Introduction:
Idiopathic pulmonary fibrosis(idiopathic pulmonary fibrosis, IPF) is an unexplained pulmonary interstitial inflammatory disease. Unexplained alveolar fibrosis and diffuse pulmonary interstitial fibrosis are synonymous. Typical IPF, mainly manifested as dry cough, progressive dyspnea, gradually worsened over several months or years, and progressed to end-stage respiratory failure or death within 3 to 8 years of symptoms. The main pathological features are interstitial fibrosis and alveolar fibrosis and inflammatory cell infiltration. Although the pathogenesis of the disease has not been fully elucidated, its clinical features and pathology are sufficient to show that this is a characteristic disease. There is no objective and decisive prognostic factor or therapeutic response in the treatment of IPF. Corticosteroids (hereinafter referred to as hormones) or immunosuppressants and cytotoxic drugs are still the main therapeutic drugs, but less than 30% of patients have therapeutic response, and Can represent toxic side effects.
Cause:
(1) Causes of the disease
The cause of IPF is unknown. Viruses, fungi, environmental pollution, and toxic substances can all be affected. IPF has not been found to have a clear genetic basis or propensity, and hereditary or familial IPF is quite rare. The clinical manifestations of familial IPF are similar to those of non-familial IPF. Although the genetic transmission model has not yet been elucidated, the penetrance of the mutation can be believed to be autosomal dominant, and the special gene located on chromosome 14 may be associated with the high risk of IPF. Human leukocyte antigen on chromosome 6. (HLA) has nothing to do with IPF.
The onset of IPF may be the result of continuous superposition of inflammation, tissue damage, and repair. Pathogenic factors act on resident immune cells in the lungs, producing inflammation or immune responses, and they can also directly damage epithelial cells or endothelial cells.
1. Immune and inflammatory responses Early stages of IPF may produce an anti-specific immune response. The inflammatory response of the lower respiratory tract is the earliest detectable damage to the lungs. Lymphocytes, macrophages, and neutrophils in the interstitial and alveoli. T lymphocytes play a dual role in the regulation of lung injury and disease progression in IPF. T lymphocytes obtained from the alveoli of patients with IPF are activated, expressing IL-2 receptors and secreting INF-γ. The products secreted by T lymphocytes can inhibit the proliferation of fibroblasts as well as the collagen synthesis of fibroblasts. In addition, T lymphocytes also have a huge auxiliary effect on B lymphocytes, which is important for enhancing the production of immune complexes.
The production of specific immune responses in the lung parenchyma is important for the accumulation of inflammatory cells that affect lung tissue. Selective adhesion molecules, adhesion molecule binding molecules and immunoglobulins play important roles in the interaction between inflammatory cells and endothelial cells. The strong adhesion of many cells depends on intercellular adhesion molecule-1 (ICAM-1) and leukocyte antigen-1 (LFA-1). TNF-α induces ICAM-1 expression on the surface of endothelial cells. Extravascular leukocytes, including LFA-1 and platelet endothelial cell adhesion molecules, are expressed at the junction of leukocytes and endothelial cells. The urokinase-type plasminogen activator (urokinase u-PA) may be a degradation product of proteolytic enzymes in different tissues of inflammatory cells from blood vessels to alveolar spaces. The direct migration of IPF inflammatory cells depends on a variety of chemicals. Chemokines include interleukin-1 (IL-1) monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-Ia (MIP-1a), complement component C5a, cytokine (MCP-1, MIP-1a and fibronectin include RGD, leukotriene B4 (LTB4), IL-8 and C5a acting on leukocytes in macrophages. T lymphocytes, alveolar macrophages, endothelial cells, epithelial cells, and Fibroblasts are important sources of these cytokines. Urokinase receptor (u-PAR, CD87) is an essential chemokine for monocytes and PMN. U-PAR may affect leukocyte circulation and activate adhesion function of complement receptor 3. .
2. Injury epithelial cell damage is a hallmark of IPF. Viral infections and inflammatory cell products (oxygen free radicals, proteolytic enzymes) are mediators of damage. Epithelial cell damage causes plasma proteins to ooze out into the alveolar space. The alveolar basal layer can also be destroyed during the injury process. The presence of activated inflammatory cells (lymphocytes, macrophages, PMN) contributes to the continuous development of alveolar wall damage.
3. Repair, fibrotic damage Successful alveolar repair requires removal of plasma proteins entering the alveolar space, replacement of damaged alveolar walls, and re-storage of damaged extracellular matrices. Alveolar exudates formed during inflammatory reactions include many cytokines and mediators such as growth factors (platelet growth factor, transfer growth factor-beta, insulin-like growth factor-I), fibronectin, thromboxane, fibrinopeptide, and the like. Alveolar epithelial cells and macrophages regulate the formation and clearance of cellulose in the alveoli. Due to the presence of μ-PA, there is a network of fibrin degradation activities in the alveolar space. However, fibrin degradation activity in BAL of IPF patients is inhibited by increased levels of plasminogen activator and plasmin such as plasminogen activator inhibitor-1 (PAI-1). Similarly, fibronectin in the alveolar space is also inhibited. If the exudate in the alveoli is not removed, the fibroblasts invade and proliferate, producing new matrix proteins that turn the cellulose-rich exudate into a scar.
Arachidonic acid metabolism also plays an important role in the fibrosis reaction of IPF. Interleukins have a direct effect on fibroblasts and other mesenchymal cells, stimulating fibroblasts to release chemokines, promote cell proliferation and collagen synthesis. An important feature of alveolar repair is the epithelial remodeling of the alveolar basement membrane. In order to complete this process, type II alveolar epithelial cells proliferate, the final basement membrane surface repair, and local exudate fluidization. This process undoubtedly occurs under the influence of keratinocyte growth factor and hepatocyte growth factor, which regulate the proliferation and migration of epithelial cells.
During the formation of IPF, epithelial cells are missing, alveolar collapses, and a mass of scars is formed when a large number of alveoli are involved.
(two) pathogenesis
The histology of lung biopsy specimens is important to rule out other diagnoses and quantification of the degree of fibrosis and inflammation. The main pathological features of IPF include alveolar septum (interstitial) and varying degrees of alveolar fibrosis and inflammation. Because many inflammatory lung diseases can have similar manifestations, granulomas, vasculitis, inorganic pneumoconiosis, or organic pneumoconiosis must be excluded. The pathological changes of IPF are diverse and distributed in a sheet, mostly in the peripheral lung (under the pleura). Even in the severely affected lung lobe, some alveoli can be protected from involvement. In the early stage of the disease, the alveolar structure can remain intact, but the alveolar wall edema is thickened, and the inflammatory cells in the interstitial cells are concentrated, mainly monocytes (such as lymphocytes, plasma cells, monocytes, macrophages), but also visible. Scattered polynuclear neutrophils and eosinophils.
In the early stage of the disease, alveolar macrophages were focally clustered, and alveolar macrophages were absent in moderate or advanced IPF. As the disease progresses, the chronic inflammatory infiltration becomes less and less obvious. The alveolar structure is replaced by dense fibrous tissue, and the alveolar wall breaks, causing cystic expansion of the airway (honeycomb lung). In the advanced stage of the disease, a large amount of lung collagen, intracellular matrix, fibroblasts, and inflammatory cells in the interstitial lung are rare or absent. Longer course of disease, alveolar epithelial hyperplasia, squamous metaplasia. Some patients may have changes in smooth muscle reactive hyperplasia, pulmonary artery dilation, and secondary pulmonary hypertension. The airway can be distorted, resulting in "traction bronchiectasis." Emphysema changes can be seen in patients with smoking IPF. Emphysema and honeycomb lungs can be distinguished based on the presence of fibrous tissue around the lumen of the honeycomb.
Diffuse alveolar damage is not a feature of early IPF, but can also be found in many other lung diseases such as adult respiratory distress syndrome (ARDS), inhaled lung injury, radiation-induced lung injury, drug-induced lung injury, collagen vascular disease, infection, and the like.
I have previously subjectively divided IPF into several pathological subtypes. It is believed that desquamative interstitial pneumonia (DIP) and common interstitial pneumonia (UIP) are pathological types of IPF at different stages of the disease. According to the American Thoracic Society (ATS) and the European Respiratory Society (ERS), a new international consensus has been proposed for the diagnosis of IPF: UIP is attributed to the specific pathological manifestations of IPF, while DIP, respiratory bronchitis (RBILD), Non-specific interstitial pneumonia (NSIP), lymphocytic interstitial pneumonia (LIP), acute interstitial pneumonia (AIP), and obliterative bronchiolitis with organizing pneumonia (BOOP) are not IPF.
symptom:
I. Clinical manifestations
About 15% of IPF cases are acute, often found in upper respiratory tract infections, progressive dyspnea, and more than 6 months of death from respiratory and circulatory failure. The vast majority of IPFs are chronic (maybe intermediate subacute), although chronic, the average survival time is only 3.2 years. The chronic type does not seem to be an acute type of evolution, and the exact relationship is not known.
The main symptoms are: 1 dyspnea labor dyspnea and progressive aggravation, shallow breathing, there may be nasal wing fan and auxiliary muscles to participate in breathing, but most do not sit and breathe. 2 cough, cough, no cough in the early stage, there may be a dry cough or a small amount of mucus. It is easy to have secondary infection, mucus purulent sputum or purulent sputum, occasionally bloody. 3 systemic symptoms may have weight loss, fatigue, loss of appetite, joint pain, etc., generally less common. Acute type may have fever.
Common signs: 1 difficulty breathing and purpura. 2 thoracic dilatation and diaphragmatic activity decreased. 3 The lower part of the lungs, Velcro, has certain characteristics. 4 braided fingers. 5 end-stage respiratory failure and right heart failure corresponding signs.
Second, diagnosis
(1) Diagnostic technology
1, imaging examination
(1) Conventional X-ray chest radiography technology should pay attention to appropriate penetration conditions, apply moderate intensifying screen, and focus should be small. Early alveolitis can not show abnormalities on the X-ray; as the lesion progresses, the X-ray shows a cloud-like, faintly visible micro-dot-like diffuse shadow, like a ground glass. Further progress sees that the fibrosis becomes more and more obvious, from a fine mesh to a coarse mesh, or a reticulated knot. In the late stage, there are more cystic changes of different sizes, namely honeycomb lungs. The lung volume is reduced, the diaphragm is lifted, and the interlobular fissure is displaced.
(2) CT contrast resolution is better than X-ray. High resolution CT (HRCT) can further improve spatial resolution. It is very helpful for the diagnosis of IPF, especially the identification of early alveolitis and fibrosis and the discovery of honeycomb lung.
(3) Radionuclide IPF often has increased permeability of alveolar capillary membrane. Nuclide technology inhalation of 99mTc-DTPA aerosol to determine lung epithelial permeability (LEP) shows a shortened T1/2, which is helpful for early detection and diagnosis of interstitial lung disease, and is not specific for IPF.
2. Pulmonary function tests Typical pulmonary function changes in IPF include restricted ventilation damage, reduced lung capacity, decreased lung compliance, and decreased diffusion. In severe cases, PaO2 decreased and PA-aO2 broadened. Pulmonary function tests and imaging techniques contribute to early diagnosis, especially in exercise tests, where there is a decrease in diffusion and hypoxemia before the onset of imaging abnormalities. Pulmonary function tests can be used for dynamic observation and are useful for assessing the condition. It may also be useful to assess the efficacy. Similarly, IPF's pulmonary dysfunction is not specific and has no differential diagnostic value.
3, the total number of cells in bronchoalveolar lavage recovery fluid increased, and the increase in the proportion of neutrophils is a typical change in IPF, which is helpful for diagnosis. It is still mainly used for research.
4. The histological changes of IPF in the early and middle stages of lung biopsy have certain characteristics, and the causes of interstitial lung disease include many patients with clear causes. Therefore, lung biopsy is very meaningful for the diagnosis and activity evaluation of this disease. The preferred application of the fiberoptic bronchoscope is TBLB, but the specimen is small and it is difficult to diagnose the fashion. A thoracotomy should be performed if necessary.
(B) the establishment of diagnosis According to the typical clinical manifestations and the above examination, IPF diagnosis can be established. The core issue is to rule out other interstitial lung diseases including those that are known or unknown. "Idiopathic" or "cryptogenic" are used to indicate that the cause is unknown, but not all diseases with unexplained and pulmonary fibrosis are IPF, such as sarcoidosis. IPF is a specific disease as a whole, although it is possible that it is not a homogeneous disease. Therefore, lung biopsy is necessary for the diagnosis of IPF. However, if you are unable to receive (resistance) traumatic examination, as long as there is evidence to rule out other interstitial lung diseases, it is acceptable to establish a clinical diagnosis of IPF.
(3) Activity judgment Although there are many studies at present, there are no confirmed indications. In addition to histological evaluation of lung biopsy, it is believed that 67Ga scan, lung epithelial permeability measurement, bronchoalveolar lavage fluid cell number, especially lymphocyte count and media assay have important reference value for estimating lesion activity. Although clinical manifestations, X-ray and CT signs, and changes in lung function and activity are not completely parallel, the length of the disease, the degree of fibrosis, and the presence or absence of cellular lung and lung function damage are still helpful for estimating activity.
diagnosis:
In collagen vascular disease (such asRheumatoid arthritis, systemic lupus erythematosus, progressiveSystemic sclerosisAnd diabetes), pneumoconiosis (such as asbestosis), radiation damage, and certain drug-induced lung diseases (such as nitrofurantoin) can present the same type of interstitial inflammation and fibrosis. However, in the above cases, this type of lesion cannot be called Because it is limited to idiopathic damage and has nothing to do with other disease damage.
Need to be identified include desquamative interstitial pneumonia, respiratory bronchiol-related interstitial lung disease, inability to classify or non-specific chronic interstitial pneumonia, idiopathic obstructive bronchiolitis with organizing pneumonia , allergic pneumonia and pulmonary eosinophilic granuloma.
complication:
Complications may have secondary infections, spontaneous pneumothorax in pulmonary heart disease. Pulmonary fibrosis eventually leads to heart and lung failure. Extensive pulmonary fibrosis is easy to develop with lung cancer, and pulmonary hypertension and pulmonary heart disease occur in the late stage.
treatment:
(a) treatment
The best treatment for IPF is still controversial. The main purpose of treatment is to eliminate or inhibit inflammatory components. A few studies suggest that the fibrosis process can be reversed, but there is still insufficient evidence.
1. Corticosteroids have been used in the treatment of IPL for more than 30 years. Unfortunately, only 10% to 30% of patients are effective in treatment. Complete remission is rare. Most patients are treated with hormone therapy and their condition is still worse. The dosage and method of most scholars' claims are:
Large doses of hormones are used during initial treatment. Prednisone or prednisolone 40 ~ 80mg / d, 2 ~ 4 months, and then gradually reduce. If the hormone therapy responds, it is generally effective in February to March. In the fourth month, prednisone was reduced to 30 mg/d; in the sixth month, it was reduced to 15-20 mg/d (or other equivalent dose of hormone). Prednisone dosage and rate of reduction should be guided by clinical or physiological parameters.
Because it is impossible to completely eradicate the disease, it is reasonable to treat patients with different treatment responses with a minimum dose of 1 to 2 years. It is sufficient to use prednisone 15-20 mg/d as a long-term low-dose maintenance therapy. High-dose methylprednisolone (1 ~ 2g, once or twice a week) intravenous "shock" treatment, but not superior to oral hormones.
For patients who have failed hormone therapy, addAzathioprine(AZP) orCyclophosphamide(CTX), and hormone reduction, 4 to 6 weeks off. When hormones are reduced, some patients progress or worsen. For these patients, prednisone (20-40 mg) can be administered orally every other day, plus immunosuppressants or cytotoxic drugs.
2. Currently recommended treatments have not been proven which treatments are best, it is recommended to use hormone plus azathioprine or cyclophosphamide for patients who are expected to have better results.
Hormone: the initial treatment, withPrednisone(or other equivalent dose of hormone) 0.5mg / (kg · d) (ideal weight, IaqM), oral for 4 weeks; then 0.25mg / (kg · d) (133M), oral for 8 weeks; followed by reduction to 0.125 mg / (kg · d) or 0.25 mg / kg, once every other day.
Azathioprine: 2 ~ 3mg / (kg · d) (LBM), oral, starting dose of 25 ~ 50mg / d, increase 25mg every 7 ~ 14 days, until the maximum dose of 150mg / d. Or cyclophosphamide: 2mg / (kg · d) (LBM) orally, the initial dose is 25 ~ 50mg / d, increase 25mg every 7 ~ 14 days, until the maximum dose of 150mg / d.
Treatment should last for at least 6 months if no side effects or complications occur. The therapeutic response should be observed during this time. Care should be taken to monitor the side effects of the drug and to achieve the best possible results with minimal dose and minimal side effects.
3. Auxiliary treatment of oxygen can reduce hypoxemia caused by exercise and improve exercise capacity. Oral codeine and other antitussives may be useful in some patients and in patients with cough recurrence. Like all patients with chronic lung disease, pneumococcal and flu vaccines can be taken regularly.
4. Lung Transplantation Single lung transplantation is an important treatment option for endogenous pulmonary fibrosis in some medical treatments. Patients with failed medical treatment have a poor prognosis. Patients with severe impaired lung function (Vc or TLC <60% predicted or DLCO <40% predicted) and hypoxemia have a 2-year mortality rate of more than 50%. Lung transplants should be considered in patients with severe functional impairment, hypoxia, and worsening conditions. Unless special contraindications exist, such as older than 60 years of age, general instability, or important extrapulmonary lesions (liver, kidney, cardiac insufficiency).
5. Prospects for treatment Although the treatment of pulmonary fibrosis consistently emphasizes the benefits of existing treatments, the main advancement in survival is to wait for the development of new therapies. Possible future therapeutic strategies include cytokine-inhibiting drugs, protease inhibitors and/or antioxidants, anti-fibrotic agents, and the like.
New formulations: For example, glutathione is an effective scavenger of oxygen free radicals that inhibits fibroblast proliferation of fibroblasts caused by mitotic stimulation. Taurine niacin inhibits the development and progression of experimental pulmonary fibrosis in animal models. N-acetylcysteine is a precursor of glutathione and has an adjuvant immunosuppressive effect in the treatment of IPF patients. Leukocyte adhesion molecule antibodies prevent collagen deposition and inhibit specific fibroblast factors, which may help block the fibrotic process. Platelet activating factor receptor antagonists also contribute to anti-fibrosis. Other anti-fibrotic preparations such as toluenePirfenidone(pyridone) A valine racemase inhibitor modification or the like. The emergence of new therapy strategies depends on a better understanding of the pathogenesis of this difficult disease. A review of the above mentioned drugs also requires a multicenter clinically large number of prospective controlled studies.
(two) prognosis
The natural history of IPF is characterized by irreversible progressive damage to lung function over several months or years. Very few patients are fulminant. Sometimes, the disease can be stabilized after the initial regression period, but spontaneous remission is quite rare (<1%). ). From symptom onset to death, the average survival rate is 3 to 5 years. The 5-year mortality rate of IPF is over 40%. Respiratory failure is the leading cause of death. Lymphocytosis in bronchoalveolar lavage fluid (BAL) suggests a higher response rate to glucocorticoid therapy; if BAL lymphocytes are low, mortality is high. The goal of treatment is to minimize progressive fibrosis and respiratory failure. Other causes of death from IPF are ischemic heart disease, cerebrovascular accidents,Pulmonary embolism, malignant tumors and infections. 9% to 10% of IPF patients have lung cancer.
prevention:
1. Due to the slow course of the disease, medical staff should carefully check and confirm the diagnosis.
2, to encourage patients to establish confidence in the fight against disease, and actively cooperate with treatment.
3, strengthen physical exercise, enhance disease resistance, winter should pay attention to keep warm.
4, pay attention to adjust diet, increase nutrition; smokers must quit smoking.
5. Patients should be encouraged to participate in lung rehabilitation exercises such as walking every day, stepping on a fixed bicycle, etc. Although they can not increase lung capacity, they can change the tolerance of activities, reduce the symptoms of dyspnea, and improve the quality of life.
简体中文