Pulmonary Alveolar Proteinosis
Information for Patients
When you are lying on the bed, you are tilted up and down, while a physiotherapist beats your back black and blue. After that, you are sore both on the inside and on the outside, but you welcome the beating as it loosens the surfactant, which helps you breathe more easily.
A Danish PAP patient about lung massage during a whole lung lavage (WLL) procedure. Read more about WLL on page 12
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INTRODUCTION PAP IN SHORT PAP SYMPTOMS DIAGNOSIS PROGRESSION TREATMENT INVESTIGATIONAL THERAPY
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PREVALENCE CAUSES COMPLICATIONS LEARN MORE ABOUT PAP
Introduction Pulmonary Alveolar Proteinosis (PAP) is a rare lung disease, which affects approximately 7 persons in a million people. So despite the fact that you have a very rare disease, you are not the only one. Being diagnosed with a rare, chronic disease may turn your life upside down and significantly change your everyday life. According to experts the best way to deal with the change is to face your disease head on. The more you know about your condition and how to handle it, the more empowered you may feel. This handbook contains information about PAP and deals with subjects such as symptoms, progression and treatment.
PAP in Short PAP is characterised by the build-up of grainy
to clean the air sacs. Consequently, the old
material in the air sacs (alveoli) in your lungs.
surfactant material builds up gradually in your
The grainy material consists of proteins and
lungs and eventually fills the alveoli causing you
lipids from lung surfactant - an important
to feel breathless.
substance that coats the inside of the air sacs to prevent your lungs from collapsing. The air sacs
Scientific research shows that the macrophages
need to be inflated for your lungs to absorb the
need to be stimulated by a protein called
oxygen that you breathe and transfer it to the
Granulocyte Macrophage Colony-Stimulating
Factor (GM-CSF) in order to function. In PAP lungs, however, the GM-CSF protein is
Your body continuously produces new active
either inactivated or defective, rendering the
surfactant. In healthy lungs the old, inactivated
macrophages or dustmen unable to perform
surfactant is digested by immune cells called
their cleaning tasks.
alveolar macrophages. They are the dustmen or garbage collectors of the body and they have a very important task of keeping the alveoli clean. In PAP lungs, however, the macrophages fail 05
PAP Symptoms When the air sacs in your lungs fill up with
The accumulated surfactant waste material in
surfactant waste it becomes increasingly difficult
your lungs may lead to symptoms such as :
for the blood vessels in the lungs to take up oxygen from the air that you breathe.
- Breathlessness on exertion/activity but
sometimes even at rest
Consequently, you may experience shortness of
- Decreased or decreasing ability to exercise
breath and reduced physical capacity due to the
- Cough, which may be either dry or productive
lack of oxygen, as well as coughing.
with expectoration of whitish mucus
- Chest pain in various types and degrees However, the symptoms vary from person
to person. Some are very affected by the
- Fever or sweats
symptoms in their everyday lives. Others
- Generalised aches and pains
hardly notice any symptoms. But common to
- Fatigue, tiredness, depression or anxiety
all PAP patients is that they are at higher risk of
- In severe cases respiratory failure can occur
acquiring infections because the GM-CSF protein in their immune defense is inactivated or defective. 06
Diagnosis Your doctor may suspect pulmonary alveolar
densities). The pattern that the images show
proteinosis (PAP) based upon your history
is often referred to as â€œcrazy pavingâ€? and is
of symptoms such as breathlessness with
characteristic of PAP, but it is not sufficient to
very slow onset and a physical examination
establish a diagnosis.
revealing a crackling sound when listening with a stethoscope and when other, more common,
causes of lung disease have been ruled out.
If the doctor suspects that the symptoms may be caused by PAP a specific and very sensitive blood test can be performed. The blood test
Often the physical examination is supported by
can identify an increased presence or absence
a chest x-ray or CT scan. The chest x-ray in PAP
of GM-CSF autoantibodies, which is an indicator
typically reveals the presence of whitish, fluffy
of autoimmune PAP. Similarly, a series of blood
shadows scattered throughout both lungs. The
tests are being developed for the detection of
CT scan images typically reveal extensive white
patches within the lungs (ground glass opacity) with superimposed angular lines (reticular 08
Some doctors use a specialized procedure called
If the examinations mentioned above have
bronchoscopy to conduct a bronchoalveolar
not given any conclusive results about your
lavage (BAL). The BAL fluid is examined to see if
diagnosis, the doctor may choose to perform a
PAP is present.
biopsy of the tissue in your lungs. The biopsy is a surgical procedure called open lung biopsy.
When you undergo a bronchoscopy the doctor passes a bronchoscope into your lungs. A
When an open lung biopsy is performed a
bronchoscope is a tube used to see the inside
general anaesthesia is used, which means you
of the airways and lungs. The doctor sends a
are asleep and pain-free during the procedure.
saline solution through the tube into the lung
A tube is placed through your mouth down
and withdraws it again. This allows the doctor to
your throat to help you breathe. While you are
collect samples of lung cells, fluids, and other
sedated the doctor removes a small piece of
materials inside the air sacs. This part of the
tissue from your lung, which then is examined.
procedure is called a lavage.
Progression PAP usually develops slowly and remains unnoticed until you have accumulated enough surfactant for it to cause symptoms. Over time the disease may progress in several ways: - The disease spontaneously improves and clears - The disease progresses over time - The disease remains stable - The disease is never identified because the patient has no symptoms However, according to doctors most patients experience persistent symptoms that require medical treatment.
PAP affected alveoli
Treatment If treatment is required, the main treatment for
may take several hours and may be interrupted
PAP is washing of the lungs also called whole lung
by lung massage in order for the surfactant to
lavage (WLL). In a WLL procedure sterile saline
(salt water) is used to wash the abnormal build up of lung surfactant from the lungs. WLL is carried
Elisabeth, a Danish PAP patient who has had several
out under general anaesthesia where doctors wash
whole lung lavages for the treatment of PAP,
one lung at a time. The other lung is protected
describes the lung massage procedure like this:
from the saline and ventilated with oxygen. When you are lying on the bed,
During the procedure, the doctor (anaesthetist)
you are tilted up and down,
inserts a special double-barrelled breathing tube
while a physiotherapist beats
(called a double-lumen-endobronchial tube)
your back black and blue. After
through the mouth and into the windpipe so that
that, you are sore both on the
the left and right lungs can be isolated from each
inside and on the outside, but
other. The lung is washed until all the â€˜milkynessâ€™
you welcome the beating as it
of the lung surfactant is washed out and the
loosens the surfactant, which
fluid is crystal clear. In some cases this
helps you breathe more easily.
After the lung massage, the procedure is repeated.
Any remaining saline is drained out of the lung and both lungs are ventilated with oxygen.
Plasmapheresis is a process that filters the blood and removes harmful antibodies by removing the
Though whole lung lavage is standard treatment
plasma portion of the blood where antibodies
for PAP, some patients are offered other types of
are located. In PAP patients, GM-CSF antibodies
treatment. This is typically because WLL does not
are removed from the blood preventing it from
have the intended effect or because the patients
inactivating the GM-CSF proteins.
are not suited for the treatment.
Investigational therapy As a cure for pulmonary alveolar proteinosis
body's immune system. The immune system is composed of immune cells and the proteins that they produce. These cells and proteins serve to protect the body against harmful bacteria, viruses, fungi, and other foreign invaders.
(PAP) has not been found yet and patients respond differently or sometimes not at all to
Immune modulating medicine is treatment that
the existing treatments, the search for new
uses certain parts of your immune system
effective therapies is a continuous process.
to fight diseases. Clinical trials are ongoing to find out if such medicine can be used to treat
Currently, researchers are conducting clinical
pulmonary alveolar proteinosis (PAP). This can
trials looking into the effect and safety of
be done in a different ways. In the treatment
immune-modulating treatment or immune-
of PAP, immune modulating therapy tested in
suppressive treatment for autoimmune PAP.
clinical trials consists of an immune system
Immune modulating medicine
component called Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF), which is given to relieve the symptoms of
Immune modulating medicine also called immunotherapy is medication that affects the 14
Experimental treatment with GM-CSF The most common form of PAP, autoimmune PAP, is related to a defective immune control with high levels of antibodies that inactivate GM-CSF. GM-CSF serves to mature and stimulate the cells that defend your lungs against invading germs and regulate the breakdown of inactive surfactant. The discovery of GM-CSF antibodiesâ€™ role in PAP has led to the study of GM-CSF as a potential treatment of autoimmune PAP. Treatment with GM-CSF is either given subcutaneously (through a needle under your skin) or as inhalation. A number of clinical studies have been published indicating the efficacy and safety of inhaled GM-CSF in PAP patients. Scientific research also indicate that GM-CSF administration may facilitate restoration of the normal function of immune cells in the lungs (alveolar macrophages).
Experimental treatment with immuno-suppression Another treatment approach that is studied for the treatment of autoimmune PAP is immuno-suppression. Immuno-suppressive therapies reduce the immune response, for example by selectively attacking immune cells which produce excess quantities of antibodies. As such, it is used to decrease the number of B-cells that produce antibodies, such as autoantibodies to GM-CSF antibodies. This may prevent the development of antibodies that inactivate the GM-CSF proteins. The same type of therapy is used for treatment of other diseases related to development of antibodies to your own tissue, such as rheumatoid arthritis and systemic lupus erythematosus. However, at the moment further studies are needed in order to determine the efficacy and safety in PAP patients.
Prevalence PAP is a rare disease. The yearly prevalence
silica, titanium oxide, aluminum, and
(number of patients that are affected by
indiumtin oxide or insecticides, you may
the disease) in USA is 6.9 persons per
also be at increased risk of developing PAP.
million. In Japan, the yearly prevalence is similar (6.2/ million).
In Europe, however, the prevalence in
Though PAP is a rare disease the typical
the general population has not been
PAP patient can be characterised by being:
investigated in large studies. But it is assumed to be the same as in USA.
- Aged 25-50 at time of diagnosis - Male (men are 4 times more likely than
If you have other diseases such as HIV or
women to be diagnosed with PAP)
certain types of bone marrow cancer it
- Smoker (the disease seems to be more
increases your risk of developing PAP.
frequent in smokers)
Further to this, if you work in environments where you inhale mineral dust such as 17
Causes When you look for a cause of your disease, it
all is the build-up of waste material from lung
is important to bear in mind that in 90 % of all
surfactant in your lungs. This causes symptoms
cases of PAP there is no known cause.
like shortness of breath and cough.
3 types of PAP
Autoimmune PAP – no known cause
When you are diagnosed with PAP, your doctor will
The most common form of PAP is called acquired or
probably be able to tell you which kind of PAP you
autoimmune PAP. Approx. 90 % of all people with
have. It will be one of the three different forms:
PAP have this type of the disease .
- Autoimmune PAP
Patients suffering from this form have antibodies to
- Secondary PAP
a GM-CSF protein in the blood and the lungs. These
- Congenital/familial PAP
antibodies inactivate the protein so that it cannot function properly. It is not known why some people
The three forms are distinguished by the cause of
develop antibodies to their own GM-CSF. This is why
the disease and the different mechanisms in the
doctors sometimes refer to it as idiopathic PAP as
body that cause symptoms. Common to them
idiopathic means ‘with no known cause’.
Secondary PAP â€“ underlying diseases Secondary PAP is the second most common form of PAP and accounts for approx. 10 % of all PAP patients . Unlike autoimmune PAP it is possible to identify a specific cause of the disease when you have secondary PAP. The cause of secondary PAP may be: - Massive inhalation of toxic substances such as mineral and metal dust - HIV - Some types of cancers - Some types of lung infections
Congenital PAP Congenital PAP is a very rare form of PAP. It is usually diagnosed among infants and young children as it is linked to gene defects. The defects may occur in genes for surfactant proteins or for the receptor transferring GM-CSF signals to the cells. 19
Complications The most common form of PAP, autoimmune
Wash your hands
PAP, is related to a defective immune control
with high levels of antibodies that inactivate the
Regular hand-washing is one of the most
GM-CSF protein. Your bodyâ€™s defense against
important things you can do to reduce your risk
infections is therefore weakened. This is why
of infection. Wash your hands thoroughly and
you are at higher risk of lung infections and
often, especially when you are around a lot of
other infections, when diagnosed with
people, for example in a hospital or doctor's
office, or at school or work.
There is a simple and effective way of reducing
Still, always contact your physician if you
the risk of developing infections without you
experience a severe infection or have other
having to live a bubble.
Learn more about PAP If you are looking for more information about PAP, treatment of PAP and/or life with PAP you may find the following websites useful: - The PAP Foundation www.papfoundation.org - PAP Info www.PAP.info - National Organization for Rare Disorders (NORD)
You can also contact your local lung disease patient organisation.
This folder has been produced by Serendex in collaboration with medical specialists who have contributed with their knowledge about a number of aspects about PAP. Serendex Pharmaceuticals Slotsmarken 17 2970 HĂ¸rsholm Denmark www.serendex.com Info@serendex.com Tel: +45 7930 1414
Information folder for patients about pulmonary alveolar proteinosis (PAP)