Pulmonary alveolar proteinosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Your Name

Synonyms and keywords: Synonym 1; Synonym 2; Synonym 3

Historical Perspective

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• In [year], [gene] mutations were first identified in the pathogenesis of [disease name].
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Classification

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• [group1]
• [group2]
• [group3]

• Other variants of [disease name] include [disease subtype 1], [disease subtype 2], and [disease subtype 3].

Pathophysiology

• The pathogenesis of [disease name] is characterized by [feature1], [feature2], and [feature3].
• The [gene name] gene/Mutation in [gene name] has been associated with the development of [disease name], involving the [molecular pathway] pathway.
• On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
• On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Causes

• [Disease name] may be caused by either [cause1], [cause2], or [cause3].
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• There are no established causes for [disease name].

Differentiating [disease name] from other Diseases

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Epidemiology and Demographics

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Age

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Gender

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Race

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Risk Factors

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Natural History, Complications and Prognosis

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Diagnosis

Diagnostic Criteria

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Symptoms

• [Disease name] is usually asymptomatic.
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• [symptom 1]
• [symptom 2]
• [symptom 3]
• [symptom 4]
• [symptom 5]
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Physical Examination

• Patients with [disease name] usually appear [general appearance].
• Physical examination may be remarkable for:

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Laboratory Findings

• There are no specific laboratory findings associated with [disease name].

• A [positive/negative] [test name] is diagnostic of [disease name].
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• Other laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3].

Imaging Findings

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Other Diagnostic Studies

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Treatment

Medical Therapy

• There is no treatment for [disease name]; the mainstay of therapy is supportive care.

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Surgery

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Prevention

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Overview

Pulmonary alveolar proteinosis -(PAP) is a rare lung disease in which abnormal accumulation of surfactant occurs within the alveoli, interfering with gas exchange. PAP can occur in a primary form or secondarily in the settings of malignancy (especially in myeloid leukemia), pulmonary infection, or environmental exposure to dusts or chemicals. Rare familial forms have also been recognized, suggesting a genetic component in some cases.

Historical Perspective

PAP was first described in 1958 by the physicians Samuel Rosen, Benjamin Castleman, and Averill Liebow. In their case series published in the New England Journal of Medicine on June 7th of that year, they described 27 patients with pathologic evidence of periodic acid Schiff positive material filling the alveoli. This lipid rich material was subsequently recognized to be surfactant.

Pathophysiology

Although the cause of PAP remains obscure, a major breakthrough in the understanding of the etiology of the disease came by the chance observation that mice bred for experimental study to lack a hematologic growth factor known as granulocyte-macrophage colony stimulating factor (GM-CSF) developed a pulmonary syndrome of abnormal surfactant accumulation resembling human PAP. The implications of this finding are still being explored, but significant progress was reported in February, 2007. Researchers in that report discussed the presence of anti-GM-CSF autoantibodies in patients with PAP, and duplicated that syndrome with the infusion of these autoantibodies into mice.

Causes

Pulmonary alveolar proteinosis is an idiopathic disease, but studies have linked causes to production of antibodies that neutralize GM-CSF, granulocyte-macrophage colony-stimulating factor. Occasionally, development of pulmonary alveolar proteinosis is related to exposure of toxic substances, such as inorganic dusts, infection with Pneumocystis jirovecii, certain cancers, and immunosuppressants. It rarely occurs in newborns.

There are several types of clinical forms of Pulmonary alveolar proteinosis; primary, secondary, and congenital. Primary PAP involves high levels of antibodies that neutralize GM-CSF, granulocyte-macrophage colony-stimulating factor. Secondary PAP occurs from clinical conditions that reduce the numbers and functions of alveolar macrophages. Congenital PAP is due to genetic mutations in the genes encoding surfactant proteins of the receptor for granulocyte-macrophage colony-stimulating factor.

Causes

Common Causes

• Pneumocystis jirovecii
• Respiratory failure
• Uncontrolled infection
• Respiratory Pathogens
• Opportunistic Pathogens: Nocardia
• Sirolimus
• Prednisone
• Inorganic dusts
• Inhalation of silica dust
• Exposure to insecticides
• aluminum dust
• titanium dioxide
• Haematological malignancies
• HIV infection.

Causes by Organ System

Cardiovascular	No underlying causes
Chemical / poisoning	No underlying causes
Dermatologic	No underlying causes
Drug Side Effect	Sirolimus, Prednisone
Ear Nose Throat	No underlying causes
Endocrine	No underlying causes
Environmental	Inorganic dusts, Inhalation of silica dust, Exposure to insecticides, aluminum dust, titanium dioxide
Gastroenterologic	No underlying causes
Genetic	No underlying causes
Hematologic	Haematological malignancies
Iatrogenic	No underlying causes
Infectious Disease	Uncontrolled infection, Respiratory Pathogens, Nocardia, HIV infection
Musculoskeletal / Ortho	[No underlying causes
Neurologic	No underlying causes
Nutritional / Metabolic	No underlying causes
Obstetric/Gynecologic	No underlying causes
Oncologic	Haematological malignancies
Opthalmologic	No underlying causes
Overdose / Toxicity	No underlying causes
Psychiatric	No underlying causes
Pulmonary	Pneumocystis jirovecii, Respiratory failure
Renal / Electrolyte	No underlying causes
Rheum / Immune / Allergy	No underlying causes
Sexual	No underlying causes
Trauma	No underlying causes
Urologic	No underlying causes
Dental	No underlying causes
Miscellaneous	No underlying causes

Causes in Alphabetical Order

• Aluminum dust
• Haematological malignancies
• HIV infection

• Inorganic Dusts
• Insecticides
• Opportunistic Pathogens: Nocardia
• Pneumocystis jirovecii
• Prednisone

• Respiratory failure
• Respiratory Pathogens
• Silica dust
• Sirolimus
• Titanium dioxide
• Uncontrolled infection

Natural History

The clinical course of PAP is unpredictable. Spontaneous remission is recognized; some patients have stable symptoms.

Complications

Death may occur due to progression of PAP or due to the underlying disease associated with PAP. Individuals with PAP are more vulnerable to infection of the lung by bacteria or fungi.

History and Symptoms

The symptoms of PAP include:

• Dyspnea
• Cough
• Sputum
• Fatigue
• Fever
• Anorexia
• Hemoptysis
• Crackles
• Cyanosis
• Clubbing

Chest X Ray

Classic radiographic finding is bilateral, symmetric alveolar consolidation or ground-glass opacity, particularly in a perihilar or hilar distribution resembling pulmonary edema.

CT

• CT typically shows diffuse ground-glass attenuation with superimposed crazy-paving pattern (intra- and interlobular septal thickening, often in polygonal shapes representing the secondary pulmonary lobule).

Patient#1

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Patient #1: Proven PAP but not quite the classic crazy-paving pattern

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Other Diagnostic Studies

Diagnosis is generally made by surgical or endoscopic biopsy of the lung, revealing the distinctive pathologic finding.

Histopathological Findings: Pulmonary alveolar proteinosis

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Medical Therapy

The use of GM-CSF injections has also been attempted, with variable success.

Surgery

The standard treatment for PAP is whole-lung lavage, in which sterile fluid is instilled into the lung and then removed, along with the abnormal surfactant material. This is generally effective at ameliorating symptoms, often for prolonged periods. Lung transplantation can be performed in refractory cases.