CONTENTS

• Basics
• Epidemiology
• Clinical presentation
• Radiology
• Bronchoscopy
• Laboratory studies
• Diagnosis
• Treatment
• Questions & discussion

abbreviations used in the pulmonary section: 7

• ABPA: Allergic bronchopulmonary aspergillosis 📖
• AE-ILD: Acute exacerbation of ILD 📖
• AEP: Acute eosinophilic pneumonia 📖
• AFB: Acid fast bacilli
• AIP: Acute interstitial pneumonia (Hamman-Rich syndrome) 📖
• ANA: Antinuclear antibody 📖
• ANCA: Antineutrophil cytoplasmic antibodies 📖
• ARDS: Acute respiratory distress syndrome 📖
• ASS: Antisynthetase syndrome 📖
• BAL: Bronchoalveolar lavage 📖
• BiPAP: Bilevel positive airway pressure 📖
• CEP: Chronic eosinophilic pneumonia 📖
• CF: Cystic fibrosis 📖
• COP: Cryptogenic organizing pneumonia 📖
• CPAP: Continuous positive airway pressure 📖
• CPFE: Combined pulmonary fibrosis and emphysema 📖
• CTD-ILD: Connective tissue disease associated interstitial lung disease 📖
• CTEPH: Chronic thromboembolic pulmonary hypertension 📖
• DAD: Diffuse alveolar damage 📖
• DAH: Diffuse alveolar hemorrhage 📖
• DIP: Desquamative interstitial pneumonia 📖
• DLCO: Diffusing capacity for carbon monoxide 📖
• DRESS: Drug reaction with eosinophilia and systemic symptoms 📖
• EGPA: Eosinophilic granulomatosis with polyangiitis 📖
• FEV1: Forced expiratory volume in 1 second 📖
• FVC: Forced vital capacity 📖
• GGO: Ground glass opacity 📖
• GLILD: Granulomatous and lymphocytic interstitial lung disease 📖
• HFNC: High flow nasal cannula 📖
• HP: Hypersensitivity pneumonitis 📖
• IPAF: Interstitial pneumonia with autoimmune features 📖
• IPF: Idiopathic pulmonary fibrosis 📖
• IVIG: Intravenous immunoglobulin 📖
• LAM: Lymphangioleiomyomatosis 📖
• LIP: Lymphocytic interstitial pneumonia 📖
• MAC: Mycobacterium avium complex 📖
• MCTD: Mixed connective tissue disease 📖
• NIV: Noninvasive ventilation (including CPAP or BiPAP) 📖
• NSIP: Nonspecific interstitial pneumonia 📖
• NTM: Non-tuberculous mycobacteria 📖
• OHS: Obesity hypoventilation syndrome 📖
• OP: Organizing pneumonia 📖
• OSA: Obstructive sleep apnea 📖
• PAP: Pulmonary alveolar proteinosis 📖
• PE: Pulmonary embolism 📖
• PFT: Pulmonary function test 📖
• PLCH: Pulmonary Langerhans cell histiocytosis 📖
• PPFE: Pleuroparenchymal fibroelastosis 📖
• PPF: Progressive pulmonary fibrosis 📖
• PVOD/PCH Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis 📖
• RB-ILD: Respiratory bronchiolitis-associated interstitial lung disease 📖
• RP-ILD: Rapidly progressive interstitial lung disease 📖
• TNF: Tumor necrosis factor
• UIP: Usual interstitial pneumonia 📖

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basics

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• PAP results from impaired surfactant clearance, which leads to accumulation of lipoproteinaceous material in alveoli.
• >90% of cases are due to an acquired antibody that inhibits the function of GM-CSF (granulocyte-macrophage colony-stimulating factor). Other causes of PAP include a variety of disorders that impair monocyte/macrophage function (normally, circulating monocytes are a cellular precursor for macrophages that reside within the tissue).

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epidemiology

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idiopathic PAP (aka primary or autoimmune)(>90%)

• This is due to an autoantibody against GM-CSF.
• The typical age of presentation is ~30-60 years old.
• There is a 2.5:1 male predominance.
• ~60% of patients smoke tobacco. (Walker 2019; 35486081)

secondary to monocyte/macrophage dysfunction (~10%)

• Hematologic disorders (often marked by monocytopenia):
  • Myelodysplastic syndromes.
  • Myeloid or lymphoid leukemias.
  • Aplastic anemia.
  • Multiple myeloma, Waldenstrom macroglobulinemia.
  • Lymphomas.
  • Following stem cell transplantation.
• Immunodeficiency disorders:
  • Thymic alymphoplasia.
  • Subacute combined immunodeficiency.
  • IgA deficiency.
  • HIV.
  • GATA2 deficiency. (34625181)
• Chronic infection (e.g., Pneumocystis, tuberculosis). (Shah 2019)
• Medications (complete list in pneumotox.com: 🌊)
  • Anabolic androgenic steroids.
  • Chemotherapy (especially busulfan, chlorambucil).
  • Cyclosporine.
  • Dasatinib, Imatinib.
  • Fentanyl.
  • Leflunomide.
  • Mycophenolate mofetil.
  • Sirolimus.
• Environmental exposures: (Murray 2022)
  • Fumes (e.g., gasoline, paint, chlorine, cleaning products, hydrofluoric acid).
  • Organic dust (e.g., fertilizer, sawdust, bakery flour, agricultural).
  • Inorganic dust (e.g., silica, cement, aluminum, indium, titanium).
  • Marijuana.

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clinical presentation

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(1) onset is usually subacute

• Insidious onset often occurs over years, including: (18202348)
  • Dyspnea (~50%).
  • Cough (~25%) is usually nonproductive but can yield chunks of gelatinous material.
• Fatigue and weight loss may occur (but fever should raise concern for superinfection). (30855747, 32684997)
• The disease course is variable: (30855747)
  • Stable, persistent symptoms may occur.
  • Persistent deterioration may occur.
  • Spontaneous remission occurs in ~6% of patients.
  • Superinfection may cause acute deterioration (more on this in the section below).
• The diagnostic process is also variable:
  • Diagnosis is often delayed for about a year after the onset of symptoms. (Fishman 2023) Patients may be misdiagnosed as having asthma or chronic bronchitis. (Murray 2022)
  • Alternatively, about a third of patients may be incidentally detected radiographically – despite lack of any symptoms.

(2) but opportunistic superinfection can cause acute deterioration

• Key concepts:
  • (1) PAP doesn't usually cause acute respiratory failure. If acute symptoms occur, suspect superinfection.
  • (2) PAP is an immunocompromised state due to systemic granulocyte dysfunction. Although opportunistic infections commonly involve the lungs, extrapulmonary sites may also be involved. (Fishman 2023)
• PAP patients are susceptible to a broad range of pathogens, notably:
  • Nocardia infection is a relatively common opportunist here.
  • Fungal infection (e.g., Cryptococcus, Histoplasma, and especially Aspergillus). (32684997)
  • Mycobacterial infection.

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radiology

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• 🔑 Imaging may be strikingly abnormal despite only mild respiratory dysfunction.
• (1) Alveolar filling process:
  • Bilateral ground-glass opacities in a central distribution, similar to pulmonary edema (bilateral, most prominent in the hila, with relative sparing of the costophrenic angles and lung periphery).
  • Consolidation can occur, especially in the dorsal lung regions. (Walker 2019)
• (2) Increased interstitial markings.
  • A crazy-paving pattern may be generated by the combination of mosaic ground-glass opacities plus the thickening of the interlobular septa. However, the typical crazy-paving pattern is usually not seen in secondary PAP. (ERS handbook 3rd ed.)
  • Abnormal lung tissue is often sharply demarcated from normal lung tissue. (Walker 2019)
  • Further discussion of crazy paving: 📖
• Abnormalities not caused by PAP: (Murray 2022, 32684997)
  • Lymphadenopathy.
  • Pleural effusions.
  • Air trapping.
  • Pulmonary nodules.
• Complications that may rarely occur: (Walker 2019)
  • (1) Interstitial fibrosis occasionally develops (e.g., with traction bronchiectasis).
  • (2) Emphysematous bullae.
  • (3) Pneumothorax.
  • (4) Superimposed infection.

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bronchoscopy

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• Bronchoscopy has a yield of ~90% for diagnosing PAP. This might be even higher than the yield of a surgical lung biopsy (since the peripheral lung may be spared, leading to a false-negative biopsy).
• Bronchoalveolar lavage reveals turbid, milky fluid. Sediment may be noted, which settles in the container over time. (de Moraes 2024)
• Cytology reveals foamy macrophages with PAS-positive (periodic acid-Schiff-positive) inclusions. If PAS staining is negative, this may suggest an alternative diagnosis. (27144799)
  • PAS staining isn't routinely performed, so this may need to be specifically requested.
• Differential cell count may show an increase in lymphocytes.

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laboratory studies

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• GM-CSF autoantibodies are generally detected in patients with idiopathic PAP (with sensitivity and specificity close to 100%).
  • Autoantibody level >5 ug/mL indicates idiopathic PAP. (32684997)
  • Low levels of antibodies (usually <1 ug/mL) are nonspecific.
• Suppose GM-CSF autoantibody levels are close to the cutoff value. In that case, cell-based functional assays may be utilized to evaluate the amount of effective GM-CSF in the patient's blood (either CD11B stimulation index test or STAT5-phosphorylation index test). (Murray 2022)

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diagnosis

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Lung biopsy is not required for diagnosis if the following are present: (ERS handbook 3rd ed.)

• (1) Typical crazy-paving pattern on CT scan.
• (2) Bronchoalveolar lavage reveals a typical milky appearance, with cytology demonstrating foamy macrophages.
• (3) Elevated serum levels of GM-CSF autoantibodies.

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treatment

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indications for treatment of PAP

• Treatment is indicated for dyspnea on exertion or hypoxemia.
• Approximately 6% of patients undergo spontaneous remission, so if symptoms are minor, then observation may be reasonable.

whole lung lavage is the cornerstone therapy for all types of PAP

• Potential indications for whole lung lavage might include the following (but centers will vary): (Murray 2022, 32684997)
  • Dyspnea that limits daily activities.
  • PaO2 <60 mm.
  • Desaturation >5% with exercise. 
  • Radiological deterioration over time.
• Whole lung lavage involves general anesthesia and a double-lumen endotracheal tube. Warmed saline is used to lavage each lung until the return is clear.
• ~90% of patients experience improvement, which is usually substantial. However, patients often will eventually require a repeat lavage.
• Contraindications:
  • Active bacterial pneumonia (lavage could precipitate sepsis and shock). (Murray 2022)
  • Severe hypoxemia. However, venovenous ECMO could be added to support oxygenation during the procedure. Alternatively, sequential lobar lavage may be utilized. (Fishman 2023) 
• Potential complications may include:
  • Worsening hypoxemia (e.g., due to spilling fluid into both lungs).
  • Superinfection.
  • Pneumothorax. (32684997)

idiopathic/primary PAP: subcutaneous or inhaled GM-CSF

• GM-CSF is indicated only for primary PAP.
• GM-CSF therapy alone:
  • This may be useful for less severely ill patients.
  • The response rate is ~60%. Benefits may depend on the dose and duration of therapy. Inhaled therapy may be more effective than subcutaneous administration.
  • There may be a delay of at least eight weeks before a therapeutic response. (Murray 2022)
• Inhaled therapy has the advantage that it doesn't cause systemic stimulation of the bone marrow. (32684997)
• Combining whole lung lavage plus subsequent inhaled GM-CSF may improve pulmonary function compared to whole lung lavage alone.

secondary PAP

• Any underlying disease process should be treated.

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questions & discussion

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