Alveolar Proteinosis


Article Author:
Mouna Mlika
Hajira Basit


Article Editor:
Pratibha Kaul


Editors In Chief:
Juan Batlle
Jitendra Sisodia
Jeffrey Miller


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Pritesh Sheth
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Richard Ciresi
Hajira Basit
Phillip Hynes
Kavin Sugumar


Updated:
4/27/2019 7:25:55 PM

Introduction

Pulmonary alveolar proteinosis is a rare disease characterized by an accumulation of a lipoproteinaceous material within the alveoli. It can be idiopathic or secondary. It is also known as pulmonary alveolar phospholipoproteinosis and alveolar lipoproteinosis.[1]

Etiology

Pulmonary alveolar proteinosis may be idiopathic or secondary. Secondary cases may accompany the following disorders:

  • Infections: infectious causes can include bacteria (Nocardia), fungi, viruses, Mycobacteria, or Pneumocystis carinii
  • Neoplasms including lymphomas and leukemias
  • Inorganic dust exposure including silicosis and aluminum
  • Immunodeficiencies such as HIV infection, lung transplantation, and IgA deficiency

Other conditions such as surfactant deficiency and Fanconi's anemia also have associations with the disorder.

Epidemiology

The incidence and prevalence of alveolar proteinosis are not known. Pulmonary alveolar proteinosis is a rare disease mainly observed in males, with a sex ratio of 2:1. Estimates of the mean age of these patients run between 30 and 50 years with exceptional pediatric cases.[2] A small number of case reports in infants and children exist. Many patients are former or current smokers.

Pathophysiology

The pathogenesis of this disease continues to be unclear, but many theories have been proffered in the literature, including an impairment in the ability of macrophages to clear secretions or an overproduction of surfactant dealing with a deficient clearance activity of macrophages.

The macrophages themselves are a potential contributing factor in the formation of the amorphous material upon dying. The theory of impaired macrophage function is sustained by the association of this disease to immunodeficiency diseases that cause dysfunction of macrophages. Moreover, reports of the presence of antibodies of immunoglobulin isotype G against granulocyte-macrophage-colony-stimulating factor (GM-CSF) in pulmonary proteinosis also exist.[2][3]

Histopathology

The diagnosis of alveolar proteinosis may be made based on the bronchoalveolar fluid findings but is frequently made based on tissue samples including open or transbronchial biopsy.

Bronchoalveolar lavage fluid is characteristic when it has a milky appearance. The presence of alveolar macrophages engorged with Periodic Acid Schiff (PAS) positive material, acellular eosinophilic bodies in a background of eosinophilic granules are key-features. The bronchoalveolar lavage formula characteristically presents with a decrease in the number of alveolar macrophages and a slight increase in T lymphocytes (with a tendency toward a high CD4/CD8 ratio). Elevated levels of several tumor markers (carcinoembryonic antigen (CEA), carbohydrate antigens sialyl Lewis (CA19-9) have been found in bronchoalveolar lavage fluid form in some patients with alveolar proteinosis. It is possible that these markers may reflect disease activity without a real consensus. Serum or BAL KL-6 has proven useful for the diagnosis of alveolar proteinosis and the estimation of its activity.

Gross features consist of a yellow-tan discolorated parenchyma. The architecture of the lung appears preserved, and the process appears to fill the alveolar spaces. The abnormality primarily affects the right and appears to fill the alveolar spaces.

In tissue specimens, the histologic hallmark consists of an intra-alveolar accumulation of a granular eosinophilic and amorphous material with diffuse and rarely patchy lesions. Within this material, rounded empty spaces, cholesterol clefts, and small dense globular eosinophilic material are distinctive features of the diagnosis. Interstitial fibrosis or inflammation is commonly absent. If observed, the association to an infection or a neoplasm has to be suspected by the pathologist. In case of an association to silicosis, the polarization microscopy may show birefringent needle-like particles.  In long-standing cases, observable tissue changes may include interstitial fibrosis.[4][1]

With electron microscopy, the characteristic features consist of multilamellar structures of trilaminar membranes separated by amorphous material. Electron-dense bodies and membranous vesicles are often found at the center of the multilamellar structures. Even if these features can be helpful, electron microscopy isn't a routine exam.

History and Physical

Pulmonary proteinosis is asymptomatic in one-third of the patients. In symptomatic patients, symptoms are non-specific consisting mainly of cough, dyspnea, fatigue, weight loss, hemoptysis and chest pain. In very rare cases, patients may report an expectoration of 'chunky' gelatinous material. Physical examination is often normal. Auscultation of crackles may be a feature on chest examination, but lung auscultation is often normal because of the absence of gas movement due to complete filling of distal airspaces.[5][6]

Evaluation

The characteristic findings on high resolution computed tomography consist of bilateral ground-glass opacities often associated with interlobular septal thickening with a characteristic feature of 'crazy paving.' In less typical cases, radiologic findings consist of bilateral and symmetrical areas of airspace consolidation or ground-glass opacities. In patients with less severe disease, the radiologic features may consist of hazy areas of ground-glass opacities rather than consolidation. The abnormalities tend to involve mainly the perihilar regions and lower lobes.[7] 

Treatment / Management

No immediate treatment is necessary in some cases because of the potential for spontaneous remission. In the majority of the cases, the treatment basis is therapeutic whole lung lavage via a double-lumen endotracheal tube.[6][7]

Differential Diagnosis

The major differential diagnoses consist in:

  • Pulmonary edema
  • Pneumocystis carinii pneumonia 
  • Alveolar mucinosis.

Pulmonary edema is characterized by edematous material that lacks coarse granules, cholesterol clefts, and foamy macrophages.

Pneumocystis pneumonia consists of intra-alveolar eosinophilic exudate with 'bubbles' corresponding to cysts of organisms that can be highlighted using Grocott special stain.

Intra-alveolar accumulation of mucin are potentially observable in association with mucinous adenocarcinomas or bronchiectasis or honeycomb fibrosis.[1][8]

Prognosis

Approximately 30% to 40% of the patients require only one lavage. Other patients may require repeat lung lavages at intervals of 6 to 12 months.

Complications

Complications have been rarely reported and consist mainly in malpositioning of the endotracheal tube, saline spillover into the unlavaged ventilated lung, and hydropneumothorax.[9]

Enhancing Healthcare Team Outcomes

Alveolar lipoproteinosis is a rare disease with non-specific diagnostic features. A multi-disciplinary approach including pathologists and pulmonologists is mandatory to assess the diagnosis competently. The pulmonologist has to suspect the diagnosis when performing a bronchoalveolar lavage to a patient explored for an interstitial disease. The gross appearance of the liquid can be suggestive of the diagnosis. On the other hand, the pathologist can make the diagnosis on liquid or tissue samples. In the bronchoalveolar lavage, the granular material with the presence of eosinophilic bodies and granules are key-features. In tissue samples, the presence of alveoli filled with PAS-positive eosinophilic material is a hallmark. The presence of fibrosis or inflammatory infiltrates have to highlight the possibility of an associated disease.


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Alveolar Proteinosis - Questions

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A 30-year-old non-smoker woman without a particular past medical history consulted for dyspnea and non-productive cough. Chest CT scan revealed bilateral ground-glass opacities with thickened interlobular septa. Bronchoalveolar lavage was performed. The fluid was opaque with a milky turbid gross appearance. On microscopic examination, finely granular amorphous material was apparent in the background along with numerous lymphocytes and fragmented macrophages. Surgical biopsy of the lung and the mediastinal lymph nodes was performed. Histological examination revealed an amorphous PAS positive lipoprotein material filling the alveolar spaces in the lung. What is the diagnosis?



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Which of the following propositions about lipoproteinosis is false?



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Which statement about the etiology of alveolar proteinosis is false?



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Which of the following is a radiologic feature that is characteristic of pulmonary alveolar proteinosis?



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Alveolar Proteinosis - References

References

Mlika M,Triki M,Kwas H,Braham E,Ghedira H,Mezni F, When the bronchoalveolar lavage makes the diagnosis of interstitial pneumonia. The clinical respiratory journal. 2018 Jan     [PubMed]
Hirakawa T,Taniwaki M,Imanaka R,Hattori N, Secondary pulmonary alveolar proteinosis in acute myeloid leukemia. QJM : monthly journal of the Association of Physicians. 2018 Oct 8     [PubMed]
Sirin Kose S,Asilsoy S,Uzuner N,Karaman O,Ozer E,Anal O, Pulmonary Alveolar Proteinosis in Hereditary and Autoimmune Forms With 2 Cases. Pediatric emergency care. 2018 Aug 14     [PubMed]
Ronsmans S,Nemery B, The presence of autoimmune antibodies in pulmonary alveolar proteinosis does not necessarily imply idiopathic disease. The Lancet. Respiratory medicine. 2018 Sep     [PubMed]
Rawat A,Mathew B,Pandiarajan V,Jindal A,Sharma M,Suri D,Gupta A,Goel S,Karim A,Saikia B,Minz RW,Imai K,Nonoyama S,Ohara O,Giliani SC,Notarangelo LD,Chan KW,Lau YL,Singh S, Clinical and molecular features of X-linked hyper IgM syndrome - An experience from North India. Clinical immunology (Orlando, Fla.). 2018 Oct     [PubMed]
Ikeda S,Sekine A,Baba T,Katano T,Yamakawa H,Oda T,Iwasawa T,Matsumura M,Takemura T,Ogura T, Secondary pulmonary alveolar proteinosis predominant in the transplanted lung in patients with idiopathic interstitial pneumonia: an autopsy case. Journal of thoracic disease. 2018 May     [PubMed]
Ramachandran P,Chaudhury A,Devaraj U,Maheshwari KU,D'Souza G, Monitoring whole-lung lavage using lung ultrasound: The changing phases of the lung. Lung India : official organ of Indian Chest Society. 2018 Jul-Aug     [PubMed]
Athayde RAB,Arimura FE,Kairalla RA,Carvalho CRR,Baldi BG, Characterization and outcomes of pulmonary alveolar proteinosis in Brazil: a case series. Jornal brasileiro de pneumologia : publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia. 2018 May-Jun     [PubMed]
Skoczynski S,Wyskida K,Rzepka-Wrona P,Wyskida M,Uszok-Gawel E,Bartocha D,Krzych L,Pierzchala W,Barczyk A, Novel method of noninvasive ventilation supported therapeutic lavage in pulmonary alveolar proteinosis proves to relieve dyspnea, normalize pulmonary function test results and recover exercise capacity: a short communication. Journal of thoracic disease. 2018 Apr     [PubMed]

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