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

  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]

  Approximately 33% of patients are asymptomatic at presentation, whereas others present with a myriad of symptoms, including dyspnea, dry cough, fever malaise, and respiratory failure. [medical-case-reports.imedpub.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]

  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]

• Weight Loss

  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 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]

  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]

  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]

  The signs and symptoms of PAP include shortness of breath, a cough, low grade fever, and weight loss. The clinical course of PAP is unpredictable. Spontaneous remission is recognized, and some patients have stable symptoms. [en.wikipedia.org]

• Asymptomatic

  Single lung lavage of the left lung was done at that time following which he was asymptomatic for 6 months. [medical-case-reports.imedpub.com]

  Family-based whole-genome analysis revealed a homozygous deletion that disrupts CSF2RA, CRLF2, and IL3RA gene in the pseudoautosomal region of the X chromosome in the affected child and one of asymptomatic siblings. [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]

  The patient was asymptomatic at discharge from the hospital 2 weeks later and remained well at follow-up 3 months later. A 45-year-old male farmer presented with a 2-month history of increasing breathlessness and dry cough. [nejm.org]

• Anemia

  […] a very rare cause of 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 [ncbi.nlm.nih.gov]

  Acquired and inherited GATA1 mutations contribute to Diamond-Blackfan anemia, acute megakaryoblastic leukemia, transient myeloproliferative disorder, and a group of related congenital dyserythropoietic anemias with thrombocytopenia. [doi.org]

• 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]

  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 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]

  Although most patients experience insidious onset of dyspnea, cough, exercise intolerance, or generalized malaise, some patients present with acute onset dyspnea or productive cough. [clinicaladvisor.com]

• Dyspnea

  If dyspnea is moderate or severe, treat with whole lung lavage. Click here for Patient Education [merckmanuals.com]

  The case presented is a 55-year-old woman with six months of progressive dyspnea, who developed hypoxemic respiratory failure requiring mechanical ventilation; she had typical findings of PAP on imaging and BAL. [ncbi.nlm.nih.gov]

  There are no absolute criteria for lavage in the setting of PAP; most often, lavage is carried out for relief of dyspnea. [journals.lww.com]

  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

  However, the low positive rate and poor quality of slices restrict the application of sputum samples in the diagnosis of PAP. [ncbi.nlm.nih.gov]

  […] protein or GM-CSF receptor genes Secondary (most common), associated with silica dust, aluminum, fiberglass, chemicals, immunosuppression, leukemia / lymphoma, Nocardia, Mycobacteria and Aspergillosis Usually adults (more common in smokers), also children Sputum [pathologyoutlines.com]

  […] period in term babies poor prognosis if left untreated (lung transplantation) may be distinct entity also know as chronic pneumonitis of infancy due to a mutation in genes encoding SP-B, SP-C, or GM-CSF receptor 8,9 Although imaging, bronchial lavage and sputum [radiopaedia.org]

• 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]

  Rarely observed symptoms include hemoptysis and cyanosis. [symptoma.com]

  […] 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]

• Productive Cough

  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]

  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]

  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]

• Chest Pain

  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 and a dry cough. [britannica.com]

  Patients may experience loss of weight, mostly non-productive cough, pleuritic chest pain and night sweats. Rarely observed symptoms include hemoptysis and cyanosis. [symptoma.com]

  […] 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 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]

  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]

  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]

• Reticulonodular Pattern

  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]

  Secondary pulmonary alveolar proteinosis can be distinguished from primary or idiopathic disease on the basis of the staining pattern of surfactant specific apoproteins in histological specimens. 64 In primary cases a uniform staining pattern is seen [doi.org]

The aim of treatment is symptomatic amelioration along with radiological and physiological improvement [ 10, 11 ]. [medical-case-reports.imedpub.com]

Treatment and prognosis Standard treatment includes therapeutic whole-lung bronchoalveolar lavage to remove alveolar material, although its role in children is less certain 6. GM-CSF supplementation has been used with varying effectiveness 12. [radiopaedia.org]

This study is one of several treatment trials to be conducted by researchers at the University of Cincinnati in conjunction with the Rare Lung Diseases Consortium. [uchealth.com]

The reported treatment of PAP using therapeutic bronchoalveolar lavage was in 1960 by Dr. [en.wikipedia.org]

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 symptoms and prognosis are extremely variable. Bronchoalveolar lavage fluid and/or transbronchial lung biopsy are useful for diagnosis; surgical lung biopsy is often unnecessary but useful in the focal involvement. [ncbi.nlm.nih.gov]

• lung biopsy • transbronchial biopsy • alveoli filled with non foamy lipo proteinaceous material 10. treatment: • steroids • mucolytics • aerosol proteinases • treating underlying cause • whole lung lavage •Prognosis: poor in neonates • adults- mortality [slideshare.net]

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]

In a recent epidemiologic study from Japan, Autoimmune PAP has an incidence and prevalence higher than previously reported and is not strongly linked to smoking, occupational exposure, or other illnesses. [en.wikipedia.org]

Epidemiology Because of the rarity of pulmonary alveolar proteinosis, it is difficult to estimate its true incidence and prevalence. [rc.rcjournal.com]

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]

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]

It is unclear whether idiopathic and secondary cases share a common pathophysiology. [merckmanuals.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]

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.medscape.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]

Instead, these children had a genetic defect that prevents macrophages from receiving signals from GM-CSF. This finding launched an effort to develop what could be the first successful form of lung gene therapy. [cincinnatichildrens.org]

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

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