-rich material.

PAS positivity is interpreted together with the location and morphology.

H&E morphology

Pink homogeneous material

In alveolar airspaces

PAS reaction

Positive precipitate

Supports PAP pattern

Slide 26 · Cholesterol clefts may be present

Cholesterol clefts within the precipitated material.

These reflect the lipid-rich composition of retained surfactant.

They are supportive but not by themselves a specific PAP test.

Alveolar spaces

Retained surfactant

Schematic — not a clinical or histologic specimen

Slide 27 · Surfactant protein immunostains

Surfactant proteins are demonstrable within intra-alveolar deposits by immunohistochemistry.

Their presence supports the biochemical identity of the precipitate.

A positive stain must be read alongside the tissue pattern.

Slide 28 · Minimal inflammatory response

The classic precipitate causes relatively little inflammation.

Septa may appear largely normal despite conspicuous luminal filling.

Marked inflammation should prompt assessment of infection or another process.

Alveolar spaces

Abundant precipitate

Confluent filling

Interalveolar septa

Often largely preserved

Minimal inflammation

Slide 29 · Ultrastructure in PAP

Type II pneumocyte surfactant lamellae are usually normal in classic PAP.

The primary problem is extracellular accumulation due to reduced catabolism.

This differs from intrinsic surfactant organelle abnormalities.

Slide 30 · PAP versus surfactant dysfunction

PAP: Impaired macrophage-mediated surfactant clearance is central.

Surfactant dysfunction: Variants impair surfactant trafficking, processing or secretion.

The adjacent Robbins topic describes abnormal lamellar bodies in some genetic disorders.

PAP

Macrophage clearance defect

Usually normal type II lamellae

Surfactant dysfunction

Epithelial surfactant defect

Lamellar body abnormalities may occur

Slide 31 · What the histology establishes

The biopsy pattern supports a PAP syndrome.

Microscopy alone generally cannot distinguish autoimmune from secondary PAP.

Etiologic classification requires serology, genetics and clinical context.

Airspace PAS-positive material

PAP histologic pattern

Serologic / clinical / genetic work-up

Slide 32 · Anatomic differential: Where is the lesion?

Airspace-filling diseases primarily occupy alveolar lumina.

Interstitial lung diseases may primarily thicken or destroy septa.

This distinction is often more useful than deposit colour alone.

PAP pattern

Intra-alveolar precipitate

Septa relatively preserved

Fibrosing interstitial process

Thickened / scarred septa

Architectural distortion may dominate

Slide 33 · PAP versus pulmonary oedema

Both conditions can produce abundant intra-alveolar material.

PAP has characteristic surfactant-rich, PAS-positive precipitate.

The final diagnosis requires integration of imaging, clinical context and laboratory findings.

PAP

Surfactant-rich precipitate

GM-CSF context often decisive

Pulmonary oedema

Protein-poor or proteinaceous oedema fluid

Haemodynamic context relevant

Slide 34 · PAP versus Pneumocystis pneumonia

Both may produce intra-alveolar eosinophilic material.

Infection requires organism-directed assessment where clinically suspected.

PAP itself may coexist with secondary opportunistic infection.

PAP

Surfactant accumulation

Evaluate GM-CSF pathway

Pneumocystis pneumonia

Infectious alveolar material

Look for organisms with appropriate stains

Slide 35 · Radiologic presentation

Bilateral pulmonary opacification is typical.

The distribution may be patchy and asymmetric.

The imaging pattern is not exclusive to PAP.

Slide 36 · CT finding: The crazy-paving pattern

Ground-glass opacity accompanied by septal or intralobular lines may create “crazy paving”.

This pattern can support suspicion of PAP.

Crazy paving is nonspecific and must be interpreted in context.

Ground-glass opacity + intersecting lines

Slide 37 · A pattern is not a molecular diagnosis

Imaging suggests airspace disease but does not define its cause.

Bronchoalveolar lavage or histology helps establish the PAP syndrome.

Anti–GM-CSF testing and selected genetic studies refine aetiology.

Compatible CT pattern

PAP syndrome assessment

GM-CSF antibody / genetic aetiology

Slide 38 · Adult presentation: Cough

Cough may be a presenting symptom in adult PAP.

Patients can have substantial expectoration.

The sputum may contain conspicuous gelatinous fragments.

Slide 39 · Why sputum can be gelatinous

Retained intra-alveolar material contains surfactant proteins and lipids.

Airway transport may move this accumulated material into expectorated sputum.

The macroscopic appearance reflects the composition of the deposits.

Surfactant-rich airspace material

Movement into airway secretions

Gelatinous sputum

Slide 40 · Dyspnoea and impaired gas exchange

Airspace filling reduces effective ventilated alveolar volume.

Progressive disease can cause dyspnoea and hypoxaemia.

Severe cases may progress to cyanosis or respiratory insufficiency.

Alveolar filling

Reduced effective gas-exchange area

Dyspnoea / hypoxaemia

Slide 41 · Secondary pulmonary infection

Intermittent febrile illness from pulmonary infections.

Impaired alveolar macrophage function plausibly weakens host defence.

Fever should not automatically be attributed to sterile surfactant deposits.

Slide 42 · Clinical course varies

Some patients have symptoms that persist for years.

Progression to respiratory insufficiency is possible.

Others have a benign course with eventual resolution of lesions.

Progressive course

Worsening dyspnoea

Hypoxaemia / respiratory failure

Improving course

Lesions may resolve

Severity is not uniform

Slide 43 · Diagnosis begins with clinicoradiologic suspicion

Consider PAP with compatible respiratory symptoms and patchy bilateral abnormalities.

Assess systemic disease, immune status and inhalational exposures.

Avoid treating the radiologic pattern as pathognomonic.

Slide 44 · Bronchoalveolar lavage contributes to diagnosis

ERS guidance includes BAL in the work-up of suspected PAP.

Lavage may yield opaque, milky material containing surfactant-rich deposits.

Cytology and special stains should be interpreted in context.

Slide 45 · Quantitative GM-CSF autoantibody testing

ERS recommends anti–GM-CSF antibody testing for suspected or confirmed PAP.

Quantitative results from an experienced laboratory help identify autoimmune PAP.

The laboratory reference threshold and assay method must be considered.

Slide 46 · An updated etiologic decision tree

Positive anti–GM-CSF testing supports autoimmune PAP.

Negative testing plus a recognised underlying disorder raises secondary PAP.

Unexplained cases may require GM-CSF signalling assessment and genetic testing.

Confirmed PAP syndrome

Quantitative anti–GM-CSF test

Evaluate cause if negative

Genetic / functional assessment

Slide 47 · Why most patients do not need a lung biopsy

BAL, serology and selected genetic tests often establish the necessary diagnosis.

ERS generally advises against routine lung biopsy.

Biopsy can be considered for unresolved cases in expert consultation.

Slide 48 · Interpretation of a pathology report

Describe alveolar luminal PAS-positive, proteinaceous material.

Comment on alveolar septa, inflammation and any suspected infection.

Use “consistent with PAP” without assigning an autoimmune cause from histology alone.

Slide 49 · Therapy addresses two different problems

Whole-lung lavage physically removes accumulated alveolar material.

GM-CSF augmentation targets deficient macrophage signalling in autoimmune PAP.

Management of an associated disorder may be necessary in secondary PAP.

Remove deposits

Whole-lung lavage

Treat the airspace burden

Restore function

GM-CSF replacement

Address macrophage dysfunction

Slide 50 · Whole-lung lavage: The treatment principle

Fluid is instilled and removed to clear accumulated surfactant material.

Whole-lung lavage as a standard therapeutic approach.

Modern ERS recommendations specify the clinical setting for autoimmune PAP.

Surfactant-filled alveoli

Therapeutic lavage

Lower luminal material burden

Slide 51 · ERS: When to perform whole-lung lavage

In autoimmune PAP with impaired gas exchange and symptoms or functional impairment.

This carries a strong recommendation, with very-low-certainty evidence.

For other PAP types, ERS does not make an equivalent general recommendation.

Slide 52 · Inhaled GM-CSF for symptomatic autoimmune PAP

ERS recommends inhaled GM-CSF in symptomatic confirmed autoimmune PAP.

Its target is the pathophysiologic deficit in GM-CSF activity.

It is not automatically applicable to every genetic or secondary form.

Slide 53 · Options for refractory autoimmune disease

ERS conditionally suggests rituximab in selected oxygen-requiring cases despite first-line therapy.

Plasmapheresis is considered for particularly refractory disease.

Lung transplantation may be considered for progressive end-stage disease.

Slide 54 · Secondary PAP requires aetiologic treatment

Identify and address the associated disease or exposure when possible.

The contribution of lavage may differ by underlying cause.

Avoid assuming that anti–GM-CSF antibody-directed therapy applies to secondary PAP.

Slide 55 · Inherited signalling defects: Therapeutic nuance

Hereditary GM-CSF pathway defects require specialised phenotyping and genetics.

Robbins mentions replacement and haematopoietic stem-cell approaches for selected primary inherited disease.

Management must be individualised rather than extrapolated from autoimmune PAP.

Slide 56 · Treatment should follow the mechanism

Establish the syndrome before selecting targeted therapy.

Identify autoimmune, secondary or inherited pathogenesis.

Match the treatment to the dominant biological problem and severity.

PAP phenotype

Aetiologic classification

Severity assessment

Appropriate therapy

Slide 57 · Case 1 — chronic cough and bilateral opacities

Constructed teaching vignette: An adult has cough, gelatinous sputum and patchy bilateral opacities.

Biopsy, if obtained, shows PAS-positive alveolar material with intact septa.

Question: What is the likely syndrome, and which test best identifies autoimmune aetiology?

What would an elevated anti–GM-CSF result establish?

Slide 58 · Case 1 — reasoning

A surfactant-rich alveolar precipitate supports a PAP syndrome.

Quantitative serum anti–GM-CSF autoantibodies assess autoimmune PAP.

The biopsy pattern alone does not prove the autoimmune subtype.

Slide 59 · Case 2 — PAP in a patient with haematologic disease

Constructed vignette: A patient with a haematologic disorder develops PAP-pattern morphology.

The anti–GM-CSF test is not elevated.

Question: Which etiologic group is most relevant, and what additional action is essential?

How would the underlying haematologic disorder affect classification?

Slide 60 · Case 2 — reasoning

The associated haematologic disorder makes secondary PAP plausible.

Evaluate disease- and therapy-related macrophage dysfunction.

Address the associated disorder in addition to the pulmonary manifestations.

Slide 61 · Case 3 — neonatal disease with GM-CSF defect

Constructed vignette: A neonate has pulmonary alveolar material and a suspected receptor-signalling defect.

The clinical presentation raises a hereditary form of PAP.

Question: Why is anti–GM-CSF neutralisation not the assumed cause?

Which tests identify a hereditary signalling defect?

Slide 62 · Case 3 — reasoning

The failure may arise from loss-of-function in the cytokine or receptor pathway.

Genetic and functional studies—not just routine H&E—identify the cause.

Distinguish hereditary signalling defects from surfactant trafficking disorders.

Slide 63 · Histology challenge — identify the compartment

An alveolar biopsy has homogeneously pink PAS-positive material within lumina.

Septa remain thin, and conspicuous fibrosis is absent.

Interpretation: The abnormal process is predominantly intra-alveolar.

Alveolar spaces

Retained surfactant

Schematic — not a clinical or histologic specimen

Slide 64 · High-yield diagnostic synthesis

PAP is an airspace-filling disease due to failed surfactant clearance.

GM-CSF signalling is central to alveolar macrophage maturation.

PAS-positive protein–lipid material with preserved septa supports the pattern.

Autoantibody testing and clinical/genetic work-up assign cause.

Impaired GM-CSF pathway

Macrophage dysfunction

PAS-positive alveolar deposits

PAP phenotype

Slide 65 · References and reading

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. 2026. The Lung, pp 637–638.

McCarthy C, et al. ERS guidelines on pulmonary alveolar proteinosis. Eur Respir J. 2024;64:2400725.

ERS summary for clinicians, Breathe. 2025; PMCID: PMC12070199.

Original Robbins Fig 15.22 is not reproduced; diagrams here are editable schematics.