What Is Secondary Pulmonary Alveolar Proteinosis?

Introduction

What is secondary pulmonary alveolar proteinosis?

Pulmonary alveolar proteinosis (PAP) is a rare respiratory disease characterised by the accumulation of surfactant lipoproteins (fats and proteins) within the alveoli (the small air sacs in the lungs).¹ This accumulation leads to variable differences in pulmonary gas transfer (transfer of oxygen and carbon dioxide), causing a range of clinical manifestations from exercise intolerance to hypoxemic respiratory failure and even death.² 

PAP can be classified based on the mechanisms leading to the dysregulation of surfactant.¹ One of them is secondary PAP, which may arise from conditions such as blood or immune system cancers. Treatment of the underlying disease is crucial for managing PAP.³

Why is it important to understand secondary PAP?

A good understanding of secondary PAP is important for several reasons: 

• Recognising secondary PAP allows you to get a diagnosis and receive appropriate treatments. Distinguishing secondary PAP from primary PAP is also important for tailoring the treatment regimen.
  • For example, whilst whole lung lavage (WLL) remains the standard therapy for all types of PAP, dealing with the root cause of secondary PAP is essential to managing this condition. 
• Knowing the underlying cause of secondary PAP provides information about how the disease may proceed, known as prognostic information. 
• Secondary PAP may be associated with complications such as respiratory issues due to chemotherapy or bone marrow transplantation done to treat blood or immune cancers. If secondary PAP is identified early, doctors can anticipate and mitigate potential complications. 
• Understanding the biological processes that lead to secondary PAP can eventually lead to advancements in targeted therapies. 

Symptoms and causes

What causes secondary pulmonary alveolar proteinosis?

Secondary PAP arises as a result of underlying disease or conditions that disrupt the normal function of alveolar macrophages. Here is a list exploring possible causes: ⁴

1. Haematological diseases: Conditions that affect the blood
2. Immunological diseases: Conditions that affect the immune system
3. Infectious diseases: Including tuberculosis 
4. Toxic inhalation syndromes: Includes exposure to inorganic dust (silica, cement), organic dust (sawdust, fertiliser) and fumes (chlorine and varnish)
5. GM-CSF signalling defects: GM-CSF represents how alveolar macrophages send messages around a cell
6. Reduction in alveolar macrophage numbers

These causes affect the number of alveolar macrophages and their ability to work properly. The surfactant lining the air sacs in the lungs is thus not cleared. It is the accumulation of this surfactant material within the alveoli that results in the characteristic features of PAP.

What are the symptoms of secondary pulmonary alveolar proteinosis?

The symptoms of secondary PAP that a person can experience are a combination of respiratory symptoms that depend on the underlying cause. A breakdown of the signs and symptoms associated with secondary PAP are:

Respiratory symptoms

• Dyspnea: This refers to the difficulty in breathing, particularly during exercise and physical activity
• Cough: Coughing may occur in isolation, or in combination with dyspnea. Also, the cough may produce a white frost sputum or nothing at all
• Gas exchange impairment: Patients may experience difficulty getting oxygen into and carbon dioxide out of their blood. This symptom may be seen as respiratory distress contributing to dyspnea

Systematic symptoms

• Fatigue: Patients experience tiredness, possibly the result of increased effort required for breathing
• Weight Loss: Unintentional weight loss can occur, likely due to the increased metabolic demands of the underlying lung condition

Other symptoms

• Fever: Fever may be a sign, even though it is uncommon. It is more likely to be present if there is an infection in addition to the lung condition. However, it is possible that a fever may be a sign of secondary PAP itself
• Haemoptysis: Coughing up blood is rare and can occur when there is additional infection

Physical symptoms 

• Crackles: These are respiratory sounds that can be heard when listening to the sounds of the lungs using a stethoscope.
• Cyanosis: Patients experience cyanosis when there is inadequate oxygenation and it is seen when their bluish discolouration of the skin
• Digital Clubbing: A small percentage of patients may experience clubbing of their fingers

Patients with secondary PAP may be misdiagnosed due to the non-specific nature of symptoms and overlapping features. Other conditions include pneumonia or asthma and may be misdiagnosed due to radiological findings and symptoms.

Given that someone with secondary PAP can have a range of signs and symptoms depending on the underlying cause and individual patient characteristics, it is essential that a thorough clinical evaluation, including a detailed medical history, physical examination, and appropriate diagnostic tests, be done for accurate diagnosis and guide management of the individual disease. 

Diagnosis and tests

How can secondary PAP be diagnosed?

Secondary PAP can be challenging due to its non-specific symptoms and radiographic findings along with the absence of specific laboratory tests. This can be overcome using a combination of clinical evaluation, radiological imaging, bronchoscopy findings, and specific biomarker testing that can help in the diagnosis. How each test contributes to diagnosis is listed below:^5,6

1. Clinical Evaluation: Patients with secondary PAP may present with progressive shortness of breath (dyspnea), chest congestions and the production of a tiny amount of whitish phlegm. These symptoms often develop gradually and subtly over time, with or without fever.
2. Radiological Imaging: Chest radiography reveals airspace disease throughout both sides of the lung, in an irregular scattered pattern. A high-resolution CT (HRCT) scan  is essential for confirming diagnosis, particularly characteristic findings referred to as “crazy paving”.
3. Bronchoscopy Findings: Bronchoalveolar lavage (BAL) fluid in secondary PAP may have a distinctive appearance, described as milky-white or yellow in non-smokers. Microscopic examination of the BAL fluid shows enlarged alveolar macrophages and a material in the fluid that stains positively with Periodic Acid-Schiff (PAS) stain.
4. Biomarker Testing: Specific biomarkers, such as lactate dehydrogenase (LDH), and C-reactive protein (CRP), may be higher but are non-specific for any particular type of PAP. Testing for circulating antibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) can help distinguish autoimmune PAP from other types of PAP.
5. Lung Biopsy: Lung biopsy may help to confirm the presence of PAP, but may not be able to identify the underlying cause of PAP. The ability to detect PAP may be limited due to the patchy involvement of the lung. 

The diagnosis of secondary PAP relies on a combination of clinical suspicion, radiological imaging, bronchoscopy findings, and specific biomarker testing. In addition, these diagnostic tests can help distinguish secondary PAP from other respiratory conditions and confirm the underlying cause of the disease. 

Management and treatment

As mentioned, secondary PAP is a condition where the accumulation of surfactant in the alveoli is caused by an underlying condition, such as cancer, infection, or inhalation exposure. The treatment approach for secondary PAP involves addressing the underlying cause, alongside managing the accumulation of surfactant in the alveoli. Here is an explanation of the treatment options:^5,6,7

Treatment of the underlying cause

The primary focus of secondary PAP is to identify and treat the underlying condition causing the disorder. This approach could be varied depending on the original cause. For example:

• Cancer - Effective treatment can range between surgery, chemotherapy, or radiation therapy, and may lead to the resolution of alveolar proteinosis in some cases
• Infection - Antibiotics or antifungal medications are prescribed to treat underlying infections that contribute to alveolar proteinosis
• Inhalation Exposure - Removal or avoidance of the triggering agent causing the lung injury is crucial. This may involve environmental controls or changes in occupation to prevent further exposure

Whole-lung lavage (WLL)

Although primarily associated with primary alveolar proteinosis, it can be considered in some cases aa a treatment for secondary alveolar proteinosis. It is done when the underlying cause cannot be effectively treated or when the disease progresses despite treatment of the underlying cause. 

WLL is an invasive procedure performed under general anaesthetic in specialised centres. During WLL, warm saline is infused into the lung and then drained out, effectively washing out the accumulated surfactant from the alveoli. The procedure may need to be repeated periodically based on the patient's symptoms and disease progression.

Novel therapies targeting GM-CSF antibodies or lipid metabolism

In cases where traditional treatments like WLL or addressing the underlying cause are not effective, newer therapies targeting specific mechanisms involved in alveolar proteinosis may be considered. These may include:

• GM-CSF supplementation - In patients with autoimmune PAP refractory to WLL or unable to undergo WLL, recombinant GM-CSF therapy can be considered. This treatment aims to address the deficiency of GM-CSF, which is implicated in the pathogenesis of autoimmune PAP
• Rituximab - A monoclonal antibody targeting CD20 of B cells may be used in selected patients with refractory autoimmune PAP to reduce the production of GM-CSF autoantibodies
• Plasmapheresis - This procedure, aimed at reducing circulating antibodies, may be considered in some cases, although evidence supporting its efficacy is limited
• Other agents and gene therapy - Experimental therapies targeting lipid metabolism or gene therapy approaches may hold promise for future treatment options, particularly in hereditary forms of PAP

Lung transplant

For patients with progressive diseases who do not respond to other treatments, lung transplantation may be considered. However, this is typically reserved for cases where all other options have been exhausted, as it carries significant risks and may not always be successful.

Summary

Pulmonary alveolar proteinosis (PAP) is a rare respiratory syndrome characterised by the accumulation of surfactant lipoproteins (fats and proteins) within the alveoli. The treatment of secondary alveolar proteinosis involves a multifaceted approach tailored to the underlying cause and disease severity. While whole-lung lavage remains a cornerstone of therapy, newer treatment modalities targeting specific pathogenic mechanisms are emerging and may offer additional options for patients with refractory disease. Additionally, addressing the underlying cause, such as malignancy or infection, is essential for achieving successful outcomes in secondary alveolar proteinosis.