Pediatric Alveolar Proteinosis Workup

Updated: Jan 16, 2021
  • Author: Danielle M Goetz, MD; Chief Editor: Girish D Sharma, MD, FCCP, FAAP  more...
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Workup

Laboratory Studies

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  • Gene mutation analysis

    • Blood of infants with genetic (congenital) pulmonary alveolar proteinosis (PAP) should be analyzed for SP-B,SP-C, ABCA-3, and SKX2-1 gene mutations.

    • As an alternative, the child's biologic parents may be analyzed.

  • Surfactant analysis

    • levels of surfactant B may be determined from bronchoalveolar lavage (BAL) fluid; low levels of SP-B are usually found.

    • Elevated levels of surfactant proteins A and D (SP-A, SP-D) have been observed in patients with PAP.

  • Lactate dehydrogenase (LDH) measurement [18]

    • The serum LDH level may be elevated. Patients with PAP may have an LDH level of 168% ±66% (mean ± standard deviation), which is the upper limit of the normal range.

    • Individual case reports suggest that serial LDH measurements may be useful to track the severity of disease.

    • Few data are available in the pediatric literature concerning the utility of LDH measurements. Mahut et al (1996) reported that 2 of 3 children with PAP had elevated LDH values. [26]

  • CBC count: Polycythemia may be found as a consequence of chronic hypoxia

  • Serum levels of KL-6, a mucin-like glycoprotein present in the human MUC1 mucin, was higher in patients with progression of their autoimmune PAP than in patients with remission. [27]

  • ABG analysis

    • In their examination of 410 patients, Seymour et al reported an arterial partial pressure of oxygen (PaO2) of 58.6 ±15.8 mm Hg. [18]

    • ABG analysis may reveal a low partial pressure of oxygen and a compensated respiratory alkalosis secondary to hyperventilation. [18]

  • Anti-GM-CSF antibodies are specific to autoimmune PAP. They may be measured by ELISA or by a functional assay, which involves using serum from patients who may have anti-GM-CSF antibodies to inhibit proliferation of the TF1 cell line, which is very sensitive to GM-CSF activity. A concentration of greater than 19 μg/mL is specific for autoimmune PAP, while a concentration less than 10 μg/mL has a good negative predictive value. [12]

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Imaging Studies

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  • Chest radiography

    • In the neonatal-onset form, radiographic appearances are indistinguishable from those of infantile respiratory distress syndrome; both conditions are characterized by a diffuse ground-glass appearance and air bronchograms, as well as lung cysts. [12]

    • In the autoimmune and secondary forms, chest radiography typically reveals widespread, bilateral patchy and asymmetric airspace consolidation without central or peripheral distribution. [18, 28]

    • Radiographic findings are typically disproportionately abnormal in comparison to the clinical presentation. [1]

    • Many radiographic patterns are demonstrated. Goldstein (1998) reported that 62% of patients had an alveolar pattern of involvement, 12% had an interstitial pattern, and 12% had a mixed pattern on chest radiography. [10]

  • Chest CT

    • Chest CT imaging reveals scattered airspace filling. Air bronchograms are uncommon.

    • Reticular interstitial attenuations may also be noted.

    • High-resolution computed tomography (HRCT) of the chest typically demonstrates a ground-glass appearance or consolidation, combined with interlobular and intralobular septae thickening, a pattern termed "crazy paving." [2, 9] . Crazy paving is suggestive of, but not specific to PAP. It may also be associated with cardiogenic pulmonary edema, alveolar hemorrhage, Mycoplasma or Pneumocystis infection, exogenous lipoid pneumonia, or bronchoalveolar carcinoma. [12]

    • Lower lung zone predominance is present in 22% of cases. [12]

    • HRCT appearances are said to be characteristic enough to strongly suggest the diagnosis in the appropriate clinical setting.

    • HRCT scanning after lung lavage usually reveals resolution of the alveolar filling and correlates with functional improvement. Albafouille et al (1999) confirmed this finding in children. [29]

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Other Tests

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  • Pulmonary function testing (PFT) may reveal a mildly restrictive pattern of lung disease and a severely diminished carbon monoxide diffusing capacity. [1, 18]

  • Exercise capacity may be reduced and desaturation may occur during the 6-minute walk test. [12]

  • Hypoxemia is caused by ventilation-perfusion inequality and intrapulmonary shunting, leading to a widened alveolar-arteriolar oxygen gradient. PAP is said to increase the shunt fraction more than other diffuse infiltrative lung processes. [1]

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Procedures

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  • BAL

    • Classic findings in diagnostic BAL include a milky or opaque aspirate with large "foamy" alveolar macrophages (2-3 times their normal size) containing eosinophilic granules. There are also increased lymphocytes (mean 57% in one study) but few other inflammatory cell types. [1, 30]

    • The aspirated material stains strongly positive for periodic acid-Schiff (PAS). [9]

    • If performed, electron microscopy of BAL fluid reveals lamellar bodies that resemble myelin. [12]

    • Cell counts and differential counts are not helpful in the diagnosis. However, elevated levels of inflammatory cells may suggest infection, as either a primary or a secondary process.

    • SP-A and SP-D levels are elevated in BAL fluid from patients with PAP, as compared with healthy volunteers. [30]

  • Lung biopsy

    • Open lung biopsy was once considered the standard for the diagnosis of PAP. [1, 9, 30]

    • Open lung biopsy is now not commonly required because the diagnosis can be established in approximately 75% of cases by the classic BAL findings. [18, 30] In addition, in autoimmune PAP, anti-GM-CSF antibodies would yield the diagnosis, and genetic mutations can be found in genetic (congenital) PAP.

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Histologic Findings

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  • The classic pathologic finding is granular, proteinaceous, fluid-filled alveolar spaces that stain strongly on PAS staining. Cholesterol crystals are sometimes observed. Alveolar structure is generally well preserved, as are intralobular septa, with some thickening of interlobular septae. No airway involvement occurs. [30, 18]

  • Electron microscopy (EM) may reveal lamellar bodies and tubular myelin within the alveolar space in PAP. The EM appearances in congenital PAP differ in that usually no tubular myelin is present. However, EM usually adds little to the diagnostic workup. [30, 18]

  • Immunohistochemistry may provide useful information in congenital PAP. Staining for surfactant proteins A, B, C, and D is possible. Levels of SP-B are reduced, whereas SP-A and SP-D levels are generally elevated. [7]

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