What Is Autoimmune Pulmonary Alveolar Proteinosis?

Overview

In this article, we will be talking about an interesting illness known as autoimmune pulmonary alveolar proteinosis. While this name may sound intimidating, we will address it as APAP or PAP. So, what exactly is PAP and how does it affect the patients struggling with it?

PAP has a prevalence of 6 to 7 cases/million population worldwide. It is a rare but devastating respiratory disease that is represented by the accumulation of surfactant lipoproteins inside the alveoli, which in turn impairs the gas transfer in the lungs and causes a wide range of clinical issues, that can be as mild as exercise intolerance and as severe as respiratory failure and death.¹

There are different types of PAP – primary, secondary, and congenital – which will be further touched upon in this article.¹ Since PAP can be very severe and deadly, it is important for us to understand this disease to be able to notice its signs, get it diagnosed appropriately and provide the proper medical care for this case.

Types of Pulmonary Alveolar Proteinosis

There are multiple forms of pulmonary alveolar proteinosis:^1,2

• Primary: involves altered white blood cell (macrophages and neutrophils) activation. This leads to the impaired clearance of surfactant and as a result its accumulation in the lungs. 90% of all PAP cases are due to an autoimmune origin which is due to the GM-CSF (granulocyte–macrophage colony-stimulating factor) autoantibodies. The remaining are hereditary forms due to mutations in the GM-CSF receptor mutations.
• Secondary: arises due to various underlying conditions that can affect various functions of the alveolar macrophages. It is most associated with haematological disorders, however, it was also reported to be related to immunosuppressants, malignancies, chronic inflammatory conditions, and exposure to toxic substances (environmentally).
• Congenital: caused by a mutation in the genes responsible for proteins involved in the surfactant production or the surfactant proteins themselves.  

Natural History

Symptoms

APAP is commonly seen in adults between their 3^rd–5^th decades of life with an insidious onset, meaning it slowly progresses without any clear symptoms.¹ Additionally, 1/3 of autoimmune pulmonary alveolar proteinosis patients are asymptomatic.¹ However, PAP can also be present in patients as young as 3 years old, or in adults in their 90s.³ The most common symptoms include exertional dyspnoea that develops into resting dyspnoea over months and years.³ Other symptoms include:³

• Throat clearing
• Chest pain
• Chest congestion
• Overproduction of sputum
• Cyanosis (in severe cases)
• Fever and haemoptysis are uncommon and usually associated with infection.

Clinical manifestations of APAP are summarised in Table 1.

Table 1. APAP clinical representations.¹

Clinical course

There are 3 patterns associated with autoimmune PAP; these include stable disease, progressive deterioration and spontaneous alleviation/resolution.³ There were several studies done to test the different patterns:³

• A meta-analysis was conducted on 343 patients which showed a 78% survival rate at 2 years, 75% at 5 years, and 68% at 10 years, with more than 80% of deaths occurring within 12 months of diagnosis. The major cause of death was due to respiratory failure, followed by uncontrolled infection.
• Another study on 223 patients showed that spontaneous resolution does occur as no deaths occurred in that study over a period of 5 years.
• In contemporary studies from China, Japan, Italy, and Germany, it is estimated that spontaneous alleviation may happen in 5 to 7% of patients.

Secondary Infection

APAP is linked to an increased risk of severe infections; this is due to the impaired innate immune functions of immune cells (myeloid), reduced phagocytosis, microbial killing, and others.³ The microbes causing these infections are either community-acquired or opportunistic pathogens; the most identified opportunistic pathogens include Nocardia spp., Mycobacteria, and Aspergillus.³ Secondary infections are common and make up 18 to 20% of the deaths in PAP.³

Pulmonary fibrosis

Pulmonary fibrosis (PF) can occur in APAP, however it is one of the least defined manifestations of the disease.³ In a recent study, 9 of 44 patients with PAP syndrome reported the development of pulmonary fibrosis, which was associated with a worse outcome.³ Even though PF can occur and may be infrequent in autoimmune PAP, it can be a prominent characteristic of secondary PAP caused by toxic inhalation of silica and other dust and is a major component of the pathology in congenital PAP caused by mutations in surfactant gene.³ 

Evaluation and diagnosis

Evaluation of PAP is done through multiple different tests including:^1,3

• Pulmonary function tests: to assess lung volume and may be normal in mild cases of APAP.
• Radiological tests: include the use of computed tomography scans and X-rays. The results usually show a nonspecific, diffuse, patchy, bilateral air space appearance like pulmonary oedema, but without the other radiographic findings of left heart failure.
• Bronchoscopy: examination of the airways is not significant in APAP, however bronchoalveolar lavage/BAL fluid can be collected and used to reflect disease severity.
• GM-CSF Autoantibody Test: this is a very sensitive test for APAP; however, it does not show disease severity prognosis or lung function.
• Lung biopsy.

Management and therapy

There are multiple methods used to treat and manage APAP. Some of these methods include:^2,3,4

• Whole Lung Lavage: currently, this is the first-line therapy for APAP. This is done by administering saline through a transtracheal catheter at 50 to 60 drops/min for 1 to 2 hours 4 times daily for 2 to 3 weeks. This is to induce cough-induced clearance, but this can be distressing and time-consuming.
• GM-CSF supplementation: administration of recombinant GM-CSF, either through subcutaneous injections or aerosolised forms. Improvements in patients were reported by 48.4% to 76.5% respectively.
• Targeted therapies aimed at GM-CSF antibodies: this includes Rituximab or Plasmapheresis.
• Lung transplantation for end-stage fibrosis: this is an option for patients who show little to no response to previous treatments and are heading into a clinical deterioration. There have been reports of recurrence of PAP post transplants. Hence, it is important to reserve this method for selected candidates and have follow-up sessions.
• Glucocorticoids: these medications are often used to treat autoimmune diseases. However, systemic glucocorticoids do not show much improvement in APAP patients. It is interesting to note that during a study of patients from different centres, 74% of patients showed deterioration when treated with high doses of steroids.
• Supportive care: since APAP patients are at high risk of infections and complications, patients should be counselled and educated regarding immunisation (influenza and COVID-19). Other measures can be taken such as avoiding smoking and even long-term oxygen therapy.

FAQs

What is the prognosis for pulmonary alveolar proteinosis?

So far, the prognosis for PAP is good, with many patients having complete remission – autoimmune PAP shows around 95% patient survival for 5 years.⁵

What are the emotional symptoms of autoimmune disease?

Many patients suffering from autoimmune diseases face hardships on an emotional level; other than physical symptoms, constant fatigue and pain can cause patients to experience a lower quality of life, low mood, worry, fear, and poor sleep patterns, which all feed into a worse emotional and mental state for the patient.⁶

Summary

Pulmonary alveolar proteinosis is one of the rare lung disorders that occurs in adults. Over 90% of the cases of PAP are due to an autoimmune origin. While this disease is insidious in nature, it has the potential to be fatal and cause multiple complications in patients (infections, pulmonary fibrosis, and even death). Due to the nature of this disease, early detection and treatment can help prevent its deterioration and provide the patient with a better life. So far, the most common method is lung lavage. Other methods such as antibody therapy and GM-CSF augmentation are possible. Proper diagnosis for the type of PAP is also important to help clinicians choose the appropriate therapy for their patients, alongside continuous check-ups and follow-ups to ensure reoccurrence is being controlled.