Pediatric Alveolar Proteinosis Workup
- Author: Danielle M Goetz, MD; Chief Editor: Girish D Sharma, MD, FCCP, FAAP more...
See the list below:
- 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
- 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.
- 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.
- 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.
See the list below:
- 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.
- 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.
- 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.
- 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.
- Lower lung zone predominance is present in 22% of cases.
- 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.
See the list below:
- 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.
- 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.
See the list below:
- 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).
- If performed, electron microscopy of BAL fluid reveals lamellar bodies that resemble myelin.
- 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.
- 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.
See the list below:
- 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.
Trapnell BC, Whitsett JA, Nakata K. Pulmonary alveolar proteinosis. N Engl J Med. 2003 Dec 25. 349(26):2527-39. [Medline].
[Guideline] Leth S, Bendstrup E, Vestergaard H and Hilberg O. Autoimmune pulmonary alveolar proteinosis: treatment options in year 2013. Respirology. 2013. 18:82-91.
Patel SM, Sekuguchi H, Reynold J and Krowks M. Pulmonary alveolar proteinosis. Canadian Respiratory Journal. 2012. 19:243-45.
Raj D, Bhutia TD, Mathur S, Kabra SK, Lodha R. Pulmonary Alveolar Proteinosis Secondary to Pneumocystis jiroveci Infection in an Infant with Common Variable Immunodeficiency. Indian J Pediatr. 2013 May 5. [Medline].
Samuels MP, Warner JO. Pulmonary alveolar lipoproteinosis complicating juvenile dermatomyositis. Thorax. 1988 Nov. 43(11):939-40. [Medline].
deMello DE, Nogee LM, Heyman S, et al. Molecular and phenotypic variability in the congenital alveolar proteinosis syndrome associated with inherited surfactant protein B deficiency. J Pediatr. 1994 Jul. 125(1):43-50. [Medline].
Enaud L, Hadchouel A, Coulomb A, Berteloot L, Lacaille F, Boccon-Gibod L, et al. Pulmonary alveolar proteinosis in children on La Réunion Island: a new inherited disorder?. Orphanet J Rare Dis. 2014 Jun 14. 9:85. [Medline].
Rosen SH, Castleman B, Liebow AA. Pulmonary alveolar proteinosis. N Engl J Med. 1958 Jun 5. 258(23):1123-42. [Medline].
Goldstein LS, Kavuru MS, Curtis-McCarthy P, et al. Pulmonary alveolar proteinosis: clinical features and outcomes. Chest. 1998 Nov. 114(5):1357-62. [Medline].
Nogee LM, Garnier G, Dietz HC, et al. A mutation in the surfactant protein B gene responsible for fatal neonatal respiratory disease in multiple kindreds. J Clin Invest. 1994 Apr. 93(4):1860-3. [Medline].
Borie R, Danel C, Debray MP, Taille C, Dombret MC, Aubier M, et al. Pulmonary alveolar proteinosis. European Respiratory Reviews. 2011. 20:98-107.
Carey B & Trapnell B. Molecular basis of pulmonary alveolar proteinosis. Clinical Immunology. 2010. 135:223-25. [Full Text].
Knight DP, Knight JA. Pulmonary alveolar proteinosis in the newborn. Arch Pathol Lab Med. 1985 Jun. 109(6):529-31. [Medline].
Coleman M, Dehner LP, Sibley RK, Burke BA, L'Heureux PR, Thompson TR. Pulmonary alveolar proteinosis: an uncommon cause of chronic neonatal respiratory distress. Am Rev Respir Dis. 1980 Mar. 121(3):583-6. [Medline]. [Full Text].
Witty LA, Tapson VF, Piantadosi CA. Isolation of mycobacteria in patients with pulmonary alveolar proteinosis. Medicine (Baltimore). 1994 Mar. 73(2):103-9. [Medline].
Prakash UB, Barham SS, Carpenter HA, Dines DE, Marsh HM. Pulmonary alveolar phospholipoproteinosis: experience with 34 cases and a review. Mayo Clin Proc. 1987 Jun. 62(6):499-518. [Medline].
Seymour JF, Presneill JJ. Pulmonary alveolar proteinosis: progress in the first 44 years. Am J Respir Crit Care Med. 2002 Jul 15. 166(2):215-35. [Medline].
Inoue Y et al. Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan. American Journal of Respiratory and Critical Care Medicine. 2008. 177:752-62.
Schumacher RE, Marrogi AJ, Heidelberger KP. Pulmonary alveolar proteinosis in a newborn. Pediatr Pulmonol. 1989. 7(3):178-82. [Medline].
Nogee LM, Dunbar AE 3rd, Wert S, Askin F, Hamvas A, Whitsett JA. Mutations in the surfactant protein C gene associated with interstitial lung disease. Chest. 2002 Mar. 121(3 Suppl):20S-21S. [Medline].
Doerschuk CM. Pulmonary Alveolar Proteinosis- Is Host Defense Awry?. N Engl J Med. Feb 2007. 356:547-49.
Khan A, Agarwal R, and Aggarwal A. Effectiveness of granulocyte-macrophage colony-stimulating factor therapy in autoimmune pulmonary alveolar proteinosis. Chest. 2012. 141:1273-83.
Uchida K, Beck DC, Yamamoto T, et al. GM-CSF autoantibodies and neutrophil dysfunction in pulmonary alveolar proteinosis. N Engl J Med. 2007 Feb 8. 356(6):567-79. [Medline].
Mahut B, Delacourt C, Scheinmann P, et al. Pulmonary alveolar proteinosis: experience with eight pediatric cases and a review. Pediatrics. 1996 Jan. 97(1):117-22. [Medline].
Bonella F, Ohshimo S, Miaotian C, Griese M, Guzman J and Costable U. Serum KL-6 is a predictor of outcome in pulmonary alveolar proteinosis. Orphanet Journal of Rare Diseases. 2013. 2013:[Full Text].
Mazzone P, Thomassen MJ, Kavuru M. Our new understanding of pulmonary alveolar proteinosis: what an internist needs to know. Cleve Clin J Med. 2001 Dec. 68(12):977-8, 981-2, 984-5 passim. [Medline].
Albafouille V, Sayegh N, De Coudenhove S, et al. CT scan patterns of pulmonary alveolar proteinosis in children. Pediatr Radiol. 1999 Mar. 29(3):147-52. [Medline].
Wang BM, Stern EJ, Schmidt RA, Pierson DJ. Diagnosing pulmonary alveolar proteinosis. A review and an update. Chest. 1997 Feb. 111(2):460-6. [Medline].
Seymour JF, Presneill JJ, Schoch OD, et al. Therapeutic efficacy of granulocyte-macrophage colony-stimulating factor in patients with idiopathic acquired alveolar proteinosis. Am J Respir Crit Care Med. 2001 Feb. 163(2):524-31. [Medline].
Kavuru MS, Sullivan EJ, Piccin R, et al. Exogenous granulocyte-macrophage colony-stimulating factor administration for pulmonary alveolar proteinosis. Am J Respir Crit Care Med. 2000 Apr. 161(4 Pt 1):1143-8. [Medline].
Malur A, Kavuru M, Marshall I, Barna B, Huizar I, Karnekar R, et al. Rituximab therapy in pulmonary alveolar proteinosis improves alveolar macrophage lipid homeostasis. Respiratory Research. 2012. 13:46. [Full Text].
Hamvas A, Cole FS, deMello DE, et al. Surfactant protein B deficiency: antenatal diagnosis and prospective treatment with surfactant replacement. J Pediatr. 1994 Sep. 125(3):356-61. [Medline].
Lingadevaru H, Romano MA, Fauman K, Cooley E, Annich GM, Cornell TT. Challenges during repeat extracorporeal life support in a patient with pulmonary alveolar proteinosis. ASAIO J. 2011 Sep-Oct. 57(5):473-4. [Medline].
Claypool WD, Rogers RM, Matuschak GM. Update on the clinical diagnosis, management, and pathogenesis of pulmonary alveolar proteinosis (phospholipidosis). Chest. 1984 Apr. 85(4):550-8. [Medline].
DiFusco LA, Verma RK. Whole-lung lavage for pediatric patients with pulmonary alveolar proteinosis. AORN J. 2013 Jul. 98(1):50-67; quiz 68-70. [Medline].
Badiozaman R, Tahereh P, Shideh D, Mohammadreza B, Ahmadreza A, Seyyedahmad T. Whole lung lavage of nine children with pulmonary alveolar proteinosis: experience in a tertiary lung center. Iran J Pediatr. 2013 Feb. 23(1):95-9. [Medline]. [Full Text].
Gonçalves BM, Teixeira VC, Bittencourt PF. Anesthesia for lung lavage in pediatric patient with pulmonary alveolar proteinosis. Rev Bras Anestesiol. 2012 Mar-Apr. 62(2):269-73. [Medline].
Wilson CA, Wilmshurst SL, Black AE. Anesthetic techniques to facilitate lung lavage for pulmonary alveolar proteinosis in children-new airway techniques and a review of the literature. Paediatr Anaesth. 2015 Jun. 25 (6):546-53. [Medline].
Reiter K, Schoen C, Griese M & Nicolai T. Whole-lung lavage in infants and children with pulmonary alveolar proteinosis. Pediatric Anesthesia. 2010. 20:1118-1123.
Spock A. Long-term survival of paediatric patients with pulmonary alveolar proteinosis treated with lung lavage. Eur Respir J. 2005 Jun. 25(6):1127. [Medline].
Parker LA, Novotny DB. Recurrent alveolar proteinosis following double lung transplantation. Chest. 1997 May. 111(5):1457-8. [Medline].
Price A, Manson D, Cutz E, Dell S. Pulmonary alveolar proteinosis associated with anti-GM-CSF antibodies in a child: successful treatment with inhaled GM-CSF. Pediatr Pulmonol. 2006 Apr. 41(4):367-70. [Medline].
Cho K, Nakata K, Ariga T, et al. Successful treatment of congenital pulmonary alveolar proteinosis with intravenous immunoglobulin G administration. Respirology. 2006 Jan. 11 Suppl:S74-7. [Medline].
Lee KN, Levin DL, Webb WR, et al. Pulmonary alveolar proteinosis: high-resolution CT, chest radiographic, and functional correlations. Chest. 1997 Apr. 111(4):989-95. [Medline].
Anton HC, Gray B. Pulmonary alveolar proteinosis presenting with pneumothorax. Clin Radiol. 1967 Oct. 18(4):428-31. [Medline].
Arora PL, Rogers RM, Mayock RL. Alveolar proteinosis. Experience with trypsin therapy. Am J Med. 1968 Jun. 44(6):889-99. [Medline].
Ballard PL, Nogee LM, Beers MF, et al. Partial deficiency of surfactant protein B in an infant with chronic lung disease. Pediatrics. 1995 Dec. 96(6):1046-52. [Medline].
Barraclough RM, Gillies AJ. Pulmonary alveolar proteinosis: a complete response to GM-CSF therapy. Thorax. 2001 Aug. 56(8):664-5. [Medline].
Clague HW, Wallace AC, Morgan WK. Pulmonary interstitial fibrosis associated with alveolar proteinosis. Thorax. 1983 Nov. 38(11):865-6. [Medline].
Fisher M, Roggli V, Merten D, et al. Coexisting endogenous lipoid pneumonia, cholesterol granulomas, and pulmonary alveolar proteinosis in a pediatric population: a clinical, radiographic, and pathologic correlation. Pediatr Pathol. 1992 May-Jun. 12(3):365-83. [Medline].
Ganguli PC, Lynne-Davies P, Sproule BJ. Pulmonary alveolar proteinosis, bronchiectasis and secondary amyloidosis: a case report. Can Med Assoc J. 1972 Mar 4. 106(5):569 passim. [Medline].
Gough J. Silicosis and alveolar proteinosis. Br Med J. 1967 Mar 11. 1(540):629. [Medline].
Hamvas A. Surfactant protein B deficiency: insights into inherited disorders of lung cell metabolism. Curr Probl Pediatr. 1997 Oct. 27(9):325-45. [Medline].
Hildebrand FL Jr, Rosenow EC 3d, Habermann TM, Tazelaar HD. Pulmonary complications of leukemia. Chest. 1990 Nov. 98(5):1233-9. [Medline].
Hirakata Y, Kobayashi J, Sugama Y, Kitamura S. Elevation of tumour markers in serum and bronchoalveolar lavage fluid in pulmonary alveolar proteinosis. Eur Respir J. 1995 May. 8(5):689-96. [Medline].
Honda Y, Kuroki Y, Shijubo N, et al. Aberrant appearance of lung surfactant protein A in sera of patients with idiopathic pulmonary fibrosis and its clinical significance. Respiration. 1995. 62(2):64-9. [Medline].
Jansen HM, Zuurmond WW, Roos CM, et al. Whole-lung lavage under hyperbaric oxygen conditions for alveolar proteinosis with respiratory failure. Chest. 1987 Jun. 91(6):829-32. [Medline].
Kitamura T, Uchida K, Tanaka N, Tsuchiya T, Watanabe J, Yamada Y. Serological diagnosis of idiopathic pulmonary alveolar proteinosis. Am J Respir Crit Care Med. 2000 Aug. 162(2 Pt 1):658-62. [Medline].
Lin FC, Chen YC, Chang HI, Chang SC. Effect of body position on gas exchange in patients with idiopathic pulmonary alveolar proteinosis: no benefit of prone positioning. Chest. 2005 Mar. 127(3):1058-64. [Medline].
Martinez-Lopez MA, Gomez-Cerezo G, Villasante C, et al. Pulmonary alveolar proteinosis: prolonged spontaneous remission in two patients. Eur Respir J. 1991 Mar. 4(3):377-9. [Medline].
Nara M, Sano K, Ogawa H, et al. Serum antibody against granulocyte/macrophage colony-stimulating factor and KL-6 in idiopathic pulmonary alveolar proteinosis. Tohoku J Exp Med. 2006 Apr. 208(4):349-54. [Medline].
Nogee LM. Alterations in SP-B and SP-C expression in neonatal lung disease. Annu Rev Physiol. 2004. 66:601-23. [Medline].
Parto K, Kallajoki M, Aho H, Simell O. Pulmonary alveolar proteinosis and glomerulonephritis in lysinuric protein intolerance: case reports and autopsy findings of four pediatric patients. Hum Pathol. 1994 Apr. 25(4):400-7. [Medline].
Paschen C, Reiter K, Stanzel F, et al. Therapeutic lung lavages in children and adults. Respir Res. 2005. 6:138. [Medline].
Paschen C, Reiter K, Stanzel F, Teschler H and Griese M. Therapeutic lung lavages in children and adults. Respiratory Research. November 2005. 6:138. [Full Text].
Ranchod M, Bissell M. Pulmonary alveolar proteinosis and cytomegalovirus infection. Arch Pathol Lab Med. 1979 Mar. 103(3):139-42. [Medline].
Santamaria F, Brancaccio G, Parenti G et al. Recurrent fatal pulmonary alveolar proteinosis after heart-lung transplantation in a child wiht lysinuric protein intolerance. Journal od Pediatrics. 2004. 145:268-72.
Seymour JF, Dunn AR, Vincent JM, et al. Efficacy of granulocyte-macrophage colony-stimulating factor in acquired alveolar proteinosis. N Engl J Med. 1996 Dec 19. 335(25):1924-5. [Medline].
Shah PL, Conway S, Scott SF, et al. A case-controlled study with dornase alfa to evaluate impact on disease progression over a 4-year period. Respiration. 2001. 68(2):160-4. [Medline].
Shah PL, Hansell D, Lawson PR, et al. Pulmonary alveolar proteinosis: clinical aspects and current concepts on pathogenesis. Thorax. 2000 Jan. 55(1):67-77. [Medline].
Stevens PA, Pettenazzo A, Brasch F, et al. Nonspecific interstitial pneumonia, alveolar proteinosis, and abnormal proprotein trafficking resulting from a spontaneous mutation in the surfactant protein C gene. Pediatr Res. 2005 Jan. 57(1):89-98. [Medline].
Summers JE. Pulmonary alveolar proteinosis. Review of the literature with follow-up studies and report of two new cases. Calif Med. 1966 Jun. 104(6):428-36. [Medline].
Sunderland WA, Campbell RA, Edwards MJ. Pulmonary alveolar proteinosis and pulmonary cryptococcosis in an adolescent boy. J Pediatr. 1972 Mar. 80(3):450-6. [Medline].
Tsai WC, Lewis D, Nasr SZ, Hirschl RB. Liquid ventilation in an infant with pulmonary alveolar proteinosis. Pediatr Pulmonol. 1998 Oct. 26(4):283-6. [Medline].
Berteloot L, Taam RA, Emond-Gonsard S, Mamou-Mani T, Lambot K, Grévent D, et al. Primary pulmonary alveolar proteinosis: computed tomography features at diagnosis. Pediatr Radiol. 2014 Jul. 44 (7):795-802. [Medline].