Lung Pathology

Traditionally transbronchial or surgical lung biopsy were considered necessary to make a diagnosis of PAP syndrome. However, a lung biopsy can have a significant false negative rate due to the patchy distribution of disease [117] and usually provides little to no information of use in identifying the specific PAP-causing disease present and, consequently, is no longer recommended for use in routine cases. However, if the diagnosis is unclear after the above tests have been successfully completed, a lung biopsy may be helpful in identifying other conditions with radiological, cytological, or pathological features similar to PAP. The classical histological findings of PAP include preserved architecture of lung parenchyma with alveoli and terminal airways filled with PASpositive eosinophilic material, abundant alveolar macrophages,­ and positive immunohistochemistry for surfactant proteins [1].

Diagnostic Approach to the Patient with PAP

Multiple conditions can present with clinical and/or radiological ndings similar to PAP and should be considered in the differential diagnosis including pneumonia, pulmonary edema, hypersensitivity pneumonitis, and a range of interstitial lung diseases. PAP patients typically present with exertional dyspnea, cough, and fatigue and undergo chest radiographic investigations and pulmonary function testing and both these tests are useful and recommended. Characteristic HRCT ndings and a reduced DLCO with or without restrictive pulmonary physiology should prompt the consideration of PAP syndrome. The observation of BAL with a milk appearance strongly supports a diagnosis of PAP syndrome. A GM-CSF autoantibody test should be performed in all patients because it is highly accurate for a diagnosis of autoimmune PAP, which is responsible for 90% of all patients with PAP syndrome. No other available clinical or genetic tests are available to speci cally diagnose autoimmune PAP. Genetic testing should be pursued in patients with a normal GM-CSF autoantibody levels and a detailed history to determine any possible causes of secondary PAP (Fig. 22.4). The criteria for diagnosis of autoimmune PAP are listed (Table 22.1).

Table 22.1  Criteria for diagnosis of autoimmune pulmonary alveolar proteinosisa

Essential criterion

  Abnormal serum GM-CSF autoantibody test resultb

Supporting criteria (at least one is required)

 • Chest HRCT scan showing diffuse ground-glass opaci cation and superimposed septal thickeningc

 • Bronchoalveolar lavage cytopathology showing extensive, mostly extracellular, amorphous PAS-positive cell fragments/ debris, ghost cells, large foamy (PAS-positive, oil-red-O- positive) macrophagesd

 • Lung biopsy histopathology showing alveoli lled with eosinophilic (PAS-positive) granular sediment, enlarged foamyappearing alveolar macrophages, cholesterol crystals (clefts)e

HRCT high-resolution computed tomography, GM-CSF granulocyte/ macrophage colony-stimulating factor, PAS periodic acid–Schiff aDiagnosis requires the presence of the essential criterion and (any) one of the supporting criteria

bUsually determined quantitatively by enzyme linked immunosorbent assay (ELISA). The (laboratory speci c) cutoff value for an abnormal test depends on the nature of the GM-CSF autoantibody reference standard and the assay protocol (see text for details)

cGround-glass opaci cation may occur without superimposed septal thickening in mild disease, usually but not always involves multiple lobes, with or without subpleural sparing

dBronchoalveolar lavage fuid usually appears opalescent, milky white (or brown in smokers) and contains a waxy sediment, which appears quickly upon standing at room temperature or in the cold

eA lung biopsy is often unnecessary and should only be obtained if clinically indicated (see text for details)

Natural History and Prognosis

While no longitudinal studies have reported on the clinical course of autoimmune PAP, a comprehensive meta-analysis of 343 patients with PAP reported a survival rate of 75% at 5 years and 68% at 10 years. Over 80% of the deaths attributable to PAP occurred within 12 months of diagnosis, with respiratory failure (72% of deaths) and uncontrolled infection (20% of deaths) as the most common causes of death. A cross-sectional cohort study of 223 patients with autoimmune PAP in Japan reported no deaths over the course of a 5-year study period [23]. Spontaneous improvement of PAP has been reported in 7.9% of patients in a large metaanalysis [9]. Autoimmune PAP typically follows one of three patterns: progressive deterioration, stable disease, or spontaneous resolution [2]. Prognosis for patients with secondary PAP is signi cantly worse with a median survival of less than 20 months reported in a study of 40 patients [118]. Congenital PAP is associated with signi cant progressive pulmonary brosis in adolescents and adults.