Pulmonary Alveolar Proteinosis Causes And Symptoms

Introduction

Pulmonary Alveolar Proteinosis (PAP) is characterised by the accumulation of surfactant proteins in the lungs and presents a complex challenge to pulmonary medicine. It is a very treatable condition, but failure to treat it early can lead to serious side effects and a reduction in quality of life. There are two types: primary and secondary, with distinct causes. Understanding these causes and recognising the symptoms of this condition is crucial for early diagnosis and effective management. 

Understanding Pulmonary Alveolar Proteinosis (PAP)

What are surfactant proteins?

Pulmonary Alveolar Proteinosis (PAP) is a rare condition in which too many surfactant proteins exist in the alveoli of the lungs.¹ Surfactant proteins in the lung are important for lowering the surface tension in the alveoli, which allows them to inflate and deflate, making it crucial for the ability to breathe in oxygen and breathe out carbon dioxide.² They also prevent small airways in the lung from collapsing during this process.² PAP occurs when there is either too much surfactant being produced, or there is an issue with the cells which are supposed to clear it away, leading to a build-up in the alveoli. 

What are alveoli?

Alveoli are the small air sacs at the end of the lungs where most gas exchange takes place, allowing the oxygen we breathe into the bloodstream and the carbon dioxide to be removed from the blood and breathed out. The alveolar walls are very thin and surrounded by blood vessels to make gas exchange as easy as possible. They also have a large surface area to allow as much gas exchange to take place as possible. It is in these air sacs that we find surfactant proteins. 

Why is an accumulation of surfactant proteins in the alveoli an issue?

While surfactant is most known for lowering surface tension in the alveoli, it also plays a key role in gas exchange. Both oxygen and carbon dioxide have to pass through the surfactant to get in or out of the blood, so having too much of it can cause issues with getting enough oxygen as well as getting the lungs to inflate properly, which can lead to difficulty breathing. 

It is not just an accumulation of surfactants that causes issues. Having too little surfactant in the lungs also causes serious breathing problems, and is most commonly seen in infants,³ as this is a life-threatening condition. Since the level of surfactant in the lungs is so important, it is a tightly regulated process using many cells and mechanisms in the body, and PAP can arise when this process is dysfunctional for some reasons.

Who does PAP affect?

PAP can affect anyone of any age, from young children right through to old age.⁴ There is no increased prevalence based on ethnicity, geographical location or socioeconomic status, however, it affects men more often than women at a 2:1 ratio⁵ and is more prevalent in smokers.⁴ There are around 7 cases per million people in the general population.⁴ 

Causes of PAP

Primary PAP

Primary PAP makes up around 90% of all PAP cases⁴ and can either be autoimmune or hereditary in nature. It occurs when granulocyte-monocyte stimulating factor (GM-CSF), which is a substance in the body which acts as a signal to the cells which are responsible for the removal of excess surfactant proteins, is disrupted.

In autoimmunity, this is due to the presence of anti-GM-CSF antibodies,¹ meaning your immune system is attacking this substance and removing it before it is able to activate the appropriate cells.

Congenital PAP is an inherited disorder where there is a genetic defect in the genes CSF2RA or CSF2RB, which causes changes to the receptor that GM-CSF binds to on the target cells.⁴ This makes it unable to bind to the cells and gives them the signal to activate and clear away the pulmonary surfactant, which causes the build-up. This form of the disease is present at birth.

Secondary PAP

Secondary PAP arises as the result of various underlying conditions which reduce the ability of the immune cells in the lungs to clear surfactant proteins.⁵ There are many cancers which have links to PAP. There are many cancers which have links to PAP, including myelodysplastic syndrome, which was found in 34.1% of secondary PAP cases, as well as many others including leukaemia, lung cancer, and glioblastoma.⁵ There are also associations with immunodeficiency and autoimmunity diseases, such as AIDS, immunosuppression from organ transplantation and rheumatoid arthritis.⁵

Symptoms of PAP

Early-stage symptoms

Symptoms of PAP are non-specific, which can make it hard to initially diagnose. They can be severe, or there can be no symptoms at all when the condition is diagnosed. Symptoms in the early stage of the disease include: 

• Dyspnoea (shortness of breath)
• Respiratory distress
• Chronic cough that does not go away after a few weeks

Progressive symptoms 

The longer PAP goes untreated, the more severe symptoms can be. Symptoms of progressed disease include: 

• Fatigue and general weakness 
• Weight loss 
• Cyanosis - this is where the skin has a bluish-purple tint to it, usually seen around the moth, earlobes and fingernails as this is where the skin is thinnest.⁶ This suggests that there is a lack of oxygen in the bloodstream, which is indicative of PAP

Complications and severe manifestations 

If PAP goes untreated for an extended period of time, serious complications can occur, including:

• Respiratory failure
• Need for lung transplantation
• Infections due to decreased function of immune cells in the lungs 
• Severely impacted quality of life due to other associated symptoms 

These symptoms are rare in well-managed PAP, which highlights the need for quick and accurate testing and diagnosis. 

Diagnosis⁷ 

Medical history and physical examination

The doctor starts by gathering a detailed medical history, including checking for symptoms such as shortness of breath, cough, and fatigue. They will also conduct a physical examination to look for signs of respiratory distress, such as decreased breath sounds or crackles in the lungs. 

Pulmonary function tests (PFTs)

These tests measure lung function parameters such as lung volumes, capacities, and gas exchange. PFTs can help assess the severity of lung disease and may show reduced lung volumes and impaired gas exchange in PAP. However, these are non-specific, so require other tests to show a definitive diagnosis. 

Bronchoalveolar lavage (BAL)

This is the most common method used to diagnose PAP, and involves flushing a small amount of sterile fluid into a specific area of the lungs are retrieving it for analysis. In PAP, it turns an opaque, milky white and can show abnormal surfactant materials and other biomarkers which suggest disease. This can be used for diagnosis of PAP but does not show the type of PAP present. 

Bronchoscopy

This is often used at the same time as BAL and involves inserting a flexible tube with a camera (bronchoscope) that is passed through the mouth or nose into the lungs. This allows direct visualization of the airways and collection of samples of lung tissues and bronchoalveolar lavage fluid (BALF). This can be used to rule out infections, conditions which mimic PAP and secondary PAP.

Analysis of lung tissue samples

A lung biopsy may be necessary in some cases to obtain a tissue sample for detailed analysis. This can involve a surgical lung biopsy or a less invasive approach such as a transbronchial lung biopsy (TBLB). The tissue sample is examined under a microscope by a pathologist to confirm the diagnosis of PAP and rule out other potential causes of lung disease. This is used much more rarely nowadays as less invasive diagnostic tools have improved

Imaging studies

Chest X-rays and CT scans are commonly used to visualize the lungs and detect abnormalities such as the characteristic “crazy paving” seen in PAP. These imaging studies can help assess how much of the lung is involved in the condition and guide further diagnostic steps. 

Once a diagnosis of PAP is confirmed, further evaluation may be needed to determine the underlying cause, especially in cases of secondary PAP. This may involve additional laboratory tests, imaging studies, or consultation with specialists depending on the suspected cause. Treatment options can then be tailored based on the specific subtype and underlying factors contributing to PAP. 

Treatment options

Whole Lung Lavage (WLL)⁸

Whole lung lavage (WLL) is often the first treatment used for PAP patients, as it is effective in clearing out the extra surfactant proteins in the lung. It is done under general anaesthesia, and a tube is placed in the airway to separate the lungs. One lung is kept ventilated while the other is cleaned. A warm saltwater solution is gently washed into the lung, and when it is drained contains the surfactant proteins. This is repeated until the fluid coming out is clear instead of milky. WLL has been shown to lead to great improvements in both the patient’s quality of life and physically in the X-rays and CT scans.

Inhaled GM-CSF¹

This is a second-line treatment for PAP if the patient doesn’t respond well to WLL. this is effective in cases when the PAP is caused by a lack of GM-CSF in the body, and so this treatment can replace this. In this treatment, a special form of GM-CSF is turned into a mist and breathed in through a mask or nebuliser. The extra GM-CSF can help activate the cells which clear out excess surfactant proteins from the lungs and prevent the build-up. The inhaled version is more effective than injected GM-CSF as it gets straight into the lungs where it is needed most and helps increase lung function and decrease the number of symptoms.

Lung transplantation⁹ 

In very severe cases, where PAP has been allowed to go untreated for a long time, a lung transplant may be needed. This happens when the lungs become covered in scar tissue due to the constant inflammation in the lungs. This is an effective and relatively safe treatment, however, there are many risks involved with transplant surgery in any condition. The long-term recurrence rates are also not well studied.

Summary 

• Pulmonary Alveolar Proteinosis (PAP) is a condition where surfactant proteins in the lung are not properly cleared away, leading to difficulty breathing 
• Primary PAP is caused by either cells in the body overreacting to chemicals which activate the cells that clear surfactant, or defects in the receptors to these signals
• Secondary PAP happens as a result of environmental exposures or illnesses such as cancers
• The main symptoms of PAP are shortness of breath, chronic cough and fatigue. Symptoms vary based on the severity and progression of the disease
• There are many ways to treat, such as manually draining the lung of surfactant proteins (WLL), inhaling GM-CSF to increase the activity of immune cells, and in extremely severe cases, lung transplantation