alveolar proteinosis



OVERVIEW

Definition.

Pulmonary alveolar proteinosis (PAP) is a rare diffuse disease of the lungs of undetermined etiology characterized by the accumulation of large amounts of surface-active substances (phospholipoprotein-like substances) in the alveolar lumen.

Impaired clearance of surface-active substances by alveolar macrophages under the influence of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies [1-2] is the main cause of pathogenesis.

Symptoms are often mild or even absent. When symptoms occur, dry cough, shortness of breath on activity, and dyspnea are relatively common, and malaise and low-grade fever are occasionally seen.

Classification

Alveolar proteinosis can be categorized according to the cause of its development into three groups: spontaneous, secondary, and congenital [1].

Spontaneous

It is also called idiopathic alveolar proteinosis, acquired alveolar proteinosis, and primary alveolar proteinosis.

It is the most common type of alveolar proteinosis, accounting for more than 90% of cases, and is mostly autoimmune-induced.

Secondary

Secondary to other diseases or factors, accounting for 5% to 10% of alveolar proteinosis.

Congenital

An autosomal recessive disorder, accounting for about 2% of alveolar proteinosis.

Pathogenesis

Alveolar proteomalacia is a rare disease, according to the data, about 7 people per 1 million people have the disease [4].

The age of onset is between 30 and 50 years, the number of male patients is approximately four times that of female patients [3], and 72% of patients have a history of smoking.

Etiology

Causes

The etiology of the disease has not been fully defined, and according to the available data, it is inconsistent from one type to another [1,5]. More than 90% of cases are essentially autoimmune [4].

Spontaneous

The cause is unknown, there is no generalization of the disease in family members, and it is rarely accompanied by other autoimmune diseases.

It is currently thought to be a disease in which autoimmune mechanisms are involved in the pathogenesis.

Secondary

It is often secondary to the following factors.

Inhalation of minerals and chemicals: e.g. silica, cement dust, aluminum dust, titanium dioxide, nitrogen dioxide, and glass fibers [3].

Specific infections: e.g. Actinomyces, Mycobacterium, Pneumocystis, Cytomegalovirus, etc.

Tumors: common in hematologic tumors, but also seen in acute lymphoma.

Other diseases causing immunodeficiency: e.g. AIDS, monoclonal gammaglobulin disease, severe combined immunodeficiency syndrome.

Organ transplantation: e.g. lung transplant patients.

Congenital

Often caused by gene mutation, occurring in infants and young children, autosomal recessive inheritance.

Pathogenesis

The pathogenesis is not fully understood.

Currently, it is thought to be mainly due to the presence of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies, which reduces the activity of GM-CSF, leading to the impaired maturation of alveolar macrophages and a decrease in the ability to remove surface-active substances, resulting in a decrease in the removal of surface-active substances from the alveoli, which are deposited in the alveolar lumen and lead to alveolar proteomalacia.

Symptoms

The disease is often insidious, and 10% to 30% of patients have no clinical symptoms at the time of diagnosis, which are only manifested as obvious abnormalities on chest radiographs found on physical examination. The lack of parallelism between clinical symptoms and imaging changes is one of the characteristics of this disease. Extensive pulmonary exudative changes are often present, but clinical symptoms are mild.

Main symptoms

At the time of presentation, the common symptoms are shortness of breath after activity, dry cough or coughing up a small amount of white mucous sputum, which may progress to dyspnea with activity.

Other symptoms

Some have weakness, weight loss, and low-grade fever manifestations, while chest pain and hemoptysis are uncommon.

In severe hypoxia, there are often pestle fingers, bruised lips and retinal speckled hemorrhage.

Consultation

Department of Medicine

Respiratory Medicine

It is recommended to consult the Department of Respiratory Medicine when the patient develops suspicious symptoms related to the respiratory system, such as coughing, coughing up sputum, fever, shortness of breath after activity, chest pain, hemoptysis, and so on.

Pediatrics

Children with suspicious symptoms can go to the Pediatrics Department first.

Emergency Department

In case of severe respiratory distress, severe chest pain, massive hemoptysis and other potentially life-threatening conditions, you should promptly go to the Emergency Department or call 120 emergency.

Preparation for medical treatment

Preparing for medical treatment: registration, preparation of documents, and common problems.

Tips for seeking medical treatment

Diagnosis is difficult and imaging is a strong indicator, so imaging tests are often needed. Avoid wearing metal jewelry or clothing with a lot of accessories.

You should be prepared for the fact that the diagnosis may not be confirmed in a single visit.

Checklist for preparing for a visit to the doctor

Particular attention needs to be paid to the time of onset of symptoms, special manifestations, etc.

What are the most noticeable symptoms now? When did they first appear?

Is there chest tightness and shortness of breath after activity?

Is there a cough? Is it a dry cough or just a small amount of white mucus?

Is there dyspnea?

Are there any chest pains, hemoptysis, recent significant weight loss, or other discomforts?

Have you had any previous chronic illnesses, such as chronic bronchitis, chronic obstructive pulmonary disease (COPD), or heart failure, that could have caused the symptoms of dyspnea, cough, or chest tightness?

Are there any autosomal genetic disorders?

Are there any hematologic tumors, such as leukemia?

Any immunodeficiency diseases, such as monoclonal gammopathy, severe combined immunodeficiency syndrome, AIDS?

Any history of organ transplantation?

What environment do you work in and how much dust are you exposed to? Any history of pneumoconiosis, etc.

Does one smoke? How long have you been smoking? How many cigarettes per day?

Checklist

Test results in the last six months, which can be brought to the doctor’s office

Laboratory tests: routine blood tests, blood gas analysis, biochemical tests, etc.

Lung function test report.

Imaging tests: chest radiograph, chest CT or high resolution CT (HRCT).

List of medications used

Medication used in the last 3 months, if available, bring the box or package to the doctor

Because the disease is secondary to medications for a number of conditions, the following medication use should be provided to your doctor.

Antiviral drugs: e.g. acyclovir tablets, ganciclovir.

Anti-tumor drugs for the blood system: e.g., doxorubicin.

Immunosuppressants: e.g. azathioprine, cyclosporine, mertiomacrolide.

Diagnosis

Relevant history, clinical manifestations, laboratory tests, imaging tests, pathologic tests, and pulmonary function tests all contribute to the diagnosis and differential diagnosis.

Diagnostic basis

medical history

Smoking.

Family history of the disease.

Presence of hematologic neoplasms such as leukemia.

Immunodeficiency diseases such as monoclonal gammopathy, severe combined immunodeficiency syndrome, AIDS.

History of organ transplantation.

Long-term exposure to various types of dust.

Clinical manifestations

The preceding symptoms are only suggestive and have no specific value.

There are few signs, usually no dry or wet rales in both lungs, and wet rales can be heard when associated with infection.

In severe hypoxia, there are often pestle-like fingers (toes), cyanosis, and retinal patchy hemorrhage.

Laboratory tests

Most patients have normal blood counts, but some may have mild leukocytosis, and leukocytes may be elevated in the presence of infection.

In the presence of hypoxia, blood gas analysis may show a decrease in PaO2 and SaO2, with exercise increasing the magnitude of the decrease.

Lactate dehydrogenase (LDH) is elevated in 80% of patients, mostly mildly, and the level may correlate with the severity of the disease, but lacks specificity.

The serum LDH isoenzyme profile is normal.

A positive PAS stain may be detected, but the false-negative rate is high.

Serum IgG, IgM, IgE and certain tumor markers (e.g., CEA, CA125, etc.) may be mildly elevated.

Specific anti-GM-CSF autoantibodies are present in the serum of the vast majority of patients with spontaneous alveolar proteomalacia and are a good serologic diagnostic indicator.

Chest imaging

Imaging changes in both lungs are symmetrical and can produce relatively uniform changes, and changes in body position can cause changes in imaging performance.

In the early stage of the disease, the chest radiograph may show a ground-glass shadow.

Gradually, it develops into a symmetrical diffuse blurred edge nodular shadow on both sides, with the lower 2/3 of the lung field mainly spreading outward from the hilum, often fused into a “butterfly”-like pattern.

It has important diagnostic significance for diagnosis.

It is often manifested as patchy shadows in both lungs, with bronchial insufflation signs, clear, sharp edges, and a sharp contrast between the lesions and the surrounding normal lung tissue, forming a “map”-like change.

Sometimes, there is a ground-glass pattern, with irregular thickening of the interlobular spaces and intervals, showing a polygonal “paving stone” or “gravel road” (CPA) pattern.

The depth of the ground-glass shadow is related to the amount of lipoprotein deposits in the alveoli, and large solid shadows are rare, except in cases of opportunistic infections.

In particular, cardiogenic pulmonary edema and certain pulmonary infections (e.g., Mycoplasma pneumoniae, pulmonary cysticercosis) may also present.

Pathologic examination

The presentation is milky, thick and opaque, with sedimentation and stratification on standing.

Alveolar macrophages are almost absent, and eosinophilic vesicles of varying sizes are seen in a diffuse distribution.

The diagnosis is confirmed by a positive peroxynitrite Schiff (PAS) stain and a negative Alcian blue (Alcian) stain [2,6].

Electron microscopy reveals abundant lamellipodia and encircling phospholipids, and alveolar type II cells are seen [1].

Transbronchial biopsy (TBLB), CT-guided percutaneous lung aspiration biopsy and dissection lung biopsy can improve the diagnostic yield, but open lung biopsy is now rarely used.

Lung function tests

Lung function tests show a decrease in lung volume and functional residual air volume, and should be performed in suspected patients who have been smoking for a long time.

Diagnostic criteria

The combination of the aforementioned clinical symptoms, the typical “map-like” or “paving-stone” appearance of chest HRCT, the typical “milk-like” fluid of bronchoalveolar lavage fluid, and the characteristic pathological manifestations will most likely lead to a definite diagnosis. The diagnosis is usually clear.

Differential diagnosis

The main differential diagnosis should be with pulmonary edema, special pathogen infection of the lung, alveolar cell carcinoma, alveolar hemorrhage syndrome, etc. [1,7].

Pulmonary edema

Both can present with similar radiographic chest images and high resolution CT (HRCT) shows butterfly shadow.

Pulmonary edema has a history of heart disease; acute onset, sudden dyspnea, cough, heavy cough pink foamy sputum, lungs can be heard wet rales; cardiac, diuretic, vasodilator treatment can be, rapid relief of the condition.

Pulmonary edema X-ray chest radiograph shows enlarged heart shadow, and CT shows pleural effusion.

Special pathogen infection

When chest imaging shows patchy and large infiltrating shadows in both lungs, accompanied by fever, attention should be paid to differentiating from specific pathogen infections.

Specific pathogen infections often have distinct clinical symptoms (e.g., fever, dyspnea) and an associated medical history.

Cytomegalovirus pneumonia is seen in immunocompromised populations, such as organ transplant recipients and AIDS patients, with a high incidence in the second and third months after renal transplantation. Cytomegalovirus-IgM and cytomegalovirus-DNA tests, among others, are helpful in the differential diagnosis.

Differential diagnosis of Pneumocystis pneumonia is often done with the help of anti-HIV antibody test.

Bronchioloalveolar carcinoma

Clinical symptoms of fine bronchioloalveolar cell carcinoma are obvious, including cough, sometimes coughing up a large amount of foamy sputum, progressive aggravation of the disease, often accompanied by lack of appetite, emaciation and so on.

In addition to typical imaging changes, HRCT can also show diffuse small nodule or mass shadow, mediastinal lymph node enlargement, etc., which need to be further identified with the help of lung biopsy.

Alveolar hemorrhage syndrome

Most of the HRCT findings of alveolar hemorrhage syndrome are diffuse adenoidal nodular shadows and solid shadows, and the paving stone sign is rare.

Clinical manifestations of alveolar hemorrhage syndrome are obvious, such as fever, anemia, arthralgia, dyspnea and hemoptysis.

Laboratory tests show a progressive decrease in hemoglobin; bronchoscopy shows bloody BALF, and macrophages phagocytizing ferritin-containing hemocytes are seen in the alveolar lumen of TBLB pathology to help differentiate it.

Treatment

Aims of treatment: those with mild symptoms are mainly to improve the symptoms, and those with obvious symptoms undergo surgical radical treatment.

Treatment principle: asymptomatic people can be observed, mild symptoms should be treated symptomatically, severe symptoms need to consider whole-lung lavage, lung transplantation and other measures.

General treatment

For patients with mild symptoms, if hypoxemia occurs, oxygen can be administered.

Drug therapy

Granulocyte-macrophage colony-stimulating factor (GM-CSF) supplementation

Also known as GM-CSF supplementation therapy, it can be inhaled or subcutaneously injected, and the effect of inhalation is better than subcutaneous injection, with no standardized dosage and cycle [1,8].

According to the data, inhaled recombinant human GM-CSF has a certain therapeutic effect on patients with severe alveolar protein deposition; while the efficacy on patients with mild to moderate disease remains unclear [9].

It may be used in patients who cannot be treated with alveolar lavage or who have poor efficacy and recurrence of the disease after use.

Rituximab.

Adverse effects of rituximab treatment include fatigue, headache, nausea, weight gain, and nasal congestion [10].

However, it is not widely used, and it can be tried in patients who cannot be treated with alveolar lavage or who have poor efficacy and relapse after its use [8].

Other drugs

Various drug treatments reported in the past, such as the use of glucocorticoids, saturated potassium iodide solution, trypsin, acetylcysteine, and heparin, are now considered ineffective.

Surgical treatment

Whole lung bronchoalveolar lavage therapy

It is the most effective treatment method.

Indications: obvious symptoms of dyspnea, PaO2 <65 mmHg at rest, PA-aO2 ≥40 mmHg, and intrapulmonary shunt rate (Qs/Qt) >10%.

Symptoms, imaging and lung function improved significantly after alveolar lavage in 85% of patients.

Most of them were treated with whole lung lavage on one side via double-lumen endotracheal tube under general anesthesia. Patients who could not tolerate general anesthesia or unilateral lung ventilation, and those with milder conditions, could be treated with transbronchoscopic lavage.

Each irrigation 500-1000ml saline, repeated irrigation until the irrigation fluid is clear, usually the whole process requires 15-20L saline.

Lung transplantation

Lung transplantation can be considered when various treatments are ineffective, but the transplanted lungs can still develop again.

Other treatments

Plasmapheresis

Plasmapheresis may be attempted in patients who cannot be treated with alveolar lavage or who have poor outcome and relapse after its use.

Bone marrow transplantation, autologous stem cell transplantation

Secondary alveolar proteinosis and congenital alveolar proteinosis do not respond well to the above treatments, and studies of bone marrow transplantation and autologous stem cell transplantation are underway.

Gene therapy

There are many studies on gene therapy for congenital PAP, but the specific efficacy needs to be confirmed, and whether it can be widely used for clinical treatment in the future also needs further research.

Anti-infection treatment

Spontaneous alveolar proteinosis is easily combined with opportunistic infections. Common pathogens of opportunistic infections include Mycobacterium, Nocardia, Aspergillus, and Cryptococcus, which need to be treated accordingly.

Prognosis

Cure

Cure varies widely depending on the severity of the disease and treatment measures, with 75% surviving for 5 years or more [1].

Untreated

Approximately 1/3 of patients resolve on their own, with some progressing to respiratory failure and others remaining stable.

Treated

In patients with significant respiratory dysfunction, whole-lung lavage is the preferred and effective treatment, with an efficiency rate of up to 85%.

Some patients respond well to GM-CSF replacement therapy, but there are insufficient efficacy statistics.

In a few patients, despite repeated lavage, the disease continues to worsen and may be complicated by infection or even develop interstitial fibrosis.

Lung transplant recipients still have a certain chance of reoccurrence.

Prognostic factors

The following factors are not conducive to recovery.

Smoking.

Inadequate nursing care.

Secondary infections.

Hazardous

Symptoms such as coughing and chest tightness can interfere with the patient’s life.

The long duration of the disease may cause anxiety and panic in the patient.

There is a possibility of progressive respiratory failure, which may be life-threatening.

Daily

Daily Management

Daily Diet

Healthy and balanced diet with a reasonable mix of meat and vegetables.

Foods should be chosen to be light and easily digestible.

Flatulence foods, such as potatoes, sweet potatoes and soybeans, should be eaten sparingly to avoid bloating and even aggravating breathing difficulties.

Life management

Bed rest is required, and appropriate activities out of bed can be done when the condition is stable.

Psychological guidance

It is necessary to keep the mood comfortable, encourage the patient to keep optimism and establish the determination of long-term treatment.

Nursing care and rehabilitation training

Closely observe the patient’s condition changes after lavage, and do airway management before waking up [11].

Rest in semi-recumbent position after alveolar lavage, inhale oxygen, and encourage patients to cough and cough up sputum.

Instruct patients to perform respiratory function exercises after awakening, such as deep breathing training and coughing training [11].

Disease monitoring

Observe the changes of respiratory frequency, rhythm and amplitude.

Changes in blood oxygen saturation were monitored by home finger-clip oximeter.

Follow-up review

Follow the doctor’s instructions for regular follow-up, and consult the doctor promptly if there is an aggravation of dyspnea.

Prevention

Cessation of smoking.

Exercise to improve immunity.

Follow the principle of eugenics and screen for genetic diseases before pregnancy.

Reducing inhalation of dust and harmful gases can reduce recurrence [11].