| disease | Idiopathic Pulmonary Fibrosis |
| alias | IPF, Cryptogenic Fibrosing Alveolitis, CFA, Idiopathic Pulmonary Fibrosis, Cryptogenic Fibrogenic Alveolitis |
Idiopathic pulmonary fibrosis (IPF) is a disease of unknown cause characterized by diffuse alveolitis and disordered alveolar structure, ultimately leading to pulmonary interstitial fibrosis. Based on the disease course, it can be classified into acute, subacute, and chronic forms. The so-called Hamman-Rich syndrome belongs to the acute type, while subacute and chronic forms are more commonly seen in clinical practice. European scholars often refer to this disease as cryptogenic fibrosing alveolitis (CFA), whereas the term IPF is commonly used in the United States. In China, the name CFA was prevalent in the past, but IPF has been increasingly used in recent years. The disease is mostly sporadic, with an estimated incidence of 3–5 per 100,000, accounting for approximately 65% of all interstitial lung diseases. It can occur in all age groups, but diagnosis is typically made between the ages of 50 and 70, with a male-to-female ratio of 1.5–2:1. The prognosis is poor; even in early-stage cases that respond to corticosteroid therapy, the survival period is generally only about 5 years.
bubble_chart Pathogenesis
The cause of IPF disease is unknown, and the pathogenesis is not fully elucidated, but sufficient evidence suggests its association with immune-inflammatory injury. The characteristics of immune-inflammatory responses vary across different specimens (Table 1). Peripheral blood primarily reflects prominent immune abnormalities, while bronchoalveolar lavage fluid predominantly shows inflammatory reactions, and local lung tissue exhibits distinct abnormalities. Therefore, such differences must be considered when evaluating various research data.
Table 1 Immuno-inflammatory Features of IPF| Blood | Lavage Fluid | Tissue |
| Immune | ||
| Hypergammaglobulinemia | IgG | Plasma Cells |
| Autoantibodies | ||
| Antinuclear Antibodies | - | - |
| Rheumatoid Factor | - | - |
| Soluble Immune Complexes | (Soluble Immune Complexes) | (Soluble Immune Complexes) |
| C3Elevation | - | - |
| Sensitized Lymphocytes | ||
| Nuclear Products | -(Lymphocytes) | Lymphocytes |
| Collagen | - | - |
| Inflammation | ||
| Acute-Phase Reactant Proteins | Activated Macrophages | Alveolar Macrophages |
| Activated Neutrophils | (Neutrophils) | |
| Activated Eosinophils | (Eosinophils) | |
| Mast Cells | ||
Based on recent research, the pathogenesis and process of IPF can be summarized as follows: ①An unknown antigen activates B cells, leading to the production of Ig and the formation of immune complexes, which in turn stimulate and activate alveolar macrophages. This immune response occurs locally in the lungs. If B lymphocytes in the alveolar wall also produce antibodies, certain components of the alveolar wall may be mistakenly recognized as foreign substances. Therefore, some consider IPF to be an autoimmune disease. However, the changes and roles of T cells in IPF patients remain unclear, and the involvement of B cells alone is insufficient to confirm it as an autoimmune disease. ②Activated alveolar macrophages release various mediators. In addition to proteolytic enzymes, collagenases, reactive oxygen metabolites, and certain cytokines that directly injure lung cells, extracellular matrix, basement membrane, and other structures, there are also mediators closely related to fibrosis formation, including fibronectin (FN), alveolar macrophage-derived growth factor (AMDGF), platelet-derived growth factor (PDGF), and insulin-like growth factor (IGF). These mediators attract fibroblasts, stimulate their proliferation, and mediate collagen matrix contraction. ③Under the mediation of IL-8, TNF, and other factors released by alveolar macrophages, neutrophils migrate toward the alveoli, aggregate, and become activated, forming alveolitis characterized by an increased neutrophil ratio (20%). The neutrophil inflammatory response further releases a series of mediators, causing or exacerbating lung injury and fibrosis. ④Fibroblast proliferation and collagen production are critical steps and outcomes of this disease. In healthy individuals, fibroblast growth is precisely regulated by negative regulators such as prostaglandin E2
bubble_chart Pathological Changes
In the early or acute phase of IPF, the primary pathological changes are alveolitis. Infiltration of lymphocytes, plasma cells, monocytes, histiocytes, and a few neutrophils and eosinophils can be observed in the alveolar walls and interstitium. The alveolar spaces may remain unaffected but can also exhibit cellular and fibrin exudation, including shed type II alveolar cells and macrophages. There may be reticulin hyperplasia in the alveolar septa, but fibrosis is minimal at this stage. As the disease progresses, the exudation and infiltration of inflammatory cells gradually decrease, while fibroblasts and collagen fibers proliferate, leading to thickening of the alveolar walls. Type I alveolar cells diminish, while type II alveolar cells proliferate, resulting in deformation and destruction of the alveolar structure, which may also affect alveolar ducts and bronchioles. In the late stage (third stage), diffuse pulmonary fibrosis is evident, with the air spaces (alveoli, alveolar ducts, bronchioles) becoming deformed and dilated into cystic structures ranging from 1 cm to several centimeters in size, known as "honeycomb lung." The alveolar-capillary membrane may exhibit asymmetric or eccentric thickening, and the pulmonary capillary bed is reduced. However, IPF does not pathologically present with vasculitis or granulomatous lesions; if these are observed, connective tissue disease or other interstitial lung diseases should be considered.
Approximately 15% of IPF cases follow an acute course, often discovered due to upper respiratory infections, with progressive worsening of dyspnea, and most patients die from respiratory and circulatory failure within 6 months. The vast majority of IPF cases are chronic (and there may also be subacute forms intermediate between acute and chronic). Although termed chronic, the average survival time is only 3.2 years. The chronic form does not appear to evolve from the acute form, and the exact relationship remains unclear.
The main symptoms include: ① Dyspnea - Exertional dyspnea that progressively worsens, with shallow and rapid breathing, possible nasal flaring and use of accessory muscles, but orthopnea is rare. ② Cough and sputum - Initially, there may be no cough, but later a dry cough or small amounts of sticky sputum may occur. Secondary infections are common, leading to mucopurulent or purulent sputum, and occasionally bloody sputum. ③ Systemic symptoms - May include weight loss, lack of strength, loss of appetite, and joint pain, though these are generally uncommon. Acute cases may present with fever.
Common signs: ① Dyspnea and cyanosis. ② Reduced chest expansion and diaphragmatic mobility. ③ Velcro crackles in the middle and lower lung fields, which are somewhat characteristic. ④ Clubbing of fingers and toes. ⑤ Signs of end-stage respiratory failure and right heart failure.
(I) Diagnostic Techniques
1. Imaging Examination
(1) Conventional Chest X-ray The technique should ensure appropriate penetration conditions, use of grade II intensifying screens, and small focal spots. Early-stage alveolitis may not show abnormalities on X-ray; as the disease progresses, the X-ray may reveal hazy, faintly visible diffuse shadows with tiny speckles, resembling ground glass. Further progression shows increasingly evident fibrosis, ranging from fine reticular patterns to coarse reticular or reticulonodular patterns. In the advanced stage, varying sizes of cystic changes, known as honeycomb lung, may appear. Lung volume decreases, the diaphragm elevates, and interlobar fissures shift.
(2) CT CT offers superior contrast resolution compared to X-rays. High-resolution CT (HRCT) further enhances spatial resolution, aiding significantly in the diagnosis of IPF, particularly in distinguishing early-stage alveolitis from fibrosis and detecting honeycomb lung.
(3) Radionuclide Imaging IPF often involves increased permeability of the alveolar capillary membrane. Radionuclide techniques, such as inhalation of 99mTc-DTPA aerosol to measure lung epithelial permeability (LEP), may show shortened T1/2, aiding in early detection and diagnosis of interstitial lung disease, though this is not specific to IPF.
2. Pulmonary Function Tests The typical pulmonary function changes in IPF include restrictive ventilatory impairment, reduced lung volume, decreased lung compliance, and diminished diffusion capacity. Severe cases may exhibit decreased PaO2 and widened PA-aO2. Pulmonary function tests, along with imaging techniques, aid in early diagnosis, particularly since exercise testing may reveal reduced diffusion capacity and hypoxemia before imaging abnormalities appear. Pulmonary function tests also allow dynamic monitoring, which is valuable for assessing disease progression and potentially evaluating treatment efficacy. However, pulmonary function abnormalities in IPF are nonspecific and lack differential diagnostic value.
3. Bronchoalveolar Lavage An increased total cell count in the lavage fluid, particularly a rise in neutrophil proportion, is a relatively typical finding in IPF and aids in diagnosis. Currently, this method is primarily used for research purposes.
4. Lung Biopsy The histological changes in early and intermediate-stage [second-stage] IPF have certain characteristics. Given that interstitial lung diseases have numerous causes, including many with identifiable etiologies, lung biopsy is highly significant for confirming the diagnosis and assessing disease activity. Transbronchial lung biopsy (TBLB) via fiberoptic bronchoscopy is the preferred method, though the small sample size may sometimes complicate diagnosis. Open lung biopsy may be necessary when required.
(II) Establishing the Diagnosis Based on typical clinical manifestations and the aforementioned examinations, a diagnosis of IPF can be established. The key challenge is excluding other interstitial lung diseases, whether their causes are known or unknown. The terms "idiopathic" or "cryptogenic" are used to denote unknown causes, but not all diseases with unknown causes and pulmonary fibrosis are IPF (e.g., sarcoidosis). IPF is a distinct disease entity, though it may not be entirely homogeneous. Therefore, lung biopsy is necessary for diagnosing IPF. However, in patients who cannot tolerate invasive procedures, a clinical diagnosis of IPF is acceptable if there is evidence to exclude other interstitial lung diseases.
(III) Assessing Disease Activity Although many studies have been conducted, no definitive indicators currently exist. Besides histological evaluation via lung biopsy, 67Ga scanning, lung epithelial permeability measurement, bronchoalveolar lavage fluid cell counts (particularly lymphocytes), and mediator measurements are considered valuable for assessing disease activity. While clinical manifestations, X-ray and CT findings, and pulmonary function changes do not always parallel disease activity, factors such as disease duration, degree of fibrosis, presence of honeycomb lung, and severity of pulmonary function impairment remain helpful in estimating activity.
bubble_chart Treatment Measures
The use of corticosteroids in IPF treatment remains controversial. However, due to the lack of definitive or specific therapies, corticosteroids are still recommended by many authors for active IPF, or even in cases where activity cannot be confirmed but there are no contraindications to corticosteroids. Prednisone at 1.0–1.5 mg/(kg·d) is administered for 2–3 weeks. If tolerated, this dose is maintained for 3 months, then gradually reduced to 0.25 mg/(kg·d) and continued for 6 months, followed by a slow tapering to a maintenance dose. If the response to corticosteroids is poor or contraindications arise, cyclophosphamide may be added or substituted. Approximately 1/5 to 1/4 of patients show objective improvement with corticosteroid therapy, while half experience symptomatic relief. Prednisone may also be combined with azathioprine for patients with an inadequate response to corticosteroids alone. IPF may be one of the best indications for lung transplantation, though this is still under further investigation.
