What is Pulmonary Alveolar Proteinosis?
Pulmonary alveolar proteinosis (PAP) is a rare lung disease that was first studied in 1958. Over time, doctors have built a deeper knowledge of this disease. Initially, it was thought to be a result of breathing in harmful substances from the environment, which led to a buildup of lung-cleaning proteins in the tiny air sacs in our lungs or alveoli. It was initially given the name “acquired or idiopathic PAP”.
However, doctors now recognize that there are three separate ways this buildup can happen: congenital (present from birth), secondary (because of another disease), and autoimmune (where the body’s immune system mistakenly attacks healthy cells). All three paths lead to a buildup of the lung-cleaning protein not because of overproduction, but because of a slower removal process from the lungs.
Autoimmune PAP is the most frequently occurring type, accounting for 90% of documented cases. In this type, substances called immunoglobulin (Ig) G anti-granulocyte macrophage colony stimulating factor (anti-GM-CSF) antibodies decrease the function of alveolar macrophages, the cells responsible for cleaning our lungs.
On the other hand, secondary PAP does not have these antibodies. Instead, this type is a result of functional macrophages being reduced due to blood cancer or diseases affecting the immune system. Lastly, congenital PAP is the least common and occurs due to genetic changes affecting the GM-CSF receptors or the lung-cleaning proteins.
What Causes Pulmonary Alveolar Proteinosis?
Autoimmune PAP is a lung condition that comes about due to antibodies attacking a substance known as GM-CSF. Some people have thought that cigarette smoke or infectious diseases might stimulate the production of these antibodies, because a lot of people with PAP smoke or have infections. However, research has not found any direct link between smoking or infections and this autoimmune PAP.
Secondary PAP, on the other hand, is caused by any disease that reduces the number of effective alveolar macrophages, a type of white blood cell in our lungs. A look back at past cases found that around a third of secondary PAP cases were linked to a condition called myelodysplastic syndrome, and about 15% were linked to chronic myelogenous leukemia. Acute myeloid leukemia is also often linked with PAP. There are less frequent connections between PAP and acute lymphoid leukemia, lymphoma, and myeloma. There have been a few reports of PAP linked with lung cancer, mesothelioma, and glioblastoma, which are non-blood related cancers. PAP has also been linked with various immune deficiency conditions.
Secondary PAP has been associated with exposure to certain substances in the environment. These include silica, talc, cement, certain kinds of metals and other materials. Animal studies have also shown that PAP can be induced by inhaling substances like aluminum, fiberglass, indium, nickel, quartz, silica, and titanium. In France, an analysis of PAP patients found that 39% had been exposed to materials like cement, cereal dust, copper, epoxy, paint among others. Reports from Japan and Korea also showed a significant percentage of PAP patients had been exposed to certain environmental substances.
Congenital PAP, which is hereditary and present at birth, is caused by a dysfunction in one of many proteins responsible for regulating a substance called surfactant. This dysfunction can be due to mutations in various genes.
Risk Factors and Frequency for Pulmonary Alveolar Proteinosis
Pulmonary Alveolar Proteinosis (PAP) is a rare lung disease, with the number of cases reported per million people varying greatly from country to country. The majority of cases, about 90%, are autoimmune PAP. Smoking is prevalent among 53% to 85% of PAP patients. Autoimmune PAP usually affects men twice as much as women, and the disease is typically diagnosed between the ages of 39 and 51. However, it can occur in people ranging from newborns to 72 years old. Secondary PAP patients tend to be diagnosed at a slightly younger age and the disease does not lean as heavily towards one gender, with the ratio of male to female patients being 1.2:1.
- Pulmonary Alveolar Proteinosis (PAP) is a rare lung disease that varies in prevalence worldwide.
- About 90% of PAP cases are autoimmune, while 4% are secondary PAP, 1% are congenital PAP, and the remaining 5% are undetermined PAP-like diseases.
- Smoking is a common habit among 53% to 85% of PAP patients.
- In autoimmune PAP, men are affected twice as much as women.
- The typical age of diagnosis for autoimmune PAP is between 39 and 51 years, but it can range from newborn to 72 years old.
- Secondary PAP tends to be diagnosed at a slightly younger age of 37 to 45 years.
- The gender ratio for secondary PAP is more balanced, at 1.2 males for every 1 female.
Signs and Symptoms of Pulmonary Alveolar Proteinosis
Pulmonary Alveolar Proteinosis (PAP) is a condition that presents in a range of ways from subtle to urgent, and the symptoms are often hard to pin down. The most common symptom is a difficulty in breathing, which is experienced by about 39% of patients. Additionally, around 21% of patients have a cough. Other symptoms like coughing up blood, experiencing a fever, or chest pain are rare and usually indicate a different diagnosis. About a quarter of individuals with secondary PAP, which coincides with blood disorders or opportunistic infections, might have a fever. Interestingly, about one third of people with PAP don’t show any symptoms when they first see a doctor.
Research shows that the majority of people diagnosed with PAP are smokers, ranging between 53% to 85%. A significant number of patients also report being exposed to certain occupational hazards. While a majority of PAP cases are autoimmune, it’s rare for these patients to have other identified autoimmune diseases. During a physical examination, a doctor might not notice anything unusual. However, some patients may appear bluish (known as cyanosis), show unusual rounding or enlargement at the tip of their fingers (known as clubbing), or doctors might hear abnormal crackling sounds during inspiration.
- Difficulty in breathing
- Cough
- Fever (in cases of secondary PAP)
- Asymptomatic in some cases
- Majority are smokers
- Possible occupational exposures
- Physical exam could reveal cyanosis, clubbing, or inspiratory crackles
Testing for Pulmonary Alveolar Proteinosis
If you’re suspected to have PAP, which is a lung condition, there are various tests your doctor might use to diagnose your health issue. The symptoms of PAP aren’t specific, it’s why other tests are necessary to confirm this disease. These tests may include chest x-rays, blood tests, lung function tests, and sometimes using a thin tube to look inside your lungs (bronchoscopy).
With a chest X-ray, the doctor is looking for patterns often referred to as “batwing” or “crazy paving”. If you have PAP, certain areas in your lungs might look hazy, which is often a sign of PAP. However, these patterns don’t always confirm the diagnosis because they can be present in other lung conditions.
Your doctor might also want to check certain proteins and antibodies in your blood, also known as biomarkers. These might indicate PAP if they’re at unusual levels. A common blood test used is an enzyme-linked immunosorbent assay (ELISA), which can help detect special antibodies tied to PAP. But these biomarkers alone aren’t enough to confirm the diagnosis.
Pulmonary function tests (PFTs), another crucial tests, measure how well your lungs are working. Even though they aren’t used alone for diagnosing PAP, they can indicate some abnormalities common with PAP, such as restricted air flow.
Bronchoscopy is a popular method to confirm a PAP diagnosis. The doctor uses a thin, flexible tube to examine your lungs and collect a sample of fluid. In PAP patients, this fluid often appears cloudy, which further supports the suspicion of PAP.
While it is not usually required, in some case, if other tests are inconclusive, a lung biopsy could be performed. During this procedure, a small piece of lung tissue is removed and examined under a microscope for further signs of PAP.
Treatment Options for Pulmonary Alveolar Proteinosis
Whole lung lavage, or cleaning out the lungs, is the standard treatment for a condition known as autoimmune PAP (Pulmonary Alveolar Proteinosis). This decision is depended on the patient’s ability to exchange oxygen and carbon dioxide (gas exchange), and any signs of difficulty breathing. If the individual has mild difficulty breathing or shows no symptoms, they could be perfectly fine with regular monitoring and supportive care. Whole lung lavage becomes a consideration for patients who have trouble breathing at rest, low oxygen levels, or oxygen desaturation during the ‘6-minute walk test’.
Whole lung lavage was first performed in 1961. Today, under general anesthesia, a tube is inserted into the patient’s lung while the other lung is cleaned using warm saline. This cleaning process continues until the saline comes out clear, which typically requires about 15 liters of saline. After a rest period of 48 hours or more, the same process is repeated for the other lung.
The way this procedure is performed can vary based on factors like the choice of lung to start with, the patient’s position during the procedure and the amount of saline used. Studies looking back at patients who’ve had this treatment found improvements in breathing and clearer lung X-rays. There are also suggestions that the patient’s survival rate at 5 years is higher when this treatment is implemented, compared to when it’s not.
Despite improvements noticed, about 50% of patients will require a second round of the whole lung lavage procedure. The benefits typically last up to an average of 15 months.
GM-CSF replacement therapy involves injecting GM-CSF, a protein that helps fight infection, under the skin or through inhalation. Though clinical trials have shown some positive improvements in a percentage of trial patients, improvement following injections has been much slower compared to the speed of improvement following a whole lung lavage.
There’s also immunomodulation therapy, which involves medications that help to adjust or regulate the immune system. Some of these medications, like corticosteroids were tested but were found to increase the risk of lung infections and thus, not effective. Others like plasmapheresis and rituximab showed improvement in some patients and are considered alternatives for those whose condition doesn’t improve with whole lung lavage.
For secondary PAP, which is caused by an underlying disease, the only confirmed treatment is to manage the underlying disease. Whole lung lavage doesn’t seem to benefit these patients. However, there are some reports suggesting the potential of using stem cell transplant as a treatment for this condition.
Congenital PAP, which is hereditary, may benefit from whole lung lavage, but it’s not a permanent solution. Ways to manage it include using corticosteroids or other substitute drugs. There’s potential in gene therapy and direct pulmonary macrophage transplantation (transplantation of certain types of white blood cells to the lungs), and stem cell transplantation has shown promise, despite its potential risks.
What else can Pulmonary Alveolar Proteinosis be?
When trying to diagnose a rare lung disease called pulmonary alveolar proteinosis (PAP), doctors should consider other diseases that can cause similar symptoms and show similar patterns on CT scans. The CT scan of a person with PAP often shows a “crazy paving” pattern, but it’s important to know that this pattern could also mean several other conditions such as:
- Cardiogenic pulmonary edema (fluid accumulation due to heart problems)
- Acute respiratory distress syndrome (a severe lung condition)
- Alveolar hemorrhage (bleeding into the lung)
- Lipoid pneumonia (lung inflammation due to fat particles)
- Mycoplasma pneumonia (a type of bacterial pneumonia)
- Pneumocystis pneumonia (a fungal infection in the lungs)
- Radiation pneumonitis (lung inflammation due to radiation therapy)
- Drug-induced pneumonitis (lung inflammation due to medicine side-effects)
- Sarcoidosis (a disease causing small lumps of inflammatory cells in the lungs)
- Non-specific interstitial pneumonitis (a type of lung inflammation)
- Bronchioloalveolar carcinoma (a form of lung cancer)
Another crucial differential diagnosis to remember is acute silicosis, a lung disease caused by inhalation of silica dust, which shows similar clinical, pathologic, and radiographic findings as PAP. Therefore, a detailed work history checking for recent exposure to silica is essential.
What to expect with Pulmonary Alveolar Proteinosis
The progression and outcome of a disease can vary greatly from person to person and can be difficult to predict. In the case of autoimmune PAP, a lung condition, the 5-year survival rate after treatment with a procedure called whole lung lavage is 95%. It was commonly reported that 50% of patients experienced spontaneous healing without treatment, but more recent studies suggest this happens in less than 10% of patients.
In one study, 64% of people with PAP who had no symptoms stayed the same and 7% got worse. When looking back at previous cases, it was found that 72% of deaths in people with PAP were due to respiratory failure, while 20% were caused by secondary infections.
Secondary PAP has a less favorable outlook, with the median survival time being less than 15 months. The reasons for deaths in secondary PAP include the original blood disease (33%), infection (25%), respiratory failure (25%) and issues with bleeding (13%).
Possible Complications When Diagnosed with Pulmonary Alveolar Proteinosis
People with PAP, or Pulmonary Alveolar Proteinosis, have a heightened risk of catching an opportunistic infection. In fact, about 5% of people with PAP will catch one. These infections are predominantly found in the lungs, but can also spread to other parts of the body in around a third of cases.
Although it’s possible to contract bacterial pneumonia, this doesn’t happen often. The most likely infections are Nocardia and Mycobacterium tuberculosis, both opportunistic infections. There have been reports of people with PAP catching fungal infections, specifically Histoplasma, Aspergillus, Cryptococcus, and Blastomyces. Other kinds of reported infections are Acinetobacter, Coccidioides, Mucorales, and Streptomyces.
Possible Infections for PAP Patients:
- Nocardia
- Mycobacterium tuberculosis
- Aspergillus
- Cryptococcus
- Blastomyces
- Acinetobacter
- Coccidioides
- Mucorales
- Streptomyces
