Blood Testing for Differential Diagnosis of Pulmonary Alveolar Proteinosis Syndrome

To the Editor:

Pulmonary alveolar proteinosis (PAP) is a rare syndrome of progressive surfactant accumulation and resulting hypoxemic respiratory failure that usually begins insidiously and goes unnoticed until parenchymal lung involvement is extensive and sufficient to cause exertional dyspnea.¹ PAP syndrome occurs in a heterogeneous group of mechanistically distinct diseases caused by granulocyte/macrophage-colony stimulating factor (GM-CSF)-neutralizing autoantibodies, various diseases, or environmental exposures that reduce the numbers and/or functions of alveolar macrophages, myeloid cell disorders, and genetic mutations that disrupt either GM-CSF receptor signaling or normal surfactant production.

The differential diagnosis of PAP syndrome is challenged by its low prevalence (approximately seven per million),² nonspecific symptoms (dyspnea, cough, chest tightness, and fatigue) and radiographic appearance (diffuse, patchy ground-glass opacification and septal thickening), and normal routine laboratory tests. The diagnostic workup frequently involves multiple tests and procedures, including pulmonary function tests, arterial blood gas analysis, chest radiographs, CT scans, and examination of BAL cytology and/or lung histopathology. Results from the US National PAP Registry³ indicate many patients with PAP undergo transbronchial biopsy, surgical lung biopsy, or both (Fig 1A), even though neither is diagnostic for any PAP-causing disease, histological examination fails to identify the presence of PAP syndrome in 28% of cases because of patchy involvement, and both are associated with significant procedure-related morbidity. Results also show PAP is usually misdiagnosed as pneumonia initially until the failure of multiple courses of ‘appropriate’ empirical antibiotic therapy prompts diagnostic reconsideration and referral, thereby delaying accurate diagnosis by a median of 1.5 years (range, 0.5-13.5 years).

Figure 1.

Diagnostic testing in patients with pulmonary alveolar proteinosis (PAP) syndrome. A, Percentages of patients with aPAP (n = 56) in the US National PAP Registry who underwent surgical biopsy, transbronchial lung biopsy, or both during their diagnostic evaluation.³ B, Serum GM-CSF autoantibody testing in patients with aPAP, hPAP, sPAP, or cPAP, patients with OLD, and HC. Red lines indicate the mean value within each group. The dotted line is the threshold cutoff value determined by receiver operating characteristic curve analysis.³ Values above the gray bar are interpreted as abnormal, whereas values below it are interpreted as normal. The gray bar represents the range of values that is sufficiently close to the cutoff to warrant additional testing if clinically indicated. aPAP = autoimmune PAP; cPAP = congenital PAP; GM-CSF = granulocyte/macrophage-colony stimulating factor; HC = healthy control individuals; hPAP = hereditary PAP; OLD = other lung diseases; sPAP = secondary PAP.

Advances from pathogenesis-based research have led to development of transformative, disease-specific, blood-based diagnostic tests for multiple PAP-causing diseases that are now available for routine clinical use and performed in clinical laboratories certified by the College of American Pathologists that operate within federal Clinical Laboratory Improvement Amendments guidelines. For example, the serum GM-CSF autoantibody test (Fig 1B) is a validated test of known accuracy and precision that is highly sensitive and specific for autoimmune PAP,⁴ the most common PAP-causing disease accounting for 90% of cases.⁵ A negative GM-CSF autoantibody test excludes autoimmune PAP but does not exclude other PAP-causing diseases. However, additional blood-based tests to measure GM-CSF receptors/signaling and other genetic tests are available and permit the rapid, accurate diagnosis of the PAP-causing disease in > 95% of patients. Importantly, diagnostic accuracy is paramount in the context of emerging novel, disease-specific pharmacologic, cell-based, and other therapies for these diseases.

We conclude that the differential diagnosis of PAP syndrome should begin with a serum GM-CSF autoantibody test and other blood-based tests as clinically indicated; lung biopsy should be reserved for patients in whom identification of the PAP cause remains uncertain after completion of disease-specific, noninvasive serologic, blood-based, and genetic tests; and patients should be evaluated at centers with expertise in PAP.