AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Pulmonary alveolar proteinosis (PAP) is an extremely rare cause of respiratory failure in the pediatric age group. PAP is characterized by intra-alveolar accumulation of lipid and proteinaceous material that is periodic acid-Schiff (PAS) positive when visualized on light microscopy.^{1, 2} The disease is not associated with inflammation, and lung architecture is typically preserved. The clinical course of PAP varies and ranges from respiratory failure and death to spontaneous resolution.

Three clinically distinct forms of PAP have been described: congenital, secondary, and acquired.² More than 90% of cases occur as an acquired (idiopathic) disorder, typically in adults.^{3, 2} The 3 distinct types of PAP differ in respect to etiology, clinical course, therapy, and outcome.^{1, 2, 4}

Pathophysiology

The alveolar airspaces are filled with a dense proteinaceous-lipid fluid mix, which is thought to occur secondary to impaired clearance of surfactant by alveolar macrophages.^{5, 3} This surfactant-derived alveolar fluid may cause increased work of breathing, a diminished surface area for gas diffusion, and, ultimately, respiratory failure.⁵ The pulmonary interstitium and airways are relatively spared.

Secondary iatrogenic lung damage may occur in the neonatal form as a consequence of the required high levels of ventilator support and high-inspired oxygen concentrations.^{6, 7} The development of superinfection, which is thought to be a relatively common consequence of pulmonary macrophage dysfunction, may further complicate the condition.^{8, 9}

Frequency

International

• PAP is extremely rare. In a 2002 report, at least 410 cases in the literature were identified.¹⁰ The estimated annual incidence was 0.36, and the prevalence was 3.76 cases per million population worldwide.

Mortality/Morbidity

• In neonates with congenital alveolar proteinosis (CAP), the mortality rate associated with conventional therapy is 100%.^{5, 6} Lung transplantation improves survival.
• In a retrospective analysis of 343 cases of acquired pulmonary alveolar proteinosis, the 5-year survival rate was 75%.¹⁰ The same retrospective analysis estimated the 5-year survival rate for children younger than 5 years to be 14% ±13%, with only one of 7 young children surviving beyond 10 months. Children with late-onset disease appear to have the best likelihood for survival, but they generally require treatment with repeated lung lavage.¹⁰
• Many children have prolonged oxygen dependence and other symptoms of respiratory compromise, including dyspnea, chronic cough, and failure to gain weight in the absence of recurrent PAP.¹⁰

Race

• No race predilection is reported in children or adults.

Sex

• Most patients with acquired PAP are men (male-to-female ratio of 2.65:1), and 72% have a history of smoking.^{2, 10}
• No male predominance is observed among nonsmokers with PAP; this observation suggests that the overall male predominance is secondary to a more common use of tobacco by men than by women.¹⁰

Age

• More than 90% of all cases of PAP are the acquired type. The median age at the time of diagnosis is 39 years.^{10, 2}
• The age distribution of PAP in children is unknown.
• The congenital form occurs shortly after birth.^{5, 6}

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.¹⁰

• Neonatal respiratory distress
• • Patients with the congenital form of pulmonary alveolar proteinosis (PAP) present with progressive respiratory failure and marked hypoxemia shortly after birth.⁵
  • 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.^{11, 7, 6}
  • 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%.^{4, 8, 10} 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.⁴
• 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.¹⁰
• Chest pain: Chest pain is uncommon, occurring in 10-20% of patients.⁴
• Fever: Fever is unusual and may signify superinfection.⁴
• 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.⁵
• 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.¹⁰

Physical

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.⁴
• Examination of the respiratory system may reveal rales, clubbing, and cyanosis. Most often, chest findings are unremarkable.⁴
• In newborns with CAP, the clinical presentation is marked by respiratory failure rapidly leading to death.⁵

Causes

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

• Congenital PAP describes a group of disorders caused by mutations in the genes that encode for surfactant protein B or C or the beta chain of the receptor for granulocyte-macrophage colony-stimulating factor (GM-CSF).¹⁰
• • Most cases of CAP are transmitted in an autosomal recessive pattern.⁵
  • 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.⁵
  • Mutations in the SP-C gene can also lead to neonatal respiratory distress.¹²
  • 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.¹⁰
  • Other cases of congenital PAP have no known abnormalities in SP-B but are associated with disturbances in the beta chain of the GM-CSF receptor.¹⁰
• Secondary development of PAP has numerous underlying causes.¹⁰
• • PAP is described in association with lysinuric protein intolerance.
  • Other inciting agents for inhaled precipitants of PAP include aluminum, titanium, silicates, and insecticides.
  • The etiology is unknown, although some have speculated that the small particles may stimulate excessive secretion of surfactant, impair macrophage clearance, or both.
• Acquired PAP, which accounts for more than 90% of all cases of PAP, has an unknown etiology; however, the understanding of the possible pathogenesis has recently advanced.^{2, 10}
• • Research with GM-CSF knockout mice revealed decreased surfactant clearance and the development of a condition similar to human PAP.
  • 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.²
  • The GM-CSF knockout mice had normal hematopoiesis but impaired surfactant clearance by alveolar macrophages.
  • Trapnell et al found GM-CSF-neutralizing autoantibody in serum and in BAL fluid obtained from humans with acquired PAP.² 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.
• 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.¹⁰
• 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.^{2, 13}

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Pneumonia (bacterial, viral, atypical)
Interstitial pneumonitis
Bronchiolitis obliterans organizing pneumonia (BOOP)
Chronic eosinophilic pneumonia
Acute eosinophilic pneumonia
Hypersensitivity pneumonitis
Usual interstitial pneumonitis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Gene mutation analysis
• • Blood of infants with congenital pulmonary alveolar proteinosis (PAP) should be analyzed for mutation analysis of the SP-B and SP-C gene.
  • 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) measurement¹⁰
• • 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.¹⁴
• CBC count: Polycythemia may be found as a consequence of chronic hypoxia
• ABG analysis
• • In their examination of 410 patients reported in the literature, Seymour et al reported a an arterial partial pressure of oxygen (PaO₂) of 58.6 ±15.8 mm Hg.¹⁰
  • ABG analysis may reveal a low partial pressure of oxygen and a compensated respiratory alkalosis secondary to hyperventilation.¹⁰
• Latex agglutination test: The finding of autoantibodies (neutralizing IgG antibody against GM-CSF) in patients with acquired PAP has led to the development of a test with 100% sensitivity and 98% specificity for diagnosis.¹⁵

Imaging Studies

• 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.
  • In the acquired and secondary forms, chest radiography typically reveals widespread, bilateral patchy and asymmetric airspace consolidation without central or peripheral distribution.^{16, 10}
  • Radiographic findings are typically disproportionately abnormal in comparison to the clinical presentation.²
  • 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.⁴
• Chest CT
• • Chest CT imaging reveals scattered airspace filling. Air bronchograms are uncommon.
  • High-resolution chest tomography (HRCT) typically demonstrates a ground-glass appearance or consolidation. Interlobular and intralobular septae are thickened and arranged in an irregular manner that has been termed "crazy paving."¹⁷
  • Reticular interstitial attenuations may also be noted.
  • 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.¹⁸

Other Tests

• Pulmonary function testing (PFT) may reveal a mildly restrictive pattern of lung disease and a diminished carbon monoxide diffusing capacity.^{10, 2}
• PAP is said to increase the shunt fraction more than other diffuse infiltrative lung processes.²

Procedures

• BAL
• • Classic findings in diagnostic BAL include a milky or opalescent aspirate with large alveolar macrophages and increased lymphocytes but few other inflammatory cell types.^{2, 19}
  • 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.
  • The aspirated material stains strongly positive for PAS, as is expected.¹
  • SP-A and SP-D levels are elevated in BAL fluid from patients with PAP, as compared with healthy volunteers.¹⁹
• Lung biopsy
• • Open lung biopsy is the criterion standard for the diagnosis of PAP.^{2, 19, 1}
  • Open lung biopsy is not commonly required because the diagnosis can be established in approximately 75% of cases by the classic BAL findings.^{19, 10}

Histologic Findings

• 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.^{19, 10}
• 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.^{19, 10}
• 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.³

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The appropriate management depends on the patient's age at presentation, the severity of symptoms, and the anticipated course of the disease. Any predisposing conditions (eg, malignancy, infection) should be treated because resolution of the primary condition may lead to remission of pulmonary alveolar proteinosis (PAP). Reports describe spontaneous remission of primary PAP without medical intervention.^{1, 10} Treatment of congenital PAP is often difficult.

• Mechanical ventilation: Mechanical ventilation is necessary in children with congenital PAP. No reports show any benefit from the use of high-frequency oscillatory ventilation (HFOV) or other unconventional forms of mechanical ventilation.³
• Gene therapy: Because congenital PAP is a single-gene defect, it may be a candidate disease for gene therapy.
• GM-CSF therapy: In addition, several trials of GM-CSF therapy for acquired PAP have shown encouraging results.^{20, 21}

Surgical Care

The mainstay of therapy in PAP is whole-lung lavage. Patients who undergo lavage during the course of their illness have improved survival rates. In addition, 84% of the published cases reported clinical, physiologic, and radiographic improvements after initial therapeutic lavage.^{10, 22} Response rates substantially differ when patients are divided into cohorts by age. Patients younger than 20 years old have a 58% response compared with 90% patients older than 40 years.¹⁰

The mechanism of improvement is unknown but is presumed to be the removal of surfactant buildup or minimizing the effect of macrophage dysfunction. Successful treatment with lobar lavage with fiberoptic bronchoscopy is also reported.

Other surgical options include extracorporeal membrane oxygenation (ECMO) and lung transplantation.²

• Lung lavage
• • In brief, the procedure involves single-lung ventilation while the contralateral lung is lavaged with sodium chloride solution. A double-lumen endotracheal tube (ETT) is used in older children to allow for simultaneous ventilation of one lung and lavage of the contralateral lung with the patient under general anesthesia.²³
  • Isotonic sodium chloride solution with or without heparin is generally instilled into the lungs. The patient is ventilated with 100% oxygen, and the dependent lung is filled with 3-5 mL/kg of fluid and drained. Lavage is repeated until no sediment material is obtained.
  • The lungs retain variable amounts of fluid. Chest percussion is reported to improve the yield of material. The patient should be intermittently suctioned through the ETT after the procedure to remove any residual fluid.
  • Serum electrolyte levels should be monitored because fluid fluxes may cause electrolyte imbalances.
  • The use of whole-lung lavage is less well established in young infants and newborns than in others primarily because of the technical difficulties associated with passing a necessarily large ETT through a small glottis. However, the success rate of this procedure is described in infants as small as 5 kg. In smaller infants, whole-lung lavage performed while the infant is receiving cardiopulmonary bypass or ECMO is reported.
• ECMO: ECMO may provide a bridge to lung transplantation or definitive lung lavage in patients who are either too critically ill or too small to undergo lavage.
• Lung transplantation
• • At this time, the only definitive therapy for CAP is bilateral lung transplantation.²
  • PAP has recurred in lungs transplanted into adults.²⁴

Consultations

• CAP
• • Consult a neonatologist and a pulmonologist when a patient has congenital PAP. An opinion from or a referral to a center with expertise in neonatal lung transplantation is required when this option is being considered.
  • Consultation with a geneticist should be offered to parents of a child with congenital PAP. Antenatal screening for this condition is now possible.
• Acquired PAP
• • For the older child, consultation with a pulmonologist is mandatory.
  • The opinions of an immunologist, an infectious disease specialist, or a hematologist may also be necessary, depending on clinical findings and suspicion for secondary PAP.

Diet

No specific diet is necessary. However, as in any chronic disease, attention should be paid to the provision of sufficient calories to maintain adequate growth. Young infants with feeding difficulties due to dyspnea may require feeding through a nasogastric or gastrostomy tube. When prescribing a high-calorie diet, ensure that the carbohydrate load is not excessive because this may exacerbate respiratory difficulties due to a high respiratory quotient and subsequent high CO₂ burden.

Activity

In general, the patient's degree of dyspnea limits his or her activity. No limitations on activity are necessary.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

To date, no medical therapy has proven effective against pulmonary alveolar proteinosis (PAP). Numerous investigators report the successful use of GM-CSF in adults with PAP.² Evidence suggests that GM-CSF leads to therapeutic responses in pediatric patients as well.²⁵ One case report described successful therapy with intravenous immunoglobulin (IVIG) for a single case of CAP.²⁶

Drug Category: Colony-stimulating factors

Seymour et al (2001) reported their experience in treating PAP with GM-CSF.²⁰ Fourteen patients received GM-CSF at an initial dosage of 5 mcg/kg/d for 6-12 weeks. The alveolar-arterial oxygen gradient, carbon monoxide diffusing capacity, chest CT scans, and exercise test results were serially monitored. Nonresponders underwent a stepwise dose increase; 5 of 14 patients (34%) responded to a dosage of 5 mcg/kg/d, and 1 patient responded to 20 mcg/kg/d. Overall, 43% of patients responded. Among responders, the mean improvement in the difference in partial pressures of oxygen in mixed alveolar gas and mixed arterial blood (A-a DO₂) was 23.2 mm Hg. Responses lasted a median of 39 weeks, and the effects were reproducible with the resumption of therapy. No serious adverse effects were noted. GM-CSF–related eosinophilia was predictive of a successful response to therapy.

Another prospective phase II trial of subcutaneous GM-CSF showed that A-a DO₂ values improved in 3 of 4 patients treated with 5-9 mcg/kg/d. Values changed from 48.3 ± 20.1 mm Hg at baseline to 18.3 ± 4.2 mm Hg at week 16.²¹

One case report described the successful treatment of a 13-year-old patient who was given inhaled GM-CSF after whole-lung lavage failed.²⁵

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Admit patients for diagnostic workup and lung lavage.
• For affected neonates, lung transplantation should be considered early.

Further Outpatient Care

• Monitor for disease progression. Increasing symptoms may warrant further lung lavage. Vigorous lung physiotherapy may be helpful.
• The optimal imaging modality for serial follow-up remains unclear. Lee et al (1997) concluded that, although HRCT findings are most closely correlated with pulmonary function, plain chest radiography provides sufficient information in conjunction with clinical findings and PFT.¹⁷

In/Out Patient Meds

• Bronchodilators may be used if evidence of airway reactivity is present.
• Mucolytics, including acetylcysteine, trypsin, and ambroxol, have all been used; their efficacy is unknown.
• Recent data suggest that GM-CSF may be useful.
• Although a high-calorie diet is essential, ensure that the carbohydrate load is not excessive because this may exacerbate respiratory difficulties by causing a high respiratory quotient and hence a high CO₂ burden.
• No medications are specifically contraindicated.

Transfer

• Transfer to a tertiary center may be necessary for further diagnostic workup, supportive care ECMO, or lung transplantation.
• In view of the rarity of this condition, consider early transfer to a tertiary level institution experienced in managing this condition.

Deterrence/Prevention

• Smoking by, or around, the patient must be discouraged.

Complications

• Death
• Superinfection
• Pulmonary fibrosis
• Secondary amyloidosis

Prognosis

• CAP: Without lung transplantation, mortality is almost inevitable in the neonatal age group.¹⁰
• Acquired pulmonary alveolar proteinosis (PAP): Analysis of published data suggested an actuarial 5-year disease-specific survival rate of 88% ±5%. The 5-year survival rate for children younger than 5 years was 14% ±13%, although this rate represented data from 7 children.¹⁰ Many investigators have reported spontaneous remission in a select group of adults with acquired PAP. Seymour and Presneill (2002) reported 24 of 303 patients (7.9%) had spontaneous improvement.¹⁰ Whether this improvement led to true resolution of the disease and restoration of lung function and surfactant clearance was unclear.

Patient Education

• Patients with PAP may benefit from postural drainage, but no data support this hypothesis.
• Smoking near the patient must be discouraged.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to recognize associated conditions, including immunodeficiency states, malignancy, and infections
• Failure to offer genetic counseling to parents of an affected child

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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32. 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. May-Jun 1992;12(3):365-83. [Medline].
33. Ganguli PC, Lynne-Davies P, Sproule BJ. Pulmonary alveolar proteinosis, bronchiectasis and secondary amyloidosis: a case report. Can Med Assoc J. Mar 4 1972;106(5):569 passim. [Medline].
34. Gough J. Silicosis and alveolar proteinosis. Br Med J. Mar 11 1967;1(540):629. [Medline].
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Article Last Updated: Aug 5, 2008