Chinese Medical Association, Respiratory Disease Branch
Concept
Idiopathic pulmonary fibrosis (IPF) is a chronic inflammatory interstitial lung disease of unknown origin characterized by generalized interstitial pneumonia (UIP) with diffuse alveolitis, structural disorders of alveolar units and pulmonary fibrosis. UIP differs from other types of idiopathic interstitial pneumonia (IIP), such as idiopathic desquamative interstitial pneumonia/respiratory bronchitis with interstitial lung disease (DIP/RBILD), idiopathic nonspecific interstitial pneumonia (NSIP) and acute interstitial pneumonia (AIP). Wang Haifeng, Department of Pulmonary Diseases, The First Affiliated Hospital of Henan College of Traditional Chinese Medicine
Diagnostic points
I. Clinical manifestations
1. the age of onset is mostly above middle age, male:female ≈ 2:1, rare in children.
2. The onset of the disease is insidious, mainly manifested by dry cough and progressive dyspnea, which is obvious after activity.
The disease rarely involves extra-pulmonary organs, but systemic symptoms such as fatigue, arthralgia and weight loss may occur.
4. pestle-like fingers (toes) appear in about 50% of patients, and velcro sounds can be heard in the lower part of both lungs in most patients.
5. Cyanosis may occur in the late stage, and occasionally pulmonary hypertension, pulmonary heart disease and right heart insufficiency may occur.
X-ray chest film (high kV film)
1. It often shows reticular or reticular nodular shadow with reduced lung volume. As the disease progresses, multiple cystic transillumination shadows (honeycomb lung) with a diameter of 3-15 mm may appear. 2.
The distribution of the lesions is diffuse and relatively symmetric, but unilateral distribution is rare. The lesions are usually located in the basal, peripheral or subpleural areas.
3. In a few patients with symptoms, there may be no abnormal changes on X-ray chest film.
High-resolution CT (HRCT)
1. HRCT scan can help to evaluate the abnormal changes in the peripheral part of the lung, diaphragm, mediastinum and around the bronchio-vascular bundle, which is important for the diagnosis of IPF. 2.
2. sublobular microstructural changes, such as linear, reticular, and glassy shadows, can be seen. 3.
The lesions are usually seen in the peripheral part of the lower and middle lung fields and often appear as reticular and foveal lung, as well as crescentic shadows, subpleural linear shadows and very few ground glass shadows. In most patients, a combination of these images is present, and in areas of severe fibrosis there is often traction bronchial and fine bronchial dilatation and/or subpleural cellulite-like changes.
Pulmonary function tests
The typical pulmonary function change is restrictive ventilation dysfunction, which is manifested by a decrease in total lung volume (TLC), functional residual volume (FRC) and residual volume (RV). One-second expiratory volume/exertional lung volume (FEV1/FVC) is normal or increased.
Single-breath diffusion of carbon monoxide (DLCO) is reduced, i.e., DLCO may be reduced in the presence of normal ventilation and lung volumes.
3. ventilation/blood flow disorders, decreased PaO2 and PaCO2, and increased alveolar-arterial partial pressure of oxygen [P(A – a) O2].
V. Bronchoalveolar lavage fluid (BAL F) test
The significance of BAL F testing is to narrow the diagnosis of diffuse interstitial lung disease (ILD), i.e., to exclude other lung diseases (e.g., tumors, infections, eosinophilic pneumonia, exogenous allergic alveolitis, nodular disease, and alveolar protein deposition). However, it is of limited value for the diagnosis of IPF. 2.
The number of neutrophils (PMN) in BAL F is increased in IPF patients, accounting for more than 5% of the total number of cells, and some patients in advanced stages also have increased eosinophils.
Blood tests
1. The blood test results of IPF lack specificity. 2.
2. increased erythrocyte sedimentation rate, increased levels of gammaglobulin and lactate dehydrogenase (LDH) may be seen.
Some antibodies may be positive or increase in titer, such as antinuclear antibody (ANA) and rheumatoid factor (RF), which may be weakly positive.
VII. Histopathological changes
1. histopathology of open/thoracoscopic lung biopsy shows UIP changes. 2.
The lesions are unevenly distributed, with the lower lungs being the most affected, and fibrosis around the subpleural and peripheral lobular septa is common.
The lesions are unevenly distributed, with inflammatory cell infiltration and alveolar septal thickening often mixed with early lesions or normal lung tissue in the extensive fibrosis and cellular lung tissue.
The lung fibrosis zone is mainly composed of dense collagenous tissue and proliferating fibroblasts. Focal proliferation of fibroblasts constitutes the so-called “fibroblast foci”. The cellular lung portion consists of cystic fibrous air spaces, often lined with fine bronchial epithelium. In addition, smooth muscle cell hyperplasia is seen in the fibrotic and cellular lung areas.
5. exclude other known causes of ILD and other types of IIP.
Diagnostic criteria
The criteria for the diagnosis of IPF can be divided into those with surgical (open/thoracoscopic) lung biopsy data and those without.
I. With surgical lung biopsy data
1. lung histopathology showing UIP features. 2.
2. pulmonary fibrosis due to other known causes of interstitial lung disease, such as drugs, environmental factors and rheumatic diseases.
3. abnormal lung function, as evidenced by restrictive ventilatory dysfunction and/or impaired gas exchange.
4. Typical abnormal images can be seen on chest radiographs and HRCT.
No surgical lung biopsy data (clinical diagnosis)
In principle, the lack of lung biopsy data cannot confirm the diagnosis of IPF, but the clinical diagnosis of IPF can be made if the patient has normal immune function and all of the following primary diagnostic conditions and at least 3/4 of the secondary diagnostic conditions are met.
1. primary diagnostic criteria: ① Excluding known causes of ILD, such as toxic effects of certain drugs, history of occupational exposure and rheumatic diseases; ② abnormal pulmonary function, including restrictive ventilatory dysfunction (reduced VC with normal or increased FEV1/FVC) and/or impaired gas exchange [P(A – a) at rest/exercise Modern Practical Medicine, Vol. 15, No. 2, February 2003. 129 ・© 1995-2004 Tsinghua Tongfang Optical Disc Co., Ltd. All rights reserved. The diagnosis of other diseases is not supported by BAL F examination.
Secondary diagnostic criteria: ① age > 50 years; ② insidious onset or progressive dyspnea without clear cause; ③ duration of disease ≥ 3 months; ④ inspiratory velcro sounds can be heard on auscultation of both lungs.
Differential diagnosis
IPF accounts for more than 60% of all IIPs, followed by NSIP, while DIP/RBILD and AlP are relatively uncommon. The distinction from other types of IIP is crucial.
It is important to distinguish them from other types of IIP because their treatment and prognosis are very different.
I. DIP/RBILD
1. DIP: It is more common in males and most of them are smokers. The onset is insidious, with a dry cough and progressive dyspnea. Half of the patients have pestle-like fingers (toes). There is no specific laboratory examination, and pulmonary function is restrictive with reduced diffusion function, but not as significant as IPF/UIP. On imaging, there are glassy changes in both lungs in the early stage and linear, reticular and nodular interstitial images in the later stage. Unlike UIP, DIP usually does not show foveal changes. RBILD: Clinical presentation is the same as DIP. pestle-like fingers (toes) are relatively rare. On imaging, 2/3 of the patients showed reticular nodular shadow on HRCT, but no ground glass shadow was seen. 2.
The significant pathological changes of DIP are uniform distribution of alveolar macrophages (AM) in the alveolar cavity and scattered multinucleated giant cells. This is accompanied by mild to moderate alveolar septal thickening with a small amount of inflammatory cell infiltration, without significant fibrosis or fibroblast foci. At low magnification, the lesions were uniformly distributed with a consistent temporal pattern, in contrast to the diverse distribution of UIP. When the AM accumulation is predominantly in the peribronchial airspace and the distal airspace is not involved, this pathology is referred to as RBILD.
Most glucocorticoids respond well to treatment.
AIP
1. AIP has an unknown cause, with a rapid onset and clinical manifestations of cough, severe dyspnea, followed by respiratory failure soon after. Most cases have “cold”-like symptoms before the onset of the disease, and more than half of the patients have fever. Pulmonary imaging shows diffuse bilateral reticular, fine nodular and ground glass shadows. They may fuse into patches or even solid shadows with rapid progression.
The pathology of AIP is diffuse alveolar damage (DAD) with organic phase changes.
The prognosis of AIP is poor, with a high mortality rate and a short survival period, most of which die within 1-2 months.
NSIP
The main clinical manifestations are cough, shortness of breath, and fever in a few patients. 2.
The main clinical manifestations are cough, shortness of breath, and fever in a few patients. 2.
The pathological changes are marked thickening of the alveolar wall with varying degrees of inflammation and fibrosis, and the lesions are consistent in time, but lack the specific changes of UIP, DIP or AIP. The alveolar structure is lightly damaged, and chronic inflammatory cell infiltration consisting of a mixture of lymphocytes and plasma cells in the alveolar septum is characteristic of NSIP.
The disease responds well to glucocorticoids and has a good prognosis.
Pharmacological treatment of IPF
I. Recommended drugs and doses
To date, there is no satisfactory treatment for pulmonary fibrosis. The more commonly used drugs include glucocorticoids, immunosuppressive/cytotoxic drugs and antifibrotic agents. These drugs can be used alone or in combination, and the dose and duration of treatment should be tailored to the patient. The recommended treatment regimen is glucocorticoids combined with cyclophosphamide or azathioprine, as follows (for reference).
1. glucocorticoids: prednisone or other equivalent doses of glucocorticoids at 0.5 mg/kg/day (ideal body weight, hereinafter) orally for 4 weeks, followed by 0.25 mg/kg/day orally for 8 weeks, and then reduced to 0.125 mg/kg/day or 0.25 mg/kg orally every other day.
Cyclophosphamide: administered at 2mg/kg per day. The initial dose can be 25-50mg/day orally, increasing by 25mg every 7-14 days, until the maximum amount of 150mg/day.
3. Azathioprine: administered at 2-3mg/kg/day. The initial dose is 25~50mg/d, then increase 25mg orally every 7~14 days until the maximum amount of 150mg/d.
Second, the course of treatment and efficacy determination
1. Course of treatment: ①General treatment after 3 months to observe the efficacy, if the patient tolerates well, no complications and side effects continue treatment for at least 6 months.
If the patient has been treated for more than 6 months, if the condition deteriorates, the treatment should be stopped or changed or combined with other drugs; if the condition is stable or improving, the original treatment should be maintained. Generally, the combination of drugs is recommended. If the condition of the patient has been treated for more than 12 months, the treatment should be stopped or changed or combined with other drugs if the condition deteriorates; if the condition is stable or improving, the original treatment should be maintained. (4) For patients who have been treated for more than 18 months, the continuation of treatment should be individualized.
2. Judgment of efficacy: (1) Good response or improvement: ①Reduced symptoms and increased mobility. (2) Reduction of abnormal images on X-ray chest film or HRCT. (3) Lung function performance TLC, VC, DLCO and PaO2 remain stable for a longer period of time. The following data are for reference: TLC or VC increase ≥ 10%, or at least ≥ 200ml; DLCO increase ≥ 15% or at least 3ml ・min-1・mmHg-1; SaO2 increase > 4%; PaO2 increase ≥ 4mmHg in cardiopulmonary exercise test (with 2 or more items are considered as improvement of pulmonary physiological function). (2) Poor response or failure of treatment; ①Worsening of symptoms, especially dyspnea and cough. (2) Increased abnormal images on X-ray chest or HRCT, especially signs of cellular lung or pulmonary hypertension. (iii) deterioration of pulmonary function. The following data are for reference: decrease in TLC or VC by ≥10 % or by ≥200 ml; decrease in DLCO by ≥15 % or by at least ≥3 ml/min-1 ・mmHg-1; decrease in SaO2 by ≥4 %, or exercise test
P(A – a) O2 increase ≥4mmHg in exercise test (2 or more of these are considered as deterioration of pulmonary function).
Third, the efficacy is not yet certain, is in the research and observation stage of the drug
NAC recommends a high dose (1.8g/d) orally.
2. Gamma interferon, tolypyridone, prostaglandin E2 and transforming growth factor are cytokine antagonists that have inhibitory effects on collagen synthesis. 3.
Erythromycin has anti-inflammatory and immunomodulatory functions, and its therapeutic effect on pulmonary fibrosis is achieved by inhibiting PMN function. It is recommended to be given orally in small doses (0.25g/ d) for a long time.
Colchicine can inhibit collagen synthesis and regulate the extracellular matrix, and play an anti-fibrotic role. The oral dose of 0.6 mg/d is well tolerated. However, some studies have shown that colchicine does not improve the prognosis of pulmonary fibrosis.