Pulmonary Alveolar Proteinosis Diagnosis And Treatment

  • Chandana Raccha MSc in Pharmacology and Drug Discovery, Coventry University

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Pulmonary alveolar proteinosis (PAP)

Protein alveolar proteinosis (PAP) is an illness where excessive amounts of a certain natural compound clog up parts of our lungs. This makes it more and more difficult to get enough oxygen. In the most severe cases, this can lead to a lack of oxygen (respiratory failure)1 which is fatal if left untreated.2

The two parts of our lungs that are affected by PAP are the distal airways and the alveoli.2 The distal airways are tiny ‘air ducts’ that direct the flow of air and thereby oxygen towards the alveoli when we breathe in. The alveoli are tiny air sacs of the lung where the oxygen passes into the bloodstream.3,4 That is where the red blood cells will pick up the oxygen and distribute it throughout our bodies.5

Now, the natural compound accumulating and eventually blocking both our distal airways and alveoli due to PAP is called surfactant. Found on the surface of alveoli, a surfactant is a mixture of mostly lipids6 (fatty compounds) and some proteins which act as a detergent to reduce the surface tension.2 Without surfactant, the surface tension would cause the alveoli to collapse and also prevent them from opening up again. That would make it impossible to get enough oxygen.2,7

Therein lies the irony. While an adequate amount of surfactant is vital for our survival, an excessive amount of surfactant has the opposite effect. Surfactants in such quantities will begin to congest our distal airways and our alveoli, making it harder and harder for oxygen to reach the alveoli and enter the bloodstream. This will result in ever-decreasing amounts of oxygen available to our bodies. In the worst-case scenario, this will culminate in a lack of oxygen (respiratory failure)1 which is deadly if not treated in time.2

Cause of pulmonary alveolar proteinosis (PAP)

The overabundance of surfactant caused by PAP can be due to an increased surfactant production or a decreased removal of ‘old’ surfactant (surfactant clearance).2

The cells responsible for heightened surfactant production would be the alveolar type II epithelial cells. Alveolar type II epithelial cells (or type II pneumocytes)8 are cells on the surface of the alveoli which produce and secrete surfactant. Certain forms of PAP would prompt these cells to amplify their surfactant production and secretion, resulting in terminal airways and alveoli blockages. These cells also contribute to the removal of ‘old’ surfactant by absorbing and then either recycling it (to make new surfactant) or simply breaking it down into its components. Interestingly, this part of their function does not seem to be affected by PAP.2,8

In order to give rise to a decreased removal of ‘old’ surfactant (surfactant clearance), other forms of PAP disrupt the function of the alveolar macrophages. Alveolar macrophages are cells in the alveoli which have many functions. One of their most important functions is surfactant clearance by absorbing ‘old’ surfactant and taking it apart. Therefore, interfering with this function of alveolar macrophages or with the alveolar macrophages themselves will result in surfactant accumulating in the terminal airways and alveoli, eventually congesting them.2,8

Forms of pulmonary alveolar proteinosis (PAP)

Pulmonary alveolar proteinosis (PAP) can be divided into primary PAP, secondary PAP and surfactant production disorders.2

Primary PAP

The defining trait of primary PAP is the impairment of GM-CSF signalling. Since the disassembly of ‘old’ surfactant (part of surfactant clearance) in the alveolar macrophages is dependent on GM-CSF signalling, disruption of GM-CSF signalling would in time lead to the accumulation of ‘old’ surfactant in the alveolar macrophages and eventually in the terminal airways and alveoli. GM-CSF signalling involves a certain signalling molecule called GM-CSF and its corresponding receptor on the surface of the alveolar macrophages. When GM-CSF binds to its receptor, GM-CSF signalling is engaged and alveolar macrophages proceed to dismantle previously absorbed ‘old’ surfactant. Inhibition of this signalling pathway would prevent this process from occurring. 2 forms of primary PAP have been established, each one with its own way of interrupting GM-CSF signalling.2

Autoimmune PAP

Autoimmune PAP disrupts GM-CSF signalling and thereby the surfactant clearance function of alveolar macrophages due to a high concentration of anti-GM-CSF autoantibodies in the blood.2

Antibodies are proteins which bind to their target (= antigen). Antibodies do this to curb the threat these antigens pose and also to mark them as targets for the immune system. The immune system will then destroy or remove the marked antigens as quickly as possible. They are normally produced by certain cells of the immune system to combat dangerous entities such as bacteria, viruses, toxins and cancer cells (the ‘foreign’). In contrast, autoantibodies will target and bind to parts of our own bodies (the ‘self’). In great numbers, these autoantibodies are a sign of an autoimmune disease like autoimmune PAP where the immune system attacks the ‘self’ when it should only fight the ‘foreign’.2,9,10

Therefore, the previously mentioned anti-GM-CSF autoantibodies found in autoimmune PAP will proceed to bind to the GM-CSF signalling molecules. By doing so, they prevent these GM-CSF molecules from binding to their receptors and activating GM-CSF signalling. As a result, the dismantling of ‘old’ surfactant is disengaged and the alveolar macrophages and eventually the alveoli and the terminal airways will start clogging up with undigested ‘old’ surfactant.2

Hereditary PAP

Hereditary PAP interferes with GM-CSF signalling in the alveolar macrophages because of certain genetic mutations. These mutations are found in the genes which give rise to certain components of the GM-CSF receptor. Now, due to the mutations, these resulting components of the GM-CSF receptor on the alveolar macrophages are defective, severely hampering the ability to activate GM-CSF signalling. Consequently, the absorbed ‘old’ surfactant will not be digested and instead start accumulating in the alveolar macrophages and end up blocking the alveoli and the terminal airways. As the name suggests, this form of PAP is hereditary so the mutations in these genes can be passed on from parent to child meaning the children can be born with these gene defects.2

Secondary PAP

Secondary PAP is defined as having an underlying disease or condition which indirectly affects alveolar macrophage numbers or function which in turn would impact the digestion of ‘old’ surfactant (part of surfactant clearance). The conditions or diseases which can bring about secondary PAP are incredibly numerous. Secondary PAP can be caused by:2

  • Certain blood disorders (e.g. myelodysplastic syndrome11 and leukaemia)12
  • Some cancers (e.g. melanoma)13
  • Certain infectious diseases (e.g. tuberculosis)14
  • Some diseases affecting the immune system (e.g. severe combined immunodeficiency disease)15
  • Inhalation of certain substances (e.g. cement dust, bakery flour and paint fumes)
  • Rare genetic mutations2

Surfactant production disorders

Surfactant production disorders are caused by specific mutations in the genes which control surfactant production in the alveolar type II epithelial cells. These genetic mutations result in excessive production and secretion of surfactant, eventually congesting the alveoli and the terminal airways.2

Frequency of pulmonary alveolar proteinosis (PAP)

Autoimmune PAP is by far the most common PAP, with autoimmune PAP accounting for approximately 90% of PAP cases. It is estimated to affect about 6.2 people per million.2,16

Secondary PAP is the second most frequent PAP, making up approximately 8 - 9% of all PAP cases. About 0.5 people per million are believed to be afflicted by it.2

Hereditary PAP is rather rare. It accounts for less than 1% of all PAP cases.2

The surfactant production disorders are suspected to be very rare, definitely the least common of all the PAPs.2

Symptoms of pulmonary alveolar proteinosis (PAP)

The most commonly seen symptoms of pulmonary alveolar proteinosis (PAP) are:2

  • Exertional dyspnea17 (shortness of breath during physical activity)
  • Cough
  • Fatigue18 (being extremely tired)
  • Weight loss

Diagnosis of pulmonary alveolar proteinosis (PAP)

Initial examination

It is not only important to diagnose PAP as soon as possible but also to determine which form of PAP one is dealing with. 

Certain information including the patient’s medical history19 can suggest that a patient might have PAP. For example, a family history of PAP or the result of a physical examination can be indicative of PAP.20 Furthermore, a chest X-ray21 or chest CT scan22 can result in images which are highly characteristic of PAP.2

STAT5-PI

The STAT5 phosphorylation index (STAT5-PI) is often the first test used after PAP is suspected. It is performed using a blood sample of the patient and gives information about the status of GM-CSF signalling.2 As mentioned before, primary PAP (autoimmune PAP and hereditary PAP) are characterised by strongly decreased GM-CSF signalling. Therefore, the STAT5-PI test would result in a low STAT5-PI in primary PAP. A low STAT5-PI is most commonly referred to as abnormal STAT5-PI.2,23

A normal STAT5-PI points towards secondary PAP or surfactant production disorders.2

Diagnosis of autoimmune PAP

If an abnormal STAT5-PI is found, a primary PAP is very likely. Since autoimmune PAP is by far the most common form of primary PAP and PAP in general, the patient’s blood is next tested for anti-GM-CSF autoantibodies.2 A patient with an abnormal (= high) concentration of anti-GM-CSF autoantibodies in the blood and without any underlying diseases or conditions which are known to cause PAP is diagnosed with autoimmune PAP.2

A normal concentration of anti-GM-CSF autoantibodies in the blood rules out autoimmune PAP which means that hereditary PAP is the next most likely candidate.2

Diagnosis of hereditary PAP

The combination of an abnormal STAT5-PI and a normal concentration of anti-GM-CSF autoantibodies leads to yet another blood test. Here, the concentration of the GM-CSF in the blood is determined. In hereditary PAP, higher amounts of GM-CSF are present in the blood. The reason for this is not yet fully understood. Such an abnormal (= high) blood concentration of GM-CSF combined with a lack of underlying conditions or diseases known to cause PAP leads to genetic tests. These will look for the mutations in the genes of the GM-CSF receptor which are characteristic of hereditary PAP. If found, the patient will be diagnosed with hereditary PAP.2

Diagnosis of secondary PAP and surfactant production disorders

Even if detecting a normal STAT5-PI, an anti-GM-CSF autoantibody test is often performed just to make sure. Normal STAT5-PI and normal anti-GM-CSF autoantibody levels in the blood definitely rule out primary PAP. Additionally, if a disease or condition is discovered which is known to result in PAP, the diagnosis of secondary PAP is established.2

In contrast, normal STAT5-PI, normal anti-GM-CSF autoantibody levels in the blood and no underlying condition or disease known to cause PAP means it could be a surfactant production disorder. Genetic testing for the specific gene mutations linked to surfactant overproduction can confirm a surfactant production disorder.2

Diagnosis of unclassified PAP

Unclassified PAP is a PAP with an unknown cause. Its presence cannot be confirmed by the tests mentioned above but via different means, e.g. a lung biopsy. A biopsy24 involves extracting a very small piece of a certain part of your body to examine it, in this case from the patient’s lung. Examining this tiny piece of lung, under the microscope, for example, will allow healthcare professionals to detect unclassified PAP.2

Treatment of pulmonary alveolar proteinosis (PAP)

The treatment of choice for all forms of PAP is called whole lung lavage (WLL). It is essentially a procedure where one lung is given oxygen via a breathing tube while the other lung is rinsed with saline (sterile salt water) via a different tube (bronchoscope). At the same time, the patient wears a vibrating vest to shake loose the surfactant. This allows the saline to wash off the surfactant and mix with it. Subsequently, the saline-surfactant mix is syphoned off and replaced with fresh saline. This is done numerous times to free the alveoli and terminal airways of surfactant. It is carried out under anaesthesia25 or sedation26 and takes about 4 to 5 hours. Eventually, the same procedure is performed for the other lung to remove the surfactant there as well. 

Depending on how severe and quick the surfactant buildup is, WLL will have to be performed either every few months or every year.20

Other treatments include:20

  • Bronchodilators (causing the muscles around your airways to relax, making breathing easier)
  • Supply of additional oxygen (oxygen is given via tubes or a face mask to increase the dropping oxygen levels in the blood)
  • Inhalation or injection of GM-CSF (boosting the effectiveness of alveolar macrophages to improve surfactant removal)
  • Plasmapheresis and plasma exchange27 (removing the anti-GM-CSF autoantibodies by replacing the liquid part of the blood with that of a healthy donor)
  • Lung transplant (in the most severe cases of PAP, one or both lungs will need to be replaced)

FAQ’s

How do you diagnose pulmonary alveolar proteinosis?

Pulmonary alveolar proteinosis (PAP) is usually diagnosed using various different tests. 

These tests also determine which type of PAP it is. 

What is the life expectancy of pulmonary alveolar proteinosis?

Without treatment, it is estimated that about 85% of patients are still alive 5 years after diagnosis. With whole lung lavage therapy, the percentage increases to 94%28

What is the confirmatory test for pulmonary alveolar?

Each type of PAP tends to have at least a couple of tests which need to be conclusive in order to confirm the diagnosis. 

How do you treat proteinosis?

Whole lung lavage (WLL) is applied the most frequently. It basically involves rinsing one lung at a time with sterile saltwater in order to remove the surfactant. There are other treatment options which are used less often, some of which are only employed if the need arises. 

Summary

Pulmonary alveolar proteinosis (PAP) is an illness which causes the excessive buildup of a natural lipid-protein compound called surfactant in the lungs. Over time, the surfactant can start blocking parts of the lung, causing less oxygen to be available to the body. In the most severe cases, this can lead to a complete lack of oxygen (respiratory failure) which is deadly if left untreated. Depending on the underlying cause of the PAP, one distinguishes between autoimmune PAP (by far the most common PAP), hereditary PAP, secondary PAP and surfactant production disorders. Common symptoms include shortness of breath, cough and feeling extremely tired. PAP is normally diagnosed by an array of different tests. Some measure STAT5-PI and concentrations of GM-CSF and anti-GM-CSF autoantibodies, others detect genetic mutations. Each one of these is linked to a different form of PAP. The most common treatment is whole lung lavage (WLL) where one lung at a time is washed with sterile salt water to remove the surfactant. Other treatment options are used either to treat the symptoms or to attempt to temporarily override or remove the underlying cause. 

References

  • Cleveland Clinic [Internet]. [cited 2024 Mar 21]. Respiratory failure. Available from: https://my.clevelandclinic.org/health/diseases/24835-respiratory-failure
  • Suzuki T, Trapnell BC. Pulmonary alveolar proteinosis syndrome. Clin Chest Med. 2016 Sep;37(3):431–40.
  • Jain M, Sznajder JI. Bench-to-bedside review: Distal airways in acute respiratory distress syndrome. Crit Care [Internet]. 2007 [cited 2024 Mar 18];11(1):206. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2151900/
  • Ball M, Hossain M, Padalia D. Anatomy, airway. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 [cited 2024 Mar 18]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK459258/
  • Cleveland Clinic [Internet]. [cited 2024 Mar 18]. Red blood cells: function, role & importance. Available from: https://my.clevelandclinic.org/health/body/21691-function-of-red-blood-cells
  • Cleveland Clinic [Internet]. [cited 2024 Mar 18]. What are lipids? Available from: https://my.clevelandclinic.org/health/body/24425-lipids
  • Seadler BD, Toro F, Sharma S. Physiology, alveolar tension. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 [cited 2024 Mar 18]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK539825/
  • Brandt JP, Mandiga P. Histology, alveolar cells. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 [cited 2024 Mar 20]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK557542/
  • Cleveland Clinic [Internet]. [cited 2024 Mar 20]. Antibodies: definition, types & function. Available from: https://my.clevelandclinic.org/health/body/22971-antibodies
  • Cleveland Clinic [Internet]. [cited 2024 Mar 21]. Autoimmune diseases: causes, symptoms, what is it & treatment. Available from: https://my.clevelandclinic.org/health/diseases/21624-autoimmune-diseases
  • Cleveland Clinic [Internet]. [cited 2024 Mar 21]. Myelodysplastic syndrome. Available from: https://my.clevelandclinic.org/health/diseases/6192-myelodysplastic-syndrome-myelodysplasia
  • Cleveland Clinic [Internet]. [cited 2024 Mar 21]. Leukemia: symptoms, signs, causes, types & treatment. Available from: https://my.clevelandclinic.org/health/diseases/4365-leukemia
  • Cleveland Clinic [Internet]. [cited 2024 Mar 21]. Melanoma: symptoms, stages, diagnosis, treatment & prevention. Available from: https://my.clevelandclinic.org/health/diseases/14391-melanoma
  • Cleveland Clinic [Internet]. [cited 2024 Mar 21]. Tuberculosis: causes, symptoms, diagnosis & treatment. Available from: https://my.clevelandclinic.org/health/diseases/11301-tuberculosis
  • Https://www. Cancer. Gov/publications/dictionaries/cancer-terms/def/severe-combined-immunodeficiency-disease [Internet]. 2011 [cited 2024 Mar 21]. Available from: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/severe-combined-immunodeficiency-disease
  • Inoue Y, Trapnell BC, Tazawa R, Arai T, Takada T, Hizawa N, et al. Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan. Am J Respir Crit Care Med. 2008 Apr 1;177(7):752–62.
  • Sharma S, Hashmi MF, Badireddy M. Dyspnea on exertion. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 [cited 2024 Mar 21]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK499847/
  • Cleveland Clinic [Internet]. [cited 2024 Mar 22]. Fatigue. Available from: https://my.clevelandclinic.org/health/symptoms/21206-fatigue
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  • Mayo Clinic [Internet]. [cited 2024 Mar 22]. How biopsy procedures are used to diagnose cancer. Available from: https://www.mayoclinic.org/diseases-conditions/cancer/in-depth/biopsy/art-20043922
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  • Cleveland Clinic [Internet]. [cited 2024 Mar 22]. Plasmapheresis (Plasma exchange): therapy, procedure & what it is. Available from: https://my.clevelandclinic.org/health/treatments/24197-plasmapheresis-plasma-exchange
  • Seymour JF, Presneill JJ. Pulmonary alveolar proteinosis: progress in the first 44 years. Am J Respir Crit Care Med. 2002 Jul 15;166(2):215–35.

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Julio Grimm de Guibert

Doctorate in Medical Studies – PhD, University of Plymouth, England

Julio has lived in Brazil, Peru, Germany, Nigeria, South Africa, Greece, the US and England. He has a BSc and MSc in Biomedicine from the University of Würzburg, Germany and a PhD in Medical Studies from the University of Plymouth, England. After working in biomedical research for over 3 years, this biomedical scientist by training now wishes to use his knowledge about medical topics to inform readers.

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