Pediatric Alveolar Proteinosis Clinical Presentation

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

History

Predominant symptoms depend on the patient's age at presentation and include neonatal respiratory distress, progressive exertional dyspnea with insidious onset, cough, fatigue, low-grade fever, and weight loss. [18] Chest pain and hemoptysis occur less commonly, especially if secondary infection is present. [1] Note the following:

  • Neonatal respiratory distress: Patients with the congenital form of pulmonary alveolar proteinosis (PAP) present with progressive respiratory failure and marked hypoxemia shortly after birth. [11] The condition is initially indistinguishable from other causes of neonatal respiratory distress, including infant respiratory distress syndrome, congenital pneumonia, sepsis, and some forms of congenital heart disease. Patients were typically born after normal, uncomplicated pregnancies. [14, 15, 21] Prolonged ventilator dependence is ascribed to slow resolution of the initial illness, persisting atelectasis, or pneumonia.

  • Dyspnea: In children and young adults, the most consistent finding is shortness of breath upon exertion. Case series showed that the prevalence of dyspnea in adults with PAP was 50-80%. [10, 17, 18] In the initial stages of illness, dyspnea may manifest as diminished exercise tolerance.

  • Cough: Patients may have associated mild cough that occasionally produces thick sputum or solid material. As many as 80% of adults report having a cough. [10]

  • Failure to thrive: Although failure to thrive is obviously more common in young children and infants than in others, poor weight gain, poor appetite, and malaise are often present in older children as well. Patients often have a decreased level of activity and difficulty feeding. [18]

  • Chest pain: Chest pain is uncommon, occurring in 10-20% of patients. [10]

  • Fever: Fever is unusual and may signify superinfection. [10]

  • Unusual presentations: Rare patients present with pneumothorax or hemoptysis. Another uncommon presentation is a child with persisting infiltrates on chest radiography.

  • Family history: Because the congenital form is transmitted as an autosomal recessive disease, families may report a history of a previous child with neonatal respiratory distress. [11]

  • Risk factors: Young adults may have risk factors, such as a smoking history or exposure to metallic dust. The patient's history may also suggest predisposing conditions, such as immunodeficiency, malignancy, or autoimmune disease. [18]

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Causes

Three types of PAP have been described: congenital (genetic), secondary (acquired), and idiopathic (primary). All lead to impaired clearance of surfactant from the alveolar space.

Congenital (genetic) PAP

Congenital (genetic) PAP describes a group of disorders caused by mutations in the genes that encode for surfactant protein B or C, ATP-binding cassette 3 (ABCA3), NK2 homeobox 1 (NKX2-1), or the beta chain of the receptor for granulocyte-macrophage colony-stimulating factor (GM-CSF). [12, 18] There has also been described a mutation in SLC7A7, which leads to lysinuric protein intolerance and PAP. [12]

Most cases of congenital or genetic PAP are transmitted in an autosomal recessive pattern. [11]

The most common cause of congenital PAP is homozygosity for a frame-shift mutation in the surfactant protein B (SP-B) gene that leads to unstable SP-B mRNA, decreased protein levels, and subsequent deficient processing of SP-C. [11]

Mutations in the SP-C gene can also lead to neonatal respiratory distress. [22]

Molecular genetic heterogeneity among infants with congenital SP-B deficiency has been reported. For example, patients heterozygous for the SP-B gene mutation have been found to have normal pulmonary function as of their fourth decade of life. [18]

Other cases of congenital PAP have no known abnormalities in SP-B but are associated with disturbances in the alpha chain of the GM-CSF receptor, encoded by CSF2RA, or in the beta chain of the GM-CSF receptor, encoded by CSF2RB [12]

Lysinuric protein intolerance is an autosomal recessive disease caused by mutation of SLC7A7, leading to defective transport of cationic amino acids at the membrane of epithelial cells in the intestine and kidney. The clinical picture involves failure to thrive and gastrointestinal symptoms, including pancreatic insufficiency, as well as renal insufficiency. There are excessive amounts of dibasic amino acids (arginine, lysine, and ornithine) in the urine. Pulmonary manifestations can include PAP and respiratory insufficiency. [12]

Secondary (acquired) PAP

Secondary development of PAP has numerous underlying causes, usually systemic inflammatory disease or hematologic disorders and cancers. [18, 23]

Other inciting agents for PAP include inhaled precipitants such as aluminum, titanium, silicates, cement dust, and insecticides. [3]

The etiology is unknown, although some have speculated that the small particles may stimulate excessive secretion of surfactant, impair macrophage clearance, or both.

Autoimmune PAP

Autoimmune (formerly known as idiopathic, or primary PAP), which accounts for more than 90% of all cases of PAP, is due to the presence of anti-GM-CSF antibodies. These antibodies prevent the binding of GM-CSF to GM-CSF receptors on alveolar macrophages. [1, 12, 18]

Research with GM-CSF knockout mice in 1994 revealed decreased surfactant clearance and the development of a condition similar to human PAP.

The GM-CSF knockout mice had normal hematopoiesis but impaired surfactant clearance by alveolar macrophages.

This first suggested that intracellular signaling initiated by the binding of GM-CSF to its receptor is necessary for pulmonary surfactant homeostasis. [23]

GM-CSF is a cytokine that stimulates proliferation and differentiation of neutrophil, monocyte, and macrophage hematopoietic cells in vitro when it engages with its receptor. The GM-CSF receptor comprises a specific alpha chain and common beta chain. Alveolar macrophages and alveolar type II epithelial cells express this beta chain. [1]

The interruption of GM-CSF signaling leads to failure of PU.1-mediated terminal differentiation of alveolar macrophages, impaired catabolism of surfactant, and progressive accumulation in structurally normal alveoli. [24]

Trapnell et al found GM-CSF – neutralizing autoantibody in serum and in BAL fluid obtained from humans with acquired PAP. [1] They suggested that the antibody inhibits GM-CSF activity and leads to the accumulation of proteinaceous fluid in the alveoli. This antibody has not been identified in patients with congenital or secondary PAP.

Other considerations

Various microorganisms are described in association with PAP, including Nocardia species, Mycobacterium tuberculosis and Mycobacterium avium-intracellulare, human immunodeficiency virus (HIV), Pneumocystis species, Cryptococcus species, and cytomegalovirus. [18]

Recent research examining host defense in GM-CSF knockout mice demonstrated the restoration of immune function with return to GM-CSF expression. This finding supports the conclusion that GM-CSF plays a role in local immunity in the lung. [1, 25]

Recent research examining therapy with GM-CSF by inhaled or subcutaneous route in patients with autoimmune PAP suggests benefit. [24]

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Physical Examination

PAP has been termed a silent pulmonary condition in which the auscultatory findings are usually relatively benign compared with the radiographic evidence of disease.

  • Physical examination may reveal evidence of failure to thrive or poor weight gain. Other findings include signs of a predisposing disease process (eg, malignancy, infection, immunodeficiency).

  • Digital clubbing is a late sign and is present in a small percentage of patients. [1, 10]

  • Examination of the respiratory system may reveal crackles, clubbing, and cyanosis. Most often, chest findings are unremarkable. [10]

  • In newborns with CAP, the clinical presentation is marked by respiratory failure rapidly leading to death. [11]

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