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].

• Fever

  Common presenting features include dyspnea, cough, low-grade fever, inspiratory crackles, and digital clubbing. Pulmonary function shows a restrictive ventilatory defect. [ncbi.nlm.nih.gov]

  Symptoms consisted of a high fever and a distressing cough. He was discharged 1 week later, but continued to have attacks of fever and coughing. He had had no known contact with tuberculosis. [doi.org]

  Other symptoms may include fatigue, weight loss, and low-grade fever. Lung infections may occur, and this can quickly worsen symptoms of shortness of breath and cause fever. [merckmanuals.com]

• Weight Loss

  A 34-year-old white male patient presented at the respiratory intensive care with severe respiratory failure, aggravated in the last two months, cough, night sweats and important weight loss and left spontaneous pneumothorax. [ncbi.nlm.nih.gov]

  Symptoms of PAP include: Exercise intolerance Shortness of breath Cough Fatigue Unintentional weight loss Some patients experience few or no symptoms. [pennmedicine.org]

  There may also be general fatigue and weight loss. The skin becomes tinged with blue in the most serious cases, an indication that blood is not being adequately oxygenated or rid of carbon dioxide. [britannica.com]

  Clinical features • 20-50 years males, smokers •1/3 asymptomatic • 1/3: persistent dry cough progressive dyspnoea fatigue,malaise,weight loss,failure to thrive intermittent low grade fever,night sweats pleuritic chest pain,hemoptysis • 1/3 land into PHTN [slideshare.net]

• Coarctation of the Aorta

  Here, we describe a case of total anomalous pulmonary venous return with coarctation of the aorta that was diagnosed as pulmonary alveolar proteinosis at autopsy in a male infant. [ncbi.nlm.nih.gov]

• Cough

  Common symptoms are dyspnea and cough. Chest X-ray shows bilateral perihilar infiltrates. Open-lung biopsy is the gold standard for the diagnosis. [ncbi.nlm.nih.gov]

• Dyspnea

  The clinical findings of slow-onset dyspnea or dyspnea on exertion and persistent dry cough are nonspecific; radiographic findings of "bat-wing configuration" and "crazy paving" appearance in high-resolution computed tomography are suggestive, but not [ncbi.nlm.nih.gov]

  The clinical findings of slow-onset dyspnea or dyspnea on exertion and persistent dry cough are nonspecific; radiographic findings of “bat-wing configuration” and “crazy paving” appearance in high-resolution computed tomography are suggestive, but not [doi.org]

• Sputum

  KEYWORDS: Bronchoalveolar lavage fluid; electron microscopy; induced sputum; pathology; pulmonary alveolar proteinosis; sputum [ncbi.nlm.nih.gov]

  Gastric washings, bronchial washings and sputum were all negative on culture for tubercle bacilli; bronchial washings cultured on Sabouraud's medium were negative, and a sputum smear was negative for acid-fast bacteria. [doi.org]

  […] silica or insecticides and hematologic malignancies) Diagnosis is usually made by lung biopsy Clinical Findings Almost 1/3 may be asymptomatic even with abnormal chest radiographs Symptoms, which are usually gradual in onset, include: Dry cough (or scant sputum [learningradiology.com]

  Cough is usually nonproductive, but is sometimes accompanied by sputum described as 'white and gummy' or 'chunky'. Fever and weight loss can also occur. [jmedicalcasereports.com]

• Hemoptysis

  Also hemoptysis was found to be the independent factor that can predict treatment failure. [ncbi.nlm.nih.gov]

  Clinical features • 20-50 years males, smokers •1/3 asymptomatic • 1/3: persistent dry cough progressive dyspnoea fatigue,malaise,weight loss,failure to thrive intermittent low grade fever,night sweats pleuritic chest pain,hemoptysis • 1/3 land into PHTN [slideshare.net]

  […] chest radiographs Symptoms, which are usually gradual in onset, include: Dry cough (or scant sputum production) Progressive dyspnea Fatigue and malaise Weight loss Intermittent low-grade fever and/or night sweats Pleuritic chest pain Rarely cyanosis or hemoptysis [learningradiology.com]

  The bronchoscopy was complicated by hemoptysis which resolved spontaneously and a left pneumothorax which necessitated placement of a left chest tube. [jtd.amegroups.com]

  He denied having had fever, chills, night sweats, hemoptysis, dyspnea or wheezing, and loss of weight. He smoked only a little. [doi.org]

• Productive Cough

  A 30-year-old male with progressively worsening dyspnea and non-productive cough for one year. He was a sugar cane plantation worker and had prior recurrent respiratory infections. [ncbi.nlm.nih.gov]

  Other symptoms include: - fatigue - weight loss - low-grade fever - non-productive cough - clubbing of fingers (advanced stages) - cyanosis (bluish tinge) of fingernails Diagnosis and Treatment of PAP Diagnostic tests include blood tests, chest X-rays [empowher.com]

  Clinical presentation is usually with non-specific respiratory symptoms such as dyspnea or a minimally-productive cough. Approximately one-third of patients may be asymptomatic. [radiopaedia.org]

• Severe Clinical Course

  PubMed Google Scholar Parenti G, Sebastio G, Strisciuglio P, Incerti B, Pecoraro C, Terracciano L, Andria G: Lysinuric protein intolerance characterized by bone marrow abnormalities and severe clinical course. [doi.org]

• Hepatomegaly

  […] congenital pulmonary alveolar proteinosis.We report a 6-month-old boy born with symmetrical intrauterine growth retardation presented with unexplained persistent tachypnea and hypoxemia associated with severe failure to thrive, anemia, hypoalbuminemia and hepatomegaly [ncbi.nlm.nih.gov]

• Chest Pain

  … The disease manifests itself in laboured breathing at rest or shortness of breath with exertion, and it is often accompanied by chest pain and a dry cough. There may also be general fatigue and weight loss. [britannica.com]

  Clinical features • 20-50 years males, smokers •1/3 asymptomatic • 1/3: persistent dry cough progressive dyspnoea fatigue,malaise,weight loss,failure to thrive intermittent low grade fever,night sweats pleuritic chest pain,hemoptysis • 1/3 land into PHTN [slideshare.net]

  pain Rarely cyanosis or hemoptysis Imaging Findings Bilateral perihilar consolidation in a configuration which may mimic pulmonary edema, but without cardiomegaly or pleural effusions Occasional unilateral; lymphadenopathy is rare Typically, changes [learningradiology.com]

  PAP has the following symptoms: Shortness of breath, also called dyspnea Chest pain or tightness Fever Weight loss Cough (sometimes, but not always) Low levels of oxygen in the blood Nail clubbing (abnormal growth of toenails or fingernails) Cleveland [my.clevelandclinic.org]

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.

• Air Bronchogram

  As with plain chest radiography, air bronchograms are not a feature despite widespread pulmonary consolidation. [doi.org]

  Investigations and Differential Diagnosis Chest Radiography The presence of diffuse bilateral mostly symmetrical alveolar, sometimes patchy infiltrates with air bronchograms give first clues to interstitial lung disease due to alveolar filling ( Fig 1A [pediatrics.aappublications.org]

  Complementary examinations Chest radiography Chest radiography reveals symmetric, bilateral alveolar opacities, without air bronchogram ( fig. 1 ), showing a peri-hilar and basal distribution. [err.ersjournals.com]

• Reticulonodular Pattern

  pattern, small nodules mimicking miliary disease, and a coalescence of various sized acinar nodules have been described. 39 Figure 2 (A) Thin section CT scan through the upper lobes of a patient with alveolar proteinosis. [doi.org]

  B, A crazy paving pattern from ground-glass opacification and overlaid reticulonodular pattern is shown. C, Foamy macrophage from BAL filled with lipid material (May-Grünwad staining) is seen. [pediatrics.aappublications.org]

The case is presented of a young man who obtained complete remission following treatment with granulocyte-macrophage colony stimulating factor, a new treatment option. pulmonary alveolar proteinosis treatment GM-CSF Statistics from Altmetric.com pulmonary [dx.doi.org]

The only variable capable of predicting treatment failure was the history of hemoptysis. CONCLUSION: The study revealed sufficiency of WLL as the PAP patients' treatment. [ncbi.nlm.nih.gov]

Smoking status, symptoms, PaO2, HRCT score, and DLCO, % predicted, were integrated into a scale (severity and prognosis score of PAP (SPSP)). [ncbi.nlm.nih.gov]

Prognosis is variable, ranging from improvement (with treatment) to a chronic and terminal course. A 30% 2-year mortality has been reported in adults prior to routine use of bronchoalveolar lavage 6. [radiopaedia.org]

The etiology of PAP includes genetic, primary (anti-granulocyte-macrophage colony-stimulating factor antibodies) and secondary (oncologic, rheumatologic, infectious, chemical and immunologic) causes. [ncbi.nlm.nih.gov]

To describe the epidemiologic, clinical, physiologic, and laboratory features of autoimmune PAP in a large, contemporaneous cohort of patients with PAP. [ncbi.nlm.nih.gov]

Objectives : To describe the epidemiologic, clinical, physiologic, and laboratory features of autoimmune PAP in a large, contemporaneous cohort of patients with PAP. [doi.org]

Also documented is that alveolar macrophages from some PAP patients have decreased levels of the transcription factor peroxisome proliferator-activated receptor–gamma (PPAR-gamma), which normalize after treatment with GM-CSF. [4] Epidemiology Frequency [emedicine.com]

Recent advances in the understanding of the pathophysiology of PAP demonstrate that the idiopathic form is due to antigranulocyte macrophage-colony stimulating factor antibodies. [ncbi.nlm.nih.gov]

The nature of these associations with PAP and the underlying pathophysiology is poorly understood. C. Acquired PAP Acquired PAP is the most common and well-known form. [clinicaladvisor.com]

Pathophysiology The alveoli in pulmonary alveolar proteinosis (PAP) are filled with proteinaceous material, which has been analyzed extensively and determined to be normal surfactant composed of lipids and surfactant-associated proteins A, B, C, and D [emedicine.com]

Cellular lesions may be involved in the pathophysiology of interstitial pneumonia [ 2 ]. Abnormalities of surfactant clearance GM-CSF is a key cytokine in PAP pathophysiology. [err.ersjournals.com]

A surfactant is a normal lung component that coats the alveoli and prevents a lung collapse In Pulmonary Alveolar Proteinosis, either there is an increased production of the surfactant or there is impaired removal of the surfactant by lung macrophages [dovemed.com]

Therefore, timely detection of neutralizing anti-GM-CSF autoantibodies and development of an effective therapy are necessary to prevent deterioration of cryptococcal infection in these patients. [ncbi.nlm.nih.gov]

To prevent barotrauma, maximum inspiratory pressure was limited to 30 cmH 2 O. [elsevier.pt]

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.