Approach to the Critical Patient

Immediate priorities

Airway and breathing threats

Superimposed infection identification

Monitoring and targets

Oxygenation targets

Clinical deterioration triggers

Immediate consults

Consultation triggers

History

Presenting symptoms

Cardinal presentation

Associated constitutional symptoms

Alarm features

Red flag symptoms

Risk factors and exposures

Occupational and inhalational exposures

Smoking history

Underlying hematologic conditions

Immunodeficiency states

Past medical history

Diagnostic clues from prior history

Physical Exam

Vitals and general

Stability snapshot

Pulmonary examination

Auscultation findings

Work of breathing

General inspection

Cyanosis in advanced disease with severe hypoxemia

Plethora from secondary polycythemia

Digital clubbing

PITFALLS

Clinical-radiologic dissociation

Differential Diagnosis

Life-threatening mimics

Pulmonary edema

Pneumocystis jirovecii pneumonia

Diffuse alveolar hemorrhage

Infectious mimics

Community-acquired pneumonia

Nocardia pulmonary infection

Disseminated fungal infection

Interstitial lung disease mimics

Organizing pneumonia

Lymphangitic carcinomatosis

Sarcoidosis

Exogenous lipoid pneumonia

PAP variants and related conditions

Pulmonary alveolar proteinosis

Silicoproteinosis

Laboratory Tests

Diagnostic serology

Serum anti-GM-CSF autoantibodies

Serum GM-CSF levels

Biomarkers and severity markers

LDH

KL-6 (Krebs von den Lungen-6)

Surfactant proteins A and D

CEA and CYFRA 21-1

Gas exchange and hematologic assessment

Arterial blood gas

Complete blood count

Peripheral blood smear

Infectious and secondary cause workup

HIV testing

BAL fluid analysis

Beta-D-glucan

Sputum and BAL cultures

Diagnostic Tests

Scoring Systems

PAP disease severity scoring

Pulmonary function tests

MRI

Chest MRI role in PAP

CT

HRCT chest (gold standard imaging modality)

Ultrasound

Point-of-care ultrasound

Disposition

Admission criteria

Inpatient admission indications

ICU level care

ICU indications

Discharge criteria

Safe discharge parameters

Transfer considerations

Transfer triggers

Treatment

Supplemental oxygen and supportive care

Oxygen therapy

First-line pharmacotherapy

Inhaled GM-CSF therapy

Whole lung lavage

WLL indications

WLL procedure details

WLL contraindications and precautions

Second and third-line therapies

Inhaled GM-CSF post-WLL

Rituximab

Plasmapheresis

Statin therapy

Secondary PAP treatment

Treat underlying condition

Lung transplantation

Reserved for terminal respiratory failure

Opportunistic infection treatment

Nocardia treatment

Aspergillus treatment

Cryptococcus treatment

Special Populations

Pregnancy

Physiologic considerations

Diagnostic approach in pregnancy

Treatment in pregnancy

Geriatric

Age-related considerations

Atypical presentation in elderly

WLL in elderly

Pediatrics

Congenital and hereditary PAP

Autoimmune PAP in pediatrics

Treatment in pediatrics

Background

Epidemiology

Prevalence and incidence

Demographics

Natural history

Smoking association

Pathophysiology

Autoimmune PAP mechanism

Surfactant accumulation consequence

Secondary PAP mechanism

Hereditary PAP mechanism

Therapeutic Considerations

Inhaled GM-CSF rationale

WLL rationale

Anti-GM-CSF antibody level monitoring

Occupational exposure cessation

Patient Discharge Instructions

copy discharge instructions

Diagnosis and disease explanation

Medications and therapy

Activity and lifestyle

Follow-up schedule

Return to emergency department immediately for

Infection prevention

References

Guidelines and key sources

McCarthy C, Carey BC, Trapnell BC. Autoimmune Pulmonary Alveolar Proteinosis. American Journal of Respiratory and Critical Care Medicine. 2022. PMID 35227171

Trapnell BC, Nakata K, Bonella F, et al. Pulmonary Alveolar Proteinosis. Nature Reviews Disease Primers. 2019. PMID 30846703

Trapnell BC, Inoue Y, Bonella F, et al. Phase 3 Trial of Inhaled Molgramostim in Autoimmune Pulmonary Alveolar Proteinosis. NEJM. 2025. IMPALA-2 trial

Trapnell BC, Inoue Y, Bonella F, et al. Inhaled Molgramostim Therapy in Autoimmune Pulmonary Alveolar Proteinosis. NEJM. 2020. IMPALA trial

Papiris SA, Kallieri M, Zompatori M, et al. Autoimmune Pulmonary Alveolar Proteinosis. Seminars in Respiratory and Critical Care Medicine. 2025. PMID 41197983

Kumar A, Abdelmalak B, Inoue Y, Culver DA. Pulmonary Alveolar Proteinosis in Adults: Pathophysiology and Clinical Approach. Lancet Respiratory Medicine. 2018. PMID 29397349

Jouneau S, Chauvin P, Lederlin M, Painvin B, Kerjouan M. Pharmacotherapy for Autoimmune Pulmonary Alveolar Proteinosis. Drugs. 2025. PMID 40866780

Ataya A, Mathavan A, Wang TS. How I Do It: Whole Lung Lavage in Pulmonary Alveolar Proteinosis. Chest. 2025. PMID 41072904

Bonella F, Borie R. Pulmonary Alveolar Proteinosis. Clinics in Chest Medicine. 2025. PMID 41110926

Trapnell BC, Whitsett JA, Nakata K. Pulmonary Alveolar Proteinosis. NEJM. 2003. NEJM doi 10.1056/NEJMra023226

Lettieri S, Bonella F, Marando VA, et al. Pathogenesis-Driven Treatment of Primary Pulmonary Alveolar Proteinosis. European Respiratory Review. 2024. PMID 39142709

Ryerson CJ, Adegunsoye A, Piciucchi S, et al. Update of the International Multidisciplinary Classification of the Interstitial Pneumonias: ERS/ATS Statement. European Respiratory Journal. 2025. PMID 40774805