Pulmonary alveolar proteinosis (PAP) is a rare condition, whose symptoms are specific to pulmonary pathology, but hardly pathognomonic to the particular disease. Clinical manifestations tend to develop over a period of time; a considerable number of patients (circa 30%) do not report any symptoms, even though PAP is diagnosed due to significant radiologic findings in the lungs.

The condition encompasses three distinct clinical categories. Idiopathic PAP usually leads to symptomatology during adulthood and is diagnosed at that time; congenital PAP is diagnosed in neonates while secondary PAP is a complication of an underlying pathology and also develops in adults [1].

With regard to the symptoms associated with pulmonary alveolar proteinosis, the ones most commonly reported by patients include dyspnea, which is exertional in nature, fatigue and periodic fever, which tends to be low-grade [2]. Patients may experience loss of weight, mostly non-productive cough, pleuritic chest pain and night sweats. Rarely observed symptoms include hemoptysis and cyanosis. Congenital pulmonary alveolar proteinosis leads respiratory distress syndrome and entails tachypnea, grunting during expiration, nasal flaring, cyanosis, subcostal retractions and, in severe cases, apnea or hypothermia [3]. PAP-induced respiratory distress syndrome is refractory to corticosteroids and surfactants. Lastly, secondary PAP may underlie other pathological conditions, such as myelodysplastic syndromes, an HIV infection, thymic alymphoplasia and a variety of other disorders [4] [5] [6].

The diagnosis of pulmonary alveolar proteinosis requires a multitude of examinations and procedures, such as a bronchoalveolar lavage (BAL), chest radiograph, a high-resolution computed tomography (HRCT), pulmonary function tests, blood tests and, rarely nowadays, open lung biopsy.

Bronchoalveolar lavage

Currently, BAL is the most useful tool which renders the diagnosis possible. A histological analysis of fluid retrieved via BAL will reveal large alveolar macrophages which closely resemble monocytes and an extensive lymphocytic presence [7] [8] [9]. Approximately 3/4 of the affected patients are diagnosed with the use of BAL, which also illustrates the presence of granular, eosinophilic lipoprotein complexes.

Radiographs and HRCT

Thoracic x-rays are of use but the findings of bilateral alveolar infiltrates do not correspond to clinical symptoms and are not pathognomonic. An HRCT is expected to yield results, such as ground-glass opacifications and "crazy-paving" patterns formed by interlobular septal thickening next to healthy parenchyma [2]. Nevertheless, this particular finding can also be observed in a plethora of other conditions, such as hemorrhage, acute interstitial pneumonia lipoid pneumonia, and other conditions [10] [11].

Pulmonary function tests

Its use is supportive, but not diagnostic of PAP. It reveals a restrictive pattern, diminished FVC and a reduced diffusing capacity.

Surgical biopsy

An open lung biopsy is not commonly employed in current practice, due to the success of BAL in diagnosing pulmonary alveolar proteinosis [12]. However, cases with a high suspicion of PAP with a negative BAL may be investigated surgically for purposes of biopsy.

Blood tests

May be carried out to detect elevated serum anti-GM-CSF antibody titers if the nature of PAP is presumed to be idiopathic.

The primary treatment for PAP is a procedure called whole lung lavage, where saline is used to wash out the accumulated material from the lungs. This procedure can significantly improve symptoms and lung function. In some cases, especially in autoimmune PAP, medications that modulate the immune system, such as GM-CSF (granulocyte-macrophage colony-stimulating factor) therapy, may be used. Treatment plans are tailored to the individual, depending on the type and severity of PAP.

The prognosis for PAP varies depending on the type and severity of the disease. Many patients respond well to treatment, particularly whole lung lavage, and can lead relatively normal lives. However, some may experience recurrent symptoms or complications such as infections. Regular follow-up with a healthcare provider is essential to monitor the condition and adjust treatment as needed.

The cause of PAP depends on its type. Autoimmune PAP, the most common form, is caused by an immune system malfunction that leads to the production of antibodies against GM-CSF, a protein crucial for clearing surfactant from the lungs. Secondary PAP can result from exposure to certain environmental factors, infections, or underlying health conditions. Congenital PAP is due to genetic mutations affecting surfactant production or clearance.

PAP is a rare condition, with an estimated prevalence of 3.7 to 6.2 cases per million people. It can affect individuals of any age but is most commonly diagnosed in adults between 20 and 50 years old. There is a slight male predominance in autoimmune PAP, while congenital forms are more common in infants and children.

In PAP, the normal process of surfactant clearance from the alveoli is disrupted. Surfactant is a substance that reduces surface tension in the lungs, aiding in breathing. In autoimmune PAP, antibodies interfere with GM-CSF, impairing the function of alveolar macrophages, the cells responsible for clearing surfactant. This leads to the accumulation of surfactant and the characteristic symptoms of the disease.

Currently, there are no specific measures to prevent PAP, particularly the autoimmune and congenital forms. For secondary PAP, reducing exposure to known risk factors, such as certain occupational hazards or infections, may help lower the risk. Early diagnosis and treatment are crucial to managing the disease effectively and preventing complications.

Pulmonary Alveolar Proteinosis is a rare lung disorder characterized by the buildup of protein-rich material in the alveoli, leading to respiratory symptoms. Diagnosis involves imaging and laboratory tests, and treatment primarily includes whole lung lavage and, in some cases, immune-modulating therapies. While the prognosis is generally favorable with appropriate treatment, ongoing monitoring is essential.

If you or someone you know is experiencing symptoms like persistent shortness of breath, cough, or fatigue, it may be worth discussing the possibility of PAP with a healthcare provider. Understanding the condition, its symptoms, and available treatments can empower patients to seek appropriate care and improve their quality of life. Regular follow-up and adherence to treatment plans are key to managing PAP effectively.

1. Seymour JF, Presneill JJ. Pulmonary alveolar proteinosis: Progress in the first 44 years. Am J Respir Crit Care Med. 2002;166:215–35.
2. Juvet SC, Hwang D, Waddell DK, Downey GP. Rare lung diseases II: Pulmonary alveolar proteinosis. Can Respir J. 2008 May-Jun; 15(4): 203–210.
3. Teja K, Cooper PH, Squires JE, Schnatterly PT. Pulmonary alveolar proteinosis in four siblings. N Engl J Med. 1981;305:1390–2.
4. Cordonnier C, Fleury-Feith J, Escudier E, Atassi K, Bernaudin JF. Secondary alveolar proteinosis is a reversible cause of respiratory failure in leukemic patients. Am J Respir Crit Care Med. 1994;149:788–94.
5. Israel RH, Magnussen CR. Are AIDS patients at risk for pulmonary alveolar proteinosis? Chest. 1989;96:641–2
6. Haworth JC, Hoogstraten J, Taylor H. Thymic alymphoplasia. Arch Dis Child. 1967;42:40–54.
7. Wang BM, Stern EJ, Schmidt RA, Pierson DJ. Diagnosing pulmonary alveolar proteinosis. A review and an update. Chest. 1997;111:460–466.
8. Iyonaga K, Suga M, Yamamoto T, et al. Elevated bronchoalveolar concentrations of MCP-1 in patients with pulmonary alveolar proteinosis. Eur Respir J. 1999;14:383–389.
9. Schoch OD, Schanz U, Koller M, et al. BAL findings in a patient with pulmonary alveolar proteinosis successfully treated with GM-CSF. Thorax. 2002;57:277–280.
10. Rossi SE, Erasmus JJ, Volpacchio M, et al. “Crazy-paving” pattern at thin-section CT of the lungs: Radiologic-pathologic overview. Radiographics. 2003;23:1509–19.
11. Ebara H, Ikezoe J, Johkoh T, et al. Chronic eosinophilic pneumonia: Evolution of chest radiograms and CT features. J Comput Assist Tomogr. 1994;18:737–44
12. Shah PL, Hansell D, Lawson PR, et al. Pulmonary alveolar proteinosis: clinical aspects and current concepts on pathogenesis. Thorax. 2000;55:67–77.