What Is Bronchiolitis?

The world s first DPB concept was Honma and Yamaka of Japan ^[1] ^[2-3] . In the course of their research on emphysema in 1969, they found 7 new independent diseases with respiratory bronchioles as the main lesion, and named them diffuse panbronchiolitis. From 1980 to 1982, the Ministry of Health and Welfare of Japan organized the first national survey of DPB ^[4] ^[4] ^[5] 319 cases were confirmed, and 82 cases were confirmed as DPB by histopathology. In 1988, the second national survey of DPB organized by the Japanese Ministry of Health and Welfare Research Class [3] confirmed 229 cases. After the 1990s, cases were reported successively in Asian countries and regions such as South Korea, Taiwan, Singapore, and in Western countries such as Italy, the United Kingdom, France, and the United States. ^[6] ^[5] ^[7] ^[8-11] More than half are Asian immigrants, so DPB is currently considered to be a disease that occurs mainly in East Asian races. In 1990, Fraser described DPB in the book "Diagnosis and diseases of the chest, 3rded ^[12] ," and DPB became a new disease recognized worldwide. In the 1996 Chinese Journal of Tuberculosis and Respiratory Diseases in mainland China, Liu Youning ^[13] and Wang Houdong ^[14] reported 1 case of pathologically confirmed DPB (TBLB and open chest lung biopsy) respectively; by the end of 2002, 78 cases had been reported in the mainland literature No more than 100 cases have been reported so far ^[15] , and more than 70 cases have been treated in our department in the past 6 years.

Li Huiping

(Chief physician)

Department of Respiratory Medicine, Shanghai Pulmonary Hospital

Diffuse bronchiolitis (DPB) is a chronic inflammatory disease of the airways that diffuses into the respiratory bronchioles of both lungs. The affected area is mainly the terminal airway beyond the respiratory bronchioles. Because inflammatory lesions are diffusely distributed and involve the entire layer of respiratory bronchioles, they are called diffuse panbronchiolitis. Outstanding clinical manifestations are cough, expectoration and shortness of breath after activity. Severe cases can cause respiratory dysfunction. Clinically, it is easy to be confused with other chronic airway diseases.

Western Medicine Name: Bronchiolitis
English name: diffuse panbronchiolitis, DPB
Affiliated Department: Internal Medicine-Respiratory Medicine

The main symptoms: Cough, shortness of breath after activity
Main cause: Interstitial lung disease
Contagious: Non-contagious

Bronchiolitis epidemiology

Some scholars believe that DPB may be a global disease, but it does have different species and regions. East Asia, represented by Japan, South Korea, and China, is more common. Survey data on global morbidity are currently lacking. According to Japanese epidemiological survey data ^[7] , the characteristics of DPB are summarized as follows: The disease is spread throughout Japan, and there is no regional distribution difference; Gender of disease: male to female ratio is 1.4: 1, males are slightly higher. There is no significant difference between genders; The age of onset is distributed in all age groups from 10 to 80 years old, with the peak incidence of 40 to 50 years old, and the estimated prevalence rate is 11.1 / 100,000; no incidence of irritant gas and smoking Close relationship; 84.8% of patients with chronic parasinusitis or a previous history, and 20.0% of patients have a family history of chronic parasinusitis. However, the onset time is not related to the long-term onset of chronic parasinusitis and the operation time; The initial diagnosis of the onset is often other respiratory diseases, such as chronic bronchitis, bronchiectasis, bronchial asthma, emphysema, etc., and the diagnosis is 90%. DPB accounts for only 10.0%.

China lacks a large sample of transfer data. The author conducted a preliminary analysis of 78 cases reported as of the end of 2002. The results are as follows: more men than women; north than south; all Han; more than 90% have parasinusitis; It has nothing to do with smoking; the tendency of familial seizures is not obvious; the majority of condensing set tests are positive; HLA-B54: 11 cases have been tested and 5 cases are positive; lower respiratory tract infections: Pseudomonas aeruginosa accounts for the vast majority, and a few are pneumonia g Changes in pulmonary function: the vast majority are moderate obstructive ventilation disorder, the diffuse function is mostly normal, and it is extremely rare; the misdiagnosis rate at first diagnosis is about 75%, but the trend gradually decreases with time, This shows that the understanding of this disease has improved; the majority of macrolide antibiotics have a good prognosis.

Kang Jian et al. ^[15] retrospectively analyzed 40 cases of DPB reported in mainland China that met the Japanese diagnostic criteria in 2005, and believed that the disease was more men than women (31/40); it was distributed throughout the country; most had paranasal sinuses Yan (37/40); 12 cases of HLA-BW54 test, 5 positive (41.6%); 75% of patients were misdiagnosed before diagnosis of DPB; clinical, imaging and pathological characteristics of DPB patients in mainland China are similar to those of Japanese cases .

The data of 70 patients in our hospital at the end of 2006 has the following characteristics: 1. The ratio of male to female is 1.6: 1. Aged 21 to 80 years, with an average age of 53 ± 14 years. 2. Cough in all cases; sputum in 95.8% of cases; 91.6% of shortness of breath; 87.5% with emphysema. 3. 91.6% had paranasal sinusitis and 25% had secondary bronchiectasis. 4. Pseudomonas aeruginosa was the most common infection (41.6%), followed by Haemophilus parainfluenza (16.6%), and Klebsiella pneumoniae (12.5%). 5. 75% of patients were initially misdiagnosed as chronic bronchitis, and 79.2% of cases were misdiagnosed as bronchiectasis. 6. Not closely related to HLA-B54. HLA-B54 test was performed in 11 cases, and only 3 cases were positive (27.3%). Familial clustering was observed in 7 and 5 (7.1%) patients. 8. The time from onset to diagnosis is 1 year, 6 months to 40 years, with a median of 7 years. 9. The accuracy rate of the first diagnosis increased from 0% in 2001 to 75% in 2006, and the total correct diagnosis rate reached 62.5%; 10. The recent effective rate of comprehensive treatment based on macrolide antibiotics reached 96% .

Causes of bronchiolitis

The etiology of this disease is unclear so far, but recent advances in molecular genetic research have suggested that this disease is not a single-gene disease, but a disease involving multiple factors ^[4] ^[7] ^[16] . The relevant factors are as follows:

1. Associated with genetic factors ^[4] : the disease has a family tendency; HLA-B54 (human leukocyte antigen B54) in Japanese patients is more positive (63.2%), and the B * 5401 gene encoding HLA-B54 in DPB patients has Highly relevant, the major histocompatibility antigen is HLA-B54-Cwl-A11 / 24. HLA-B54 is a unique antigen of the Mongolian race, except for the Indians and most Jews, including the Chinese. About 14.1% are positive in Japanese and about 10.4% in Chinese. White people are extremely rare, and it is speculated that the disease may have some ethnic specificity. However, there have been reports of white people's disease. Therefore, the conclusion that this disease is related to race and region has yet to be confirmed after summing up a large number of cases. In South Korea, HLA-B55-Cwl-A11 and B62-A11 occur frequently in DPB patients, suggesting that HLA-A11 is highly correlated with disease. Therefore, Keicho et al. Put forward the hypothesis that the "DPB disease susceptibility gene" is located between HLA-B54 and HLA-A11 on chromosome 6; due to DPB and cystic fibrosis in sinusitis and bronchial lung infection, the airways A large number of high-viscosity secretions and other clinical manifestations, pathogen infections such as Pseudomonas aeruginosa have many similarities, so the role of CFTR gene mutation in the pathogenesis of DPB cannot be ruled out; another genetic disease, the so-called naked type I Lymphocyte syndrome (bare lymphocyte syndrome type I), its clinical characteristics are similar to DPB and related to incomplete processing of HLA class I antigens. Treatment with macrolide antibiotics is very effective, and it is not yet related to DPB. Clear; The increase in the condensing titer is also thought to be related to immune abnormalities.

2. Infection: DPB has more than 80% of patients with chronic sinusitis; DPB patients have varying degrees of bronchial mucosal lesions or increased airway secretions, showing chronic airway inflammation changes. Therefore, some people think that it is related to infection. The condensate set test is mostly positive and the erythromycin has a good effect, and it is speculated that it is also related to Mycoplasma pneumoniae infection.

3. Inhalation of irritating and harmful gases and air pollution: strong acid smoke, chlorine, solvent gases, chemicals and various dusts are likely to cause the disease. For example, the incidence of DPB in sulfur dioxide-contaminated areas is higher than in general areas.

Clinical manifestations of bronchiolitis and related auxiliary examinations

1. Clinical manifestations: More than 80% of patients have / or have suffered from chronic parasinusitis. Some patients have no symptoms, but imaging examination shows that they have parasinusitis. Chronic cough and a large amount of purulent sputum are common symptoms, followed by dyspnea following activity gradually. Auscultation of the lungs can often hear small wet rales or wheezing, or both. Due to repeated infections in the later period, hypoxemia gradually worsens, and may be combined with hypercapnia, pulmonary hypertension, and pulmonary heart disease. Most causes of death are chronic respiratory failure. Prior to erythromycin treatment, the 10-year survival rate after P. aeruginosa infection was only 12%, while the 10-year survival rate for those without P. aeruginosa infection was 73% ^[16] .

2. Sputum examination: Haemophilus influenzae and Pseudomonas aeruginosa are common pathogens of respiratory infections.

3. Laboratory tests: Although most patients do not find direct evidence of mycoplasma infection, the titer of serum condensation test (CHA) is often increased. Other laboratory tests mainly suggest chronic non-specific inflammation.

4. Pulmonary function and arterial blood gas examination: Pulmonary function shows obvious airflow limitation, but it is not effective for bronchodilators. Forced expiratory volume in one second Occupied vital capacity (FEV1 / FVC%) tends to decrease (<70%), reduced vital capacity (<80% of expected value), functional residual capacity usually increases (RV> 150% of expected value), and low Oxygenemia (PaO2 <80mmHg).

5. Imaging examination: The chest X-ray shows diffusely granular nodular shadows of the two lungs, the lower lungs are obvious, and there is excessive inflation. Bronchial dilatation such as curly shadow and orbital sign appeared in the later stage. Chest HRCT is very helpful for diagnosis. It can be seen that the lobular central granular nodules are diffusely distributed in the two lungs. In severe cases, cystic bronchiectasis, mainly in the lower lungs, can occur.

Bronchiolitis diagnostic criteria

1. Clinical diagnostic criteria: At present, China does not have its own diagnostic criteria, mainly referring to the second revised clinical diagnostic criteria of the Japanese Ministry of Health and Welfare in 1998 ^[17-18] . The diagnostic items include required items and reference items. Required items: persistent cough, sputum, and difficulty breathing during activities; combined with chronic parasinusitis or past history; chest X-ray see diffusely scattered granular nodular shadows of the lungs or chest CT see two Diffuse lobular central granular nodular shadows. Reference items: Continuous wet rales on chest diagnosis; FEV1 / FVC below 70% and PaO2 <80mmHg; Serum condensation test (CHA) titer 1:64. Confirmed diagnosis: meet the required items 1, 2, 3, plus 2 or more of the reference items. General diagnosis: meet the required items 1, 2, 3. Suspicious diagnosis: meet the required items 1 and 2.

2. Pathological diagnosis: It is helpful for the definite diagnosis of this disease ^[19] . Gross specimen: There are many small gray-white nodules diffusely distributed on the surface of the lung, and there is a fine sand-like, granular-like unevenness on the surface; a broad-bronchiolar-centric nodule is seen on the section, and bronchiectasis is sometimes seen. Histopathological characteristics under the microscope: DPB is located in the bronchioles and respiratory bronchioles, while other lung tissue areas can be completely normal; The main feature is bronchiolitis, and the alveolar wall is mostly unaffected; The characteristic change is fine Bronchial and respiratory bronchiolitis narrows and obstructs the bronchioles; foam-like cells are seen in the alveolar septum and stroma. The bronchioles and respiratory bronchiolitis are manifested by the thickening of the walls of the tubes and infiltration of lymphocytes, plasma cells, and tissue cells. It should be noted that typical cases can be diagnosed by X-ray and HRCT; those with atypical clinical and imaging changes need to take a lung biopsy. Pulmonary biopsy is best done with open thoracoscopy or thoracoscopy.

Differential diagnosis of bronchiolitis

The differential diagnosis of DPB can be analyzed from three levels: first, starting from diseases with similar clinical manifestations, it needs to be associated with COPD, bronchiectasis, bronchial asthma, cystic fibrosis, idiopathic ciliary motion syndrome, and occlusive Identification of airway inflammatory diseases such as bronchitis. Second, it can be identified from diseases with similar X-ray and CT manifestations, including COPD, bronchiectasis, cystic fibrosis, idiopathic ciliary immobility syndrome, occlusive bronchitis, miliary tuberculosis, sarcoidosis, Pulmonary lymphatic carcinoma, alveolar cell carcinoma, interstitial lung disease, occupational pneumoconiosis, etc. Third, identify diseases that are similar to pathological changes. In addition to DPB, the inflammatory lesions mainly distributed along the bronchioles include bronchiectasis, cystic fibrosis, chronic bronchitis, respiratory bronchiolitis with interstitial lung disease (RBILD), chronic exogenous allergic alveolitis, Cryptogenic organizing pneumonia (COP) and airway centered interstitial fibrosis (ACIF). Their pathological changes are centered on bronchioles, and they are all inflammatory changes. There are no characteristic cells for identification. The identification with the above-mentioned chronic airway inflammatory diseases is mainly based on comprehensive analysis based on clinical, imaging, and even genetic tests to identify them; and RBILD can see a large number of macrophages in the bronchioles and surrounding alveolar cavity; Chronic allergic alveolitis should have a large number of infiltration of lymphocytes, infiltration of eosinophils, and granulomas containing multinucleated giant cells. COP is characterized by hyperplasia of polypoid granulation tissue in the distal airways and alveolar cavities that are patchy distributed around the small airways; ACIF pathological manifestations are interstitial pulmonary fibrosis centered on respiratory bronchioles, The fibrosis of the small airway wall is prominent, while the infiltration of inflammatory cells is not obvious; clinically, shortness of breath is the main manifestation after the activity, and there are no more signs of airway infection such as purulent sputum. When the above pathological features are not very significant, it should be referred to relevant clinical data, especially imaging findings to help identify. For example, when chronic exogenous allergic alveolitis does not have obvious infiltration of eosinophils, it is very difficult to distinguish it from DPB pathologically, but at this time referring to changes in HRCT, the two are completely different: The patchy shadows or reticulum nodules distributed in the upper lung field are mainly distributed unevenly and may be fused: while DPB is diffusely distributed in the two lungs, the size is very uniform, and small nodules are centered on the leaflets. No fusion. The pathological manifestations of DPB have certain characteristics, and combined with HRCT can make a more accurate diagnosis.

Bronchitis disease treatment

1. History of erythromycin treatment ^[1] ^[6] ^[4] ^[16]

Prior to 1980, the treatment of DPB was mainly corticosteroids, antibiotics, phlegm and bronchodilators, but none of them could improve the prognosis. In 1982, Dr. Kudoh at the Tokyo Metropolitan Hospital was surprised to find that the clinical symptoms and chest X-ray lesions of a DPB patient improved significantly after he stopped treatment. After carefully reviewing the patient's treatment records, he found that he used 600 mg of erythromycin every day for a total of 2 years. very effective. In order to confirm the efficacy of erythromycin, Dr. Kudo immediately organized an open clinical trial of low-dose erythromycin for long-term application of DPB ^[20] . After 3 and a half years of erythromycin treatment, 18 patients had clinical symptoms and pulmonary function. Both radiographic and radiographic changes were significantly improved. Except for some cases of bronchiectasis, almost all cases have improved their clinical manifestations to varying degrees after 4 to 3 months of treatment. Later, the efficacy of erythromycin was proved by the research of many Japanese scholars. ^[4] . The results of the first prospective, double-blind, controlled clinical trial reported in the 1990 Japanese Annual Report of Diffuse Lung Disease also showed that Efficacy ^[21] .

2. Erythromycin treatment plan:

According to the DPB treatment guidelines published by the Japanese Ministry of Health and Welfare in 2000 ^[22] , the following points are emphasized:

1) Once the diagnosis of DPB is established, treatment should be started immediately because early treatment is better.

2) Drug selection: Regardless of the type of bacteria in sputum, erythromycin (ETM) should be preferred. Erythromycin is taken orally at 400 or 600 mg per day, unless discontinued unless it is ineffective or due to side effects. The other fourteen-membered ring macrolides were selected as follows: 200 or 400 mg of clarithromycin orally or 150 or 300 mg of roxithromycin orally, which had the same effect as ETM. The 15-membered ring macrolide antibiotic azithromycin (ATM) is equivalent to erythromycin, but the number of daily administration is also reduced (1 to 2 times a day), and the adverse reaction rate is significantly lower than that of ETM. 16-membered macrolide antibiotics seem to be ineffective.

3) Evaluation and duration of treatment response: Although obvious effects can be seen in 2 to 3 months, the treatment should last at least 6 months, and then evaluate the effect. If it is effective, continuous treatment should be completed for at least 2 years; if relapse after discontinuation of the drug is still effective, treatment should be restarted; if the disease progresses to extensive bronchiectasis or respiratory failure, it should last more than 2 years.

3. The treatment mechanism of erythromycin ^[4] : It is not clear at present, it may be related to its anti-inflammatory effect and potential immune regulation effect, but not related to anti-infection effect. The evidence is as follows: DPB symptoms improve without the bacteria clearing, even during Pseudomonas aeruginosa infections; the concentration of erythromycin in sputum and serum is much lower than the MIC of the main pathogenic bacteria However, this drug concentration can inhibit the formation of biofilms of P. aeruginosa. Therefore, it is believed that the therapeutic effect of erythromycin mainly comes from its anti-inflammatory effect, on the one hand, it improves the host's defense mechanism; on the other hand, it inhibits the activity and virulence of bacteria.

Erythromycin can improve the host's defense mechanism in the following ways:

1) Block the chloride ion channel of the airway epithelium, reduce the secretion of water and mucus, and reduce the sputum volume of patients with DPB.

2) Inhibition of neutrophil aggregation and activity in inflammatory sites: Erythromycin can inhibit airway epithelial cells from secreting IL-8, IL-6 and macrophage colony-stimulating factors, and inhibit nuclear factor -B and active protein- 1 secretion, thereby inhibiting neutrophils from releasing LT-B4, peroxide and elastase

3) Inhibit the proliferation and activation of peripheral blood lymphocytes, and promote the proliferation and differentiation of monocyte-macrophage system, thereby inhibiting excessive inflammation in the lower respiratory tract

In terms of inhibiting the activity and virulence of bacteria:

DPB is often associated with Haemophilus influenzae infection in the early stage and mostly Pseudomonas aeruginosa infection in the later stage. Erythromycin can inhibit the production of Pseudomonas aeruginosa and biofilms, reduce the production of bacterial metabolites (elastase and protease), and inhibit the formation of pili.

4, side effects of erythromycin: mainly including gastrointestinal discomfort, liver damage, etc .; less common are allergic dermatitis, ventricular tachycardia caused by prolonged QT interval. Azithromycin (ATM) has a significantly lower adverse reaction rate than ETM. More than 70 cases of DPB in our hospital were treated with azithromycin, and the longest medication was 3 years without obvious side effects.

5.Other treatments

1) Corticosteroids [1]: Although the effect of glucocorticosteroids is not certain, their application is widespread. Its therapeutic mechanism may mainly lie in its anti-inflammatory and immunosuppressive effects. Prednisone is usually 1 to 2 mg · kg -1 · d -1. After the symptoms are relieved, the amount is gradually reduced. It can be used in combination with macrolide drugs, gradually reducing the dosage, and the course of treatment is shorter than that of macrolide drugs.

2) Antibiotic treatment for common infectious pathogens: When the infection is severe, piperacillin, aminoglycoside antibiotics, and fluoroquinolones are given to common DPB infection bacteria such as Pseudomonas aeruginosa, Haemophilus influenzae, and Klebsiella pneumoniae. Third-generation antibiotics such as cephalosporins and carbohydranes can significantly increase the efficacy.

3) Oxygen therapy, mechanical ventilation, etc.

4) Symptomatic supportive treatment: expectorants, bronchodilators, paranasal sinusitis, immune enhancers, etc.

Prognosis and prospect of bronchiolitis

This disease is considered early as a chronic prognosis with a poor prognosis. Before the use of erythromycin in the 1970s, the 5-year survival rate of DPB was only 63%; the 5-year survival rate reached 72% during the introduction of fluoroquinolone antibiotics for Pseudomonas aeruginosa infection from 1980 to 1984; the introduction of erythromycin in 1985 The 5-year survival rate reached 91% after priming with glucosamine. The introduction of erythromycin greatly improved the prognosis of patients with DPB. If the disease can be diagnosed and treated early, DPB can be cured.

There may be a certain number of patients with DPB in patients with chronic bronchitis and bronchiectasis in mainland China. Therefore, it is particularly important to raise awareness and alertness to the disease. Finding more cases early, obtaining the epidemiological data of the DPB of the Chinese people, formulating their own diagnostic standards and treatment principles, and the impact of genetic factors on the disease are all important issues to be studied.